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Concurrent ipilimumab and CMV colitis refractory to oral steroids

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Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.3 The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.4 In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).2Recognition and management of irAEs has led to the implementation of treatment guidelines.4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.



Biopsy results subsequently revealed findings compatible with ipilimumab-induced colitis, and immunohistochemical staining demonstrated positivity for cytomegalovirus (CMV). Specifically, histologic examination showed lymphoplasmacytic expansion of the lamina propria, some architectural distortion, and increased crypt apoptosis. Scattered cryptitis and crypt abscesses were also noted, as were rare stromal and endothelial cells with characteristic CMV inclusions (Figure 2 and Figure 3).







Serum CMV polymerase chain reaction (PCR) was also positive at 652,000 IU/mL (lower limit of detection 100 IU/mL). Induction dosing of ganciclovir (5 mg/kg IV Q12h) was initiated. The combined treatment with intravenous methylprednisone and ganciclovir led to an improvement in diarrhea frequency and resolution of blood in the stool. She was transitioned to oral prednisone, but it resulted in redevelopment of grade 3 diarrhea. The patient was therefore resumed on and discharged on daily intravenous methylprednisolone.

After discharge, the patient was started on budesonide 9 mg daily. Her serum CMV PCR level reduced and she was transitioned to oral valgancyclovir (900 mg daily) for maintenance. Another unsuccessful attempt was made to switch her to oral prednisone.

About 14 weeks after the initial ipilimumab dosing, the patient underwent another flexible sigmoidoscopy that again demonstrated severe colitis from the rectum to sigmoid colon. Biopsies were negative for CMV. Patient was readmitted for recurrence of diarrhea the following week. Treatment with IV methylprednisone (1mg/kg BID) and infliximab (5 mg/kg) again led to an improvement of symptoms. She was again discharged on IV methylprednisone (1 mg/kg BID) with a taper.

In the 15th week after her initial ipilimumab dose, the patient presented with a perforated bowel, requiring a subtotal colectomy and end ileostomy. She continued on a slow taper of oral prednisone (50 mg daily and decrease by 10 mg every 5 days).

At her last documented follow-up, 8 months after her first ipilimumab dose, she was having normal output from her ileostomy. She developed secondary adrenal insufficiency because of the long-term steroids and continued to take prednisone 5 mg daily.

 

 

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.6 Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.7 Granulomas are also absent in most series, though they have been reported in some cases.8 The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.4 In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.9 In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).9

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.10 In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.11 Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.14 Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.15 In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.15

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,13 illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

References

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845-1855.

3. Glassman PM, Balthasar JP. Mechanistic considerations for the use of monoclonal antibodies for cancer therapy. Cancer Biol Med. 2014;11(1):20-33.

4. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.

5. Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013;18(6):733-743.

6. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-1682.

7. Oble DA, Mino-Kenudson M, Goldsmith J, et al. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):1130-1137.

8. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289.

9. Del Castillo M, Romero FA, Arguello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis. 2016;63(11):1490-1493.

10. Pillet S, Pozzetto B, Roblin X. Cytomegalovirus and ulcerative colitis: place of antiviral therapy. World J Gastroenterol. 2016;22(6):2030-2045.

11. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50(11):1439-1447.

12. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab. J Immunother. 2015;38(5):212-215.

13. Lankes K, Hundorfean G, Harrer T, et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology. 2016;5(6):e1128611.

14. Ko JH, Peck KR, Lee WJ, et al. Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. Clin Infect Dis. 2015;60(6):e20-26.

15. You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep. 2012;14(4):334-342.

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Andrew Perry, MD,a Jonathan Walter, MD,a Stephen Olsen, MD,b and George Ansstas, MDc

Departments of aInternal Medicine and bPathology, and cDivision of Medical Oncology, at Washington University in St Louis, Missouri

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Departments of aInternal Medicine and bPathology, and cDivision of Medical Oncology, at Washington University in St Louis, Missouri

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Andrew Perry, MD,a Jonathan Walter, MD,a Stephen Olsen, MD,b and George Ansstas, MDc

Departments of aInternal Medicine and bPathology, and cDivision of Medical Oncology, at Washington University in St Louis, Missouri

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Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.3 The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.4 In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).2Recognition and management of irAEs has led to the implementation of treatment guidelines.4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.



Biopsy results subsequently revealed findings compatible with ipilimumab-induced colitis, and immunohistochemical staining demonstrated positivity for cytomegalovirus (CMV). Specifically, histologic examination showed lymphoplasmacytic expansion of the lamina propria, some architectural distortion, and increased crypt apoptosis. Scattered cryptitis and crypt abscesses were also noted, as were rare stromal and endothelial cells with characteristic CMV inclusions (Figure 2 and Figure 3).







Serum CMV polymerase chain reaction (PCR) was also positive at 652,000 IU/mL (lower limit of detection 100 IU/mL). Induction dosing of ganciclovir (5 mg/kg IV Q12h) was initiated. The combined treatment with intravenous methylprednisone and ganciclovir led to an improvement in diarrhea frequency and resolution of blood in the stool. She was transitioned to oral prednisone, but it resulted in redevelopment of grade 3 diarrhea. The patient was therefore resumed on and discharged on daily intravenous methylprednisolone.

After discharge, the patient was started on budesonide 9 mg daily. Her serum CMV PCR level reduced and she was transitioned to oral valgancyclovir (900 mg daily) for maintenance. Another unsuccessful attempt was made to switch her to oral prednisone.

About 14 weeks after the initial ipilimumab dosing, the patient underwent another flexible sigmoidoscopy that again demonstrated severe colitis from the rectum to sigmoid colon. Biopsies were negative for CMV. Patient was readmitted for recurrence of diarrhea the following week. Treatment with IV methylprednisone (1mg/kg BID) and infliximab (5 mg/kg) again led to an improvement of symptoms. She was again discharged on IV methylprednisone (1 mg/kg BID) with a taper.

In the 15th week after her initial ipilimumab dose, the patient presented with a perforated bowel, requiring a subtotal colectomy and end ileostomy. She continued on a slow taper of oral prednisone (50 mg daily and decrease by 10 mg every 5 days).

At her last documented follow-up, 8 months after her first ipilimumab dose, she was having normal output from her ileostomy. She developed secondary adrenal insufficiency because of the long-term steroids and continued to take prednisone 5 mg daily.

 

 

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.6 Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.7 Granulomas are also absent in most series, though they have been reported in some cases.8 The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.4 In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.9 In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).9

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.10 In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.11 Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.14 Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.15 In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.15

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,13 illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.3 The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.4 In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).2Recognition and management of irAEs has led to the implementation of treatment guidelines.4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.



Biopsy results subsequently revealed findings compatible with ipilimumab-induced colitis, and immunohistochemical staining demonstrated positivity for cytomegalovirus (CMV). Specifically, histologic examination showed lymphoplasmacytic expansion of the lamina propria, some architectural distortion, and increased crypt apoptosis. Scattered cryptitis and crypt abscesses were also noted, as were rare stromal and endothelial cells with characteristic CMV inclusions (Figure 2 and Figure 3).







Serum CMV polymerase chain reaction (PCR) was also positive at 652,000 IU/mL (lower limit of detection 100 IU/mL). Induction dosing of ganciclovir (5 mg/kg IV Q12h) was initiated. The combined treatment with intravenous methylprednisone and ganciclovir led to an improvement in diarrhea frequency and resolution of blood in the stool. She was transitioned to oral prednisone, but it resulted in redevelopment of grade 3 diarrhea. The patient was therefore resumed on and discharged on daily intravenous methylprednisolone.

After discharge, the patient was started on budesonide 9 mg daily. Her serum CMV PCR level reduced and she was transitioned to oral valgancyclovir (900 mg daily) for maintenance. Another unsuccessful attempt was made to switch her to oral prednisone.

About 14 weeks after the initial ipilimumab dosing, the patient underwent another flexible sigmoidoscopy that again demonstrated severe colitis from the rectum to sigmoid colon. Biopsies were negative for CMV. Patient was readmitted for recurrence of diarrhea the following week. Treatment with IV methylprednisone (1mg/kg BID) and infliximab (5 mg/kg) again led to an improvement of symptoms. She was again discharged on IV methylprednisone (1 mg/kg BID) with a taper.

In the 15th week after her initial ipilimumab dose, the patient presented with a perforated bowel, requiring a subtotal colectomy and end ileostomy. She continued on a slow taper of oral prednisone (50 mg daily and decrease by 10 mg every 5 days).

At her last documented follow-up, 8 months after her first ipilimumab dose, she was having normal output from her ileostomy. She developed secondary adrenal insufficiency because of the long-term steroids and continued to take prednisone 5 mg daily.

 

 

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.6 Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.7 Granulomas are also absent in most series, though they have been reported in some cases.8 The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.4 In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.9 In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).9

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.10 In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.11 Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.14 Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.15 In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.15

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,13 illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

References

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845-1855.

3. Glassman PM, Balthasar JP. Mechanistic considerations for the use of monoclonal antibodies for cancer therapy. Cancer Biol Med. 2014;11(1):20-33.

4. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.

5. Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013;18(6):733-743.

6. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-1682.

7. Oble DA, Mino-Kenudson M, Goldsmith J, et al. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):1130-1137.

8. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289.

9. Del Castillo M, Romero FA, Arguello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis. 2016;63(11):1490-1493.

10. Pillet S, Pozzetto B, Roblin X. Cytomegalovirus and ulcerative colitis: place of antiviral therapy. World J Gastroenterol. 2016;22(6):2030-2045.

11. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50(11):1439-1447.

12. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab. J Immunother. 2015;38(5):212-215.

13. Lankes K, Hundorfean G, Harrer T, et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology. 2016;5(6):e1128611.

14. Ko JH, Peck KR, Lee WJ, et al. Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. Clin Infect Dis. 2015;60(6):e20-26.

15. You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep. 2012;14(4):334-342.

References

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845-1855.

3. Glassman PM, Balthasar JP. Mechanistic considerations for the use of monoclonal antibodies for cancer therapy. Cancer Biol Med. 2014;11(1):20-33.

4. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.

5. Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013;18(6):733-743.

6. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-1682.

7. Oble DA, Mino-Kenudson M, Goldsmith J, et al. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):1130-1137.

8. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289.

9. Del Castillo M, Romero FA, Arguello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis. 2016;63(11):1490-1493.

10. Pillet S, Pozzetto B, Roblin X. Cytomegalovirus and ulcerative colitis: place of antiviral therapy. World J Gastroenterol. 2016;22(6):2030-2045.

11. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50(11):1439-1447.

12. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab. J Immunother. 2015;38(5):212-215.

13. Lankes K, Hundorfean G, Harrer T, et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology. 2016;5(6):e1128611.

14. Ko JH, Peck KR, Lee WJ, et al. Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. Clin Infect Dis. 2015;60(6):e20-26.

15. You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep. 2012;14(4):334-342.

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The Journal of Community and Supportive Oncology - 16(1)
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The Journal of Community and Supportive Oncology - 16(1)
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VIDEO: Gene test guides need for sentinel node biopsy in elderly melanoma patients

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SAN DIEGO – The results of a gene expression test, along with tumor thickness and patient age, can guide the need for sentinel lymph node biopsy, based on results from more than1,400 consecutively tested patients from 26 U.S. surgical oncology, medical oncology and dermatologic practices.

The findings, presented by John Vetto, MD, at the annual meeting of the American Academy of Dermatology, indicate the DecisionDx test correctly identified patients aged 65 and older with T1-T2 tumors whose risk of sentinel node metastasis was lower than 5%. The most recent melanoma guidelines from the National Comprehensive Cancer Network recommend that clinicians “discuss and offer” sentinel node biopsy if a patient has a greater than 10% likelihood of a positive node. If the likelihood is 5%-10%, the recommendation is to “discuss and consider” the procedure. But if the likelihood of a positive node is less than 5%, the guidelines recommend against a biopsy.

“Sentinel node biopsy (has) risks, especially in medically compromised older patients,” Dr. Vetto, professor of surgery at the Oregon Health and Sciences University, Portland, said in an interview, in which he discussed clinical use of the test. “This test offers us a good way to assess the risk/benefit ratio so we can better care for patients, and follow the newest guidelines about sentinel node biopsy.”

The DecisionDx Melanoma, developed by Castle Biosciences, tests for the expression of 28 genes know to play a role in melanoma metastasis, and three control genes. Tumors are stratified either as Class 1, with a 3% chance of spreading within 5 years, or Class 2, with a 69% risk of metastasis. There are two subclasses: 1A, which has an extremely low risk of progression, and 2b, which has an extremely high risk of progression.

For patients with T1-T2 tumors who had a Class 1A test result (lowest risk of recurrence), SLN positivity was 4.6% for all ages, 2.8% in patients 55 years and older, and 1.6% in patients 65 years and older. For patients with T1-T2 tumors who had a Class 2B test result (highest risk of recurrence), SLN positivity was 18.8% for all ages, 16.4% in patients 55 years and older and 11.9% in patients 65 years and older.

Dr. Vetto is a paid speaker for Castle Biosciences.

msullivan@frontlinemedcom.com

SOURCE: Vetto et al. AAD 2018 late-breaking research, Abstract 6805

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SAN DIEGO – The results of a gene expression test, along with tumor thickness and patient age, can guide the need for sentinel lymph node biopsy, based on results from more than1,400 consecutively tested patients from 26 U.S. surgical oncology, medical oncology and dermatologic practices.

The findings, presented by John Vetto, MD, at the annual meeting of the American Academy of Dermatology, indicate the DecisionDx test correctly identified patients aged 65 and older with T1-T2 tumors whose risk of sentinel node metastasis was lower than 5%. The most recent melanoma guidelines from the National Comprehensive Cancer Network recommend that clinicians “discuss and offer” sentinel node biopsy if a patient has a greater than 10% likelihood of a positive node. If the likelihood is 5%-10%, the recommendation is to “discuss and consider” the procedure. But if the likelihood of a positive node is less than 5%, the guidelines recommend against a biopsy.

“Sentinel node biopsy (has) risks, especially in medically compromised older patients,” Dr. Vetto, professor of surgery at the Oregon Health and Sciences University, Portland, said in an interview, in which he discussed clinical use of the test. “This test offers us a good way to assess the risk/benefit ratio so we can better care for patients, and follow the newest guidelines about sentinel node biopsy.”

The DecisionDx Melanoma, developed by Castle Biosciences, tests for the expression of 28 genes know to play a role in melanoma metastasis, and three control genes. Tumors are stratified either as Class 1, with a 3% chance of spreading within 5 years, or Class 2, with a 69% risk of metastasis. There are two subclasses: 1A, which has an extremely low risk of progression, and 2b, which has an extremely high risk of progression.

For patients with T1-T2 tumors who had a Class 1A test result (lowest risk of recurrence), SLN positivity was 4.6% for all ages, 2.8% in patients 55 years and older, and 1.6% in patients 65 years and older. For patients with T1-T2 tumors who had a Class 2B test result (highest risk of recurrence), SLN positivity was 18.8% for all ages, 16.4% in patients 55 years and older and 11.9% in patients 65 years and older.

Dr. Vetto is a paid speaker for Castle Biosciences.

msullivan@frontlinemedcom.com

SOURCE: Vetto et al. AAD 2018 late-breaking research, Abstract 6805

SAN DIEGO – The results of a gene expression test, along with tumor thickness and patient age, can guide the need for sentinel lymph node biopsy, based on results from more than1,400 consecutively tested patients from 26 U.S. surgical oncology, medical oncology and dermatologic practices.

The findings, presented by John Vetto, MD, at the annual meeting of the American Academy of Dermatology, indicate the DecisionDx test correctly identified patients aged 65 and older with T1-T2 tumors whose risk of sentinel node metastasis was lower than 5%. The most recent melanoma guidelines from the National Comprehensive Cancer Network recommend that clinicians “discuss and offer” sentinel node biopsy if a patient has a greater than 10% likelihood of a positive node. If the likelihood is 5%-10%, the recommendation is to “discuss and consider” the procedure. But if the likelihood of a positive node is less than 5%, the guidelines recommend against a biopsy.

“Sentinel node biopsy (has) risks, especially in medically compromised older patients,” Dr. Vetto, professor of surgery at the Oregon Health and Sciences University, Portland, said in an interview, in which he discussed clinical use of the test. “This test offers us a good way to assess the risk/benefit ratio so we can better care for patients, and follow the newest guidelines about sentinel node biopsy.”

The DecisionDx Melanoma, developed by Castle Biosciences, tests for the expression of 28 genes know to play a role in melanoma metastasis, and three control genes. Tumors are stratified either as Class 1, with a 3% chance of spreading within 5 years, or Class 2, with a 69% risk of metastasis. There are two subclasses: 1A, which has an extremely low risk of progression, and 2b, which has an extremely high risk of progression.

For patients with T1-T2 tumors who had a Class 1A test result (lowest risk of recurrence), SLN positivity was 4.6% for all ages, 2.8% in patients 55 years and older, and 1.6% in patients 65 years and older. For patients with T1-T2 tumors who had a Class 2B test result (highest risk of recurrence), SLN positivity was 18.8% for all ages, 16.4% in patients 55 years and older and 11.9% in patients 65 years and older.

Dr. Vetto is a paid speaker for Castle Biosciences.

msullivan@frontlinemedcom.com

SOURCE: Vetto et al. AAD 2018 late-breaking research, Abstract 6805

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Dermoscopy will help diagnose pediatric melanomas

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Adding dermoscopy to the classic and modified melanoma ABCD criteria will help speed detection of melanoma in children, said Cristina Carrera, MD, of the University of Barcelona, and her associates.

Pediatric melanomas make up less than 3% of pediatric cancers and 1%-4% of all melanomas, occurring more commonly in adolescents than in children aged 5-9 years. These cancers often are thicker when first seen because of delay in diagnosis and/or differences in growth dynamics. Delay in diagnosis may occur because of the low incidence of pediatric melanoma and because classic melanoma criteria – ABCD: asymmetry, border irregularity, multiple colors, diameter (6 mm) – don’t always apply, they said.

©Zerbor/Thinkstock


A modified clinical ABCD rule of ‘‘amelanotic, bleeding bump, color uniformity, and de novo lesion of any diameter’’ was proposed to improve early detection of pediatric melanoma. And because dermoscopy improves melanoma diagnosis in adults, researchers decided to examine clinical and dermascopic findings in a group of pediatric melanoma cases.

Fifty-two pediatric melanoma cases from 51 patients were collected from pigmented lesion clinics across nine countries (Australia, Belgium, Brazil, France, Israel, Italy, Serbia, Spain, and the United States), and clinical and dermoscopic specimens were examined by two experienced reviewers.

The mean age of the patients was 15 years, and 26 of the patients were female. Histopathologically, 28% of the pediatric melanomas were classified as spitzoid and 72% as nonspitzoid. Patients with a spitzoid melanoma were significantly younger than those with nonspitzoid melanoma (12.5 vs. 16 years, P = .004). All of the spitzoid tumors were invasive, and they were significantly thicker than the nonspitzoid melanomas (2.6 vs. 1.2 mm, P = .004). Also, these lesions more frequently were ulcerated than nonspitzoid melanomas (29% vs. 8%, P = .06). Melanomas associated with a nevus more often were among nonspitzoid than spitzoid melanomas (62% vs. 27% P = .02), and the congenital type of nevus was linked most often with nonspitzoid melanomas (25 of 27 [92.6%]), Dr. Carrera and her associates reported.

The pediatric melanomas in this study appeared most frequently on the lower extremities (31%), followed by the back (27%). Spitzoid melanomas most often appeared on the limbs (73%); nonspitzoid melanomas were likely to occur on the torso (52%).

In the majority of cases (52%), the overall clinical morphology was considered to fulfill the classic melanoma ABCD criteria. The remaining lesions that did not fulfill the conventional ABCD criteria were called benign-appearing tumors or nodular/polypoid tumors. Spitzoid melanomas most often were nodular/ polypoid (47%), while most nonspitzoid melanomas (59%) were melanoma-like. Only 21% of the pediatric melanomas fulfilled the modified melanoma ABCD criteria, they noted.

On dermoscopy, which was available in 49 cases, a multicomponent pattern seen in 24 cases mostly was associated with nonspitzoid melanoma (88%, P less than.03); a nevus-like pattern in 9 cases was seen only among nonspitzoid melanomas. A vascular pink Spitz-like pattern in seven cases mostly was associated with spitzoid melanomas (86%, P less than .002). A pigmented Reed-like pattern seen in seven cases occurred more often among spitzoid melanomas, but this did not reach statistical significance, the investigators wrote.

In terms of appearance, “red and white colors, milky red areas, polymorphous vessels, and shiny white structures were associated with spitzoid melanoma. Dark brown color, atypical network, and structureless areas were associated with nonspitzoid melanomas,” Dr. Carrera and her associates said.

Dermoscopic patterns that were pink spitzoid or Reed-like were more likely to be histopathologically classified as spitzoid. These pediatric melanomas were linked with younger age, occurrence on the limbs, and de novo development. On the other hand, dermoscopic patterns that were multicomponent or nevus-like were likely to be histopathologically classified as nonspitzoid. These lesions were linked with older age, fair skin phenotype, family history of melanoma, and a preexisting nevus, the researchers said.

“In contrast to previous reports, the present study highlights the fact that the majority of melanomas diagnosed in patients younger than 20 years look similar to melanomas found in adults. Nonspitzoid melanomas were associated with adolescence and with the presence of melanoma risk factors. All nonspitzoid melanomas displayed dermoscopic features associated with melanoma. Spitzoid melanomas were associated with younger age, location on the extremities, and nodular/polypoid clinical morphology. Dermoscopy of spitzoid melanomas revealed atypical vessels and shiny white lines (if amelanotic) or an asymmetric starburst pattern (if pigmented),” Dr. Carrera and her associates concluded.

The investigators had no relevant financial disclosures. The study was supported in part through a grant from the National Institutes of Health/ National Cancer Institute. The research at the melanoma unit in Barcelona was partially funded by grants from the Spanish Fondo de Investigaciones Sanitarias and CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; it was confinanced by numerous other grants.
 

SOURCE: Carrera C et al. J Am Acad Dermatol. 2018;78(2):278-88. doi: 10.1016/j.jaad.2017.09.065.

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Adding dermoscopy to the classic and modified melanoma ABCD criteria will help speed detection of melanoma in children, said Cristina Carrera, MD, of the University of Barcelona, and her associates.

Pediatric melanomas make up less than 3% of pediatric cancers and 1%-4% of all melanomas, occurring more commonly in adolescents than in children aged 5-9 years. These cancers often are thicker when first seen because of delay in diagnosis and/or differences in growth dynamics. Delay in diagnosis may occur because of the low incidence of pediatric melanoma and because classic melanoma criteria – ABCD: asymmetry, border irregularity, multiple colors, diameter (6 mm) – don’t always apply, they said.

©Zerbor/Thinkstock


A modified clinical ABCD rule of ‘‘amelanotic, bleeding bump, color uniformity, and de novo lesion of any diameter’’ was proposed to improve early detection of pediatric melanoma. And because dermoscopy improves melanoma diagnosis in adults, researchers decided to examine clinical and dermascopic findings in a group of pediatric melanoma cases.

Fifty-two pediatric melanoma cases from 51 patients were collected from pigmented lesion clinics across nine countries (Australia, Belgium, Brazil, France, Israel, Italy, Serbia, Spain, and the United States), and clinical and dermoscopic specimens were examined by two experienced reviewers.

The mean age of the patients was 15 years, and 26 of the patients were female. Histopathologically, 28% of the pediatric melanomas were classified as spitzoid and 72% as nonspitzoid. Patients with a spitzoid melanoma were significantly younger than those with nonspitzoid melanoma (12.5 vs. 16 years, P = .004). All of the spitzoid tumors were invasive, and they were significantly thicker than the nonspitzoid melanomas (2.6 vs. 1.2 mm, P = .004). Also, these lesions more frequently were ulcerated than nonspitzoid melanomas (29% vs. 8%, P = .06). Melanomas associated with a nevus more often were among nonspitzoid than spitzoid melanomas (62% vs. 27% P = .02), and the congenital type of nevus was linked most often with nonspitzoid melanomas (25 of 27 [92.6%]), Dr. Carrera and her associates reported.

The pediatric melanomas in this study appeared most frequently on the lower extremities (31%), followed by the back (27%). Spitzoid melanomas most often appeared on the limbs (73%); nonspitzoid melanomas were likely to occur on the torso (52%).

In the majority of cases (52%), the overall clinical morphology was considered to fulfill the classic melanoma ABCD criteria. The remaining lesions that did not fulfill the conventional ABCD criteria were called benign-appearing tumors or nodular/polypoid tumors. Spitzoid melanomas most often were nodular/ polypoid (47%), while most nonspitzoid melanomas (59%) were melanoma-like. Only 21% of the pediatric melanomas fulfilled the modified melanoma ABCD criteria, they noted.

On dermoscopy, which was available in 49 cases, a multicomponent pattern seen in 24 cases mostly was associated with nonspitzoid melanoma (88%, P less than.03); a nevus-like pattern in 9 cases was seen only among nonspitzoid melanomas. A vascular pink Spitz-like pattern in seven cases mostly was associated with spitzoid melanomas (86%, P less than .002). A pigmented Reed-like pattern seen in seven cases occurred more often among spitzoid melanomas, but this did not reach statistical significance, the investigators wrote.

In terms of appearance, “red and white colors, milky red areas, polymorphous vessels, and shiny white structures were associated with spitzoid melanoma. Dark brown color, atypical network, and structureless areas were associated with nonspitzoid melanomas,” Dr. Carrera and her associates said.

Dermoscopic patterns that were pink spitzoid or Reed-like were more likely to be histopathologically classified as spitzoid. These pediatric melanomas were linked with younger age, occurrence on the limbs, and de novo development. On the other hand, dermoscopic patterns that were multicomponent or nevus-like were likely to be histopathologically classified as nonspitzoid. These lesions were linked with older age, fair skin phenotype, family history of melanoma, and a preexisting nevus, the researchers said.

“In contrast to previous reports, the present study highlights the fact that the majority of melanomas diagnosed in patients younger than 20 years look similar to melanomas found in adults. Nonspitzoid melanomas were associated with adolescence and with the presence of melanoma risk factors. All nonspitzoid melanomas displayed dermoscopic features associated with melanoma. Spitzoid melanomas were associated with younger age, location on the extremities, and nodular/polypoid clinical morphology. Dermoscopy of spitzoid melanomas revealed atypical vessels and shiny white lines (if amelanotic) or an asymmetric starburst pattern (if pigmented),” Dr. Carrera and her associates concluded.

The investigators had no relevant financial disclosures. The study was supported in part through a grant from the National Institutes of Health/ National Cancer Institute. The research at the melanoma unit in Barcelona was partially funded by grants from the Spanish Fondo de Investigaciones Sanitarias and CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; it was confinanced by numerous other grants.
 

SOURCE: Carrera C et al. J Am Acad Dermatol. 2018;78(2):278-88. doi: 10.1016/j.jaad.2017.09.065.

Adding dermoscopy to the classic and modified melanoma ABCD criteria will help speed detection of melanoma in children, said Cristina Carrera, MD, of the University of Barcelona, and her associates.

Pediatric melanomas make up less than 3% of pediatric cancers and 1%-4% of all melanomas, occurring more commonly in adolescents than in children aged 5-9 years. These cancers often are thicker when first seen because of delay in diagnosis and/or differences in growth dynamics. Delay in diagnosis may occur because of the low incidence of pediatric melanoma and because classic melanoma criteria – ABCD: asymmetry, border irregularity, multiple colors, diameter (6 mm) – don’t always apply, they said.

©Zerbor/Thinkstock


A modified clinical ABCD rule of ‘‘amelanotic, bleeding bump, color uniformity, and de novo lesion of any diameter’’ was proposed to improve early detection of pediatric melanoma. And because dermoscopy improves melanoma diagnosis in adults, researchers decided to examine clinical and dermascopic findings in a group of pediatric melanoma cases.

Fifty-two pediatric melanoma cases from 51 patients were collected from pigmented lesion clinics across nine countries (Australia, Belgium, Brazil, France, Israel, Italy, Serbia, Spain, and the United States), and clinical and dermoscopic specimens were examined by two experienced reviewers.

The mean age of the patients was 15 years, and 26 of the patients were female. Histopathologically, 28% of the pediatric melanomas were classified as spitzoid and 72% as nonspitzoid. Patients with a spitzoid melanoma were significantly younger than those with nonspitzoid melanoma (12.5 vs. 16 years, P = .004). All of the spitzoid tumors were invasive, and they were significantly thicker than the nonspitzoid melanomas (2.6 vs. 1.2 mm, P = .004). Also, these lesions more frequently were ulcerated than nonspitzoid melanomas (29% vs. 8%, P = .06). Melanomas associated with a nevus more often were among nonspitzoid than spitzoid melanomas (62% vs. 27% P = .02), and the congenital type of nevus was linked most often with nonspitzoid melanomas (25 of 27 [92.6%]), Dr. Carrera and her associates reported.

The pediatric melanomas in this study appeared most frequently on the lower extremities (31%), followed by the back (27%). Spitzoid melanomas most often appeared on the limbs (73%); nonspitzoid melanomas were likely to occur on the torso (52%).

In the majority of cases (52%), the overall clinical morphology was considered to fulfill the classic melanoma ABCD criteria. The remaining lesions that did not fulfill the conventional ABCD criteria were called benign-appearing tumors or nodular/polypoid tumors. Spitzoid melanomas most often were nodular/ polypoid (47%), while most nonspitzoid melanomas (59%) were melanoma-like. Only 21% of the pediatric melanomas fulfilled the modified melanoma ABCD criteria, they noted.

On dermoscopy, which was available in 49 cases, a multicomponent pattern seen in 24 cases mostly was associated with nonspitzoid melanoma (88%, P less than.03); a nevus-like pattern in 9 cases was seen only among nonspitzoid melanomas. A vascular pink Spitz-like pattern in seven cases mostly was associated with spitzoid melanomas (86%, P less than .002). A pigmented Reed-like pattern seen in seven cases occurred more often among spitzoid melanomas, but this did not reach statistical significance, the investigators wrote.

In terms of appearance, “red and white colors, milky red areas, polymorphous vessels, and shiny white structures were associated with spitzoid melanoma. Dark brown color, atypical network, and structureless areas were associated with nonspitzoid melanomas,” Dr. Carrera and her associates said.

Dermoscopic patterns that were pink spitzoid or Reed-like were more likely to be histopathologically classified as spitzoid. These pediatric melanomas were linked with younger age, occurrence on the limbs, and de novo development. On the other hand, dermoscopic patterns that were multicomponent or nevus-like were likely to be histopathologically classified as nonspitzoid. These lesions were linked with older age, fair skin phenotype, family history of melanoma, and a preexisting nevus, the researchers said.

“In contrast to previous reports, the present study highlights the fact that the majority of melanomas diagnosed in patients younger than 20 years look similar to melanomas found in adults. Nonspitzoid melanomas were associated with adolescence and with the presence of melanoma risk factors. All nonspitzoid melanomas displayed dermoscopic features associated with melanoma. Spitzoid melanomas were associated with younger age, location on the extremities, and nodular/polypoid clinical morphology. Dermoscopy of spitzoid melanomas revealed atypical vessels and shiny white lines (if amelanotic) or an asymmetric starburst pattern (if pigmented),” Dr. Carrera and her associates concluded.

The investigators had no relevant financial disclosures. The study was supported in part through a grant from the National Institutes of Health/ National Cancer Institute. The research at the melanoma unit in Barcelona was partially funded by grants from the Spanish Fondo de Investigaciones Sanitarias and CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; it was confinanced by numerous other grants.
 

SOURCE: Carrera C et al. J Am Acad Dermatol. 2018;78(2):278-88. doi: 10.1016/j.jaad.2017.09.065.

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FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY

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Key clinical point: In contrast to previous reports, this study found the majority of pediatric melanomas look similar to melanomas found in adults.

Major finding: On dermoscopy, a multicomponent pattern seen in 24 cases mostly was associated with nonspitzoid melanoma (88%, P less than.03).

Data source: Fifty-two pediatric melanoma cases from 51 patients were collected from pigmented lesion clinics across 9 countries.

Disclosures: The investigators had no relevant financial disclosures. The study was supported in part through a grant from the National Institutes of Health/ National Cancer Institute. The research at the melanoma unit in Barcelona was partially funded by grants from the Spanish Fondo de Investigaciones Sanitarias and CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; it was cofinanced by numerous other grants.

Source: Carrera C et al. J Am Acad Dermatol. 2018;78(2):278-88.

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Melanoma incidence increased in older non-Hispanic whites

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The incidence of melanoma has increased in non-Hispanic whites in recent years, particularly in men over 54 years of age and women over 44 years of age, reported Dawn M. Holman, MPH, of the division of cancer prevention and control at the Centers for Disease Control and Prevention, and her coauthors.

In non-Hispanic white females aged 15 years and older, 131,976 melanomas were diagnosed between January 2010 and December 2014. In non-Hispanic white males, 192,979 melanomas were diagnosed during this time period. More than 70% of melanomas were diagnosed in patients aged 55 years or older, the authors reported. In females, melanoma incidence rates ranged from 4.5/100,000 population in those aged 15-24 years to 60.9/100,000 population in those aged 85 years and older. For males, melanoma incidence ranged from 2.0/100,000 population in those aged 15-24 years to 198.3/100,000 population in men aged 85 years and older.

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Investigators analyzed data from the CDC National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Melanoma incidence rates and average annual counts by 10-year age groups were calculated from January 2010 to December 2014, as was average annual percent change (AAPC) by 10-year age groups from January 2005 to December 2014.

Overall, the increase in melanoma incidence was statistically significant for both males and females 15 years of age and older (AAPC, 1.4; P less than .05). However, melanoma incidence decreased significantly in younger patients aged 15-24 years, 25-34 years, and 35-44 years (AAPC, –5.1, –1.7, and –0.5 respectively; P less than .05), and increased significantly in those aged 55-64 years, 65-74 years, 75-84 years, and older than 85 years (AAPC, 1.3, 2.5, 3.6, and 4.6 respectively; P less than .05). The increase in melanoma incidence was statistically significant in men older than 54 years and in women older than 44 years, Ms. Holman and her associates reported in a research letter in JAMA Dermatology.

 

 


The findings suggest that recent decreases in indoor tanning and sunburn prevalence may account for the reduction in melanoma incidence over time, especially in adolescents and young adults, they said.

“Although primary skin cancer prevention efforts have often focused on children, adolescents, and young adults, the steady increase in melanoma incidence rates among older adults indicates a need for efforts that promote skin cancer preventive behaviors throughout adulthood. Such efforts could focus on groups at high risk, such as outdoor workers and intentional tanners,” Ms. Holman and her associates concluded.

The authors did not disclose any conflicts of interest. The study was partially supported by appointments to the CDC Research Participation Program through an interagency agreement with the U.S. Department of Energy.

SOURCE: Holman DM et al. JAMA Dermatol. 2018 Jan 31. doi: 10.1001/jamadermatol.2017.5541.

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The incidence of melanoma has increased in non-Hispanic whites in recent years, particularly in men over 54 years of age and women over 44 years of age, reported Dawn M. Holman, MPH, of the division of cancer prevention and control at the Centers for Disease Control and Prevention, and her coauthors.

In non-Hispanic white females aged 15 years and older, 131,976 melanomas were diagnosed between January 2010 and December 2014. In non-Hispanic white males, 192,979 melanomas were diagnosed during this time period. More than 70% of melanomas were diagnosed in patients aged 55 years or older, the authors reported. In females, melanoma incidence rates ranged from 4.5/100,000 population in those aged 15-24 years to 60.9/100,000 population in those aged 85 years and older. For males, melanoma incidence ranged from 2.0/100,000 population in those aged 15-24 years to 198.3/100,000 population in men aged 85 years and older.

Huntstock/Thinkstock

Investigators analyzed data from the CDC National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Melanoma incidence rates and average annual counts by 10-year age groups were calculated from January 2010 to December 2014, as was average annual percent change (AAPC) by 10-year age groups from January 2005 to December 2014.

Overall, the increase in melanoma incidence was statistically significant for both males and females 15 years of age and older (AAPC, 1.4; P less than .05). However, melanoma incidence decreased significantly in younger patients aged 15-24 years, 25-34 years, and 35-44 years (AAPC, –5.1, –1.7, and –0.5 respectively; P less than .05), and increased significantly in those aged 55-64 years, 65-74 years, 75-84 years, and older than 85 years (AAPC, 1.3, 2.5, 3.6, and 4.6 respectively; P less than .05). The increase in melanoma incidence was statistically significant in men older than 54 years and in women older than 44 years, Ms. Holman and her associates reported in a research letter in JAMA Dermatology.

 

 


The findings suggest that recent decreases in indoor tanning and sunburn prevalence may account for the reduction in melanoma incidence over time, especially in adolescents and young adults, they said.

“Although primary skin cancer prevention efforts have often focused on children, adolescents, and young adults, the steady increase in melanoma incidence rates among older adults indicates a need for efforts that promote skin cancer preventive behaviors throughout adulthood. Such efforts could focus on groups at high risk, such as outdoor workers and intentional tanners,” Ms. Holman and her associates concluded.

The authors did not disclose any conflicts of interest. The study was partially supported by appointments to the CDC Research Participation Program through an interagency agreement with the U.S. Department of Energy.

SOURCE: Holman DM et al. JAMA Dermatol. 2018 Jan 31. doi: 10.1001/jamadermatol.2017.5541.

 

The incidence of melanoma has increased in non-Hispanic whites in recent years, particularly in men over 54 years of age and women over 44 years of age, reported Dawn M. Holman, MPH, of the division of cancer prevention and control at the Centers for Disease Control and Prevention, and her coauthors.

In non-Hispanic white females aged 15 years and older, 131,976 melanomas were diagnosed between January 2010 and December 2014. In non-Hispanic white males, 192,979 melanomas were diagnosed during this time period. More than 70% of melanomas were diagnosed in patients aged 55 years or older, the authors reported. In females, melanoma incidence rates ranged from 4.5/100,000 population in those aged 15-24 years to 60.9/100,000 population in those aged 85 years and older. For males, melanoma incidence ranged from 2.0/100,000 population in those aged 15-24 years to 198.3/100,000 population in men aged 85 years and older.

Huntstock/Thinkstock

Investigators analyzed data from the CDC National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Melanoma incidence rates and average annual counts by 10-year age groups were calculated from January 2010 to December 2014, as was average annual percent change (AAPC) by 10-year age groups from January 2005 to December 2014.

Overall, the increase in melanoma incidence was statistically significant for both males and females 15 years of age and older (AAPC, 1.4; P less than .05). However, melanoma incidence decreased significantly in younger patients aged 15-24 years, 25-34 years, and 35-44 years (AAPC, –5.1, –1.7, and –0.5 respectively; P less than .05), and increased significantly in those aged 55-64 years, 65-74 years, 75-84 years, and older than 85 years (AAPC, 1.3, 2.5, 3.6, and 4.6 respectively; P less than .05). The increase in melanoma incidence was statistically significant in men older than 54 years and in women older than 44 years, Ms. Holman and her associates reported in a research letter in JAMA Dermatology.

 

 


The findings suggest that recent decreases in indoor tanning and sunburn prevalence may account for the reduction in melanoma incidence over time, especially in adolescents and young adults, they said.

“Although primary skin cancer prevention efforts have often focused on children, adolescents, and young adults, the steady increase in melanoma incidence rates among older adults indicates a need for efforts that promote skin cancer preventive behaviors throughout adulthood. Such efforts could focus on groups at high risk, such as outdoor workers and intentional tanners,” Ms. Holman and her associates concluded.

The authors did not disclose any conflicts of interest. The study was partially supported by appointments to the CDC Research Participation Program through an interagency agreement with the U.S. Department of Energy.

SOURCE: Holman DM et al. JAMA Dermatol. 2018 Jan 31. doi: 10.1001/jamadermatol.2017.5541.

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Key clinical point: Melanoma incidence has increased in older non-Hispanic whites, but decreased in younger members of this population.

Major finding: Overall increase in melanoma incidence was statistically significant for both males and females 15 years of age and older (AAPC = 1.4; P less than .05).

Study details: An analysis of data from the CDC’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2010 to December 2014 (for incidence and rates) and from January 2005 to December 2014 (for trends over time).

Disclosures: The authors did not disclose any conflicts of interest. The study was partially supported by appointments to the CDC Research Participation Program through an interagency agreement with the U.S. Department of Energy.

Source: Holman DM et al. JAMA Dermatol. 2018 Jan 31. doi: 10.1001/jamadermatol.2017.5541.

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Be alert for BAP1 mutations in hereditary melanomas

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MIAMI – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy James Dick
Dr. Hensin Tsao
“And melanoma becomes a window and opportunity to screen and identify these other mutations. And as with all cancer syndromes, we want to screen earlier.”

The BAP1-associated skin lesions can emerge when patients are relatively young, even as teenagers. The melanoma and renal cell cancers also can have an early onset, said Dr. Tsao, director of the melanoma genetics program at Massachusetts General Hospital, Boston. The skin lesion itself can be a tipoff for a BAP1 germline mutation. In general, they are small, dome shaped – not flat like a superficial basal cell – rarely pigmented and appear “orangey translucent.” Dr. Tsao added: “When you start seeing them, you’ll recognize them. However, to be sure, you’re going to have to biopsy to know what is going on.”

In one patient he described, the pattern of malignancies in the patient’s family was a hint that she had a BAP1 mutation, Dr. Tsao said. The proband had melanoma starting at age 31 years, a squamous cell carcinoma at 35 years, and basal cell carcinoma at age 40 years. “She had nine ‘nevoid melanomas’ over the years. Nevoid melanomas are rare, and with nine in a row, you know something odd is going on.” Dr. Tsao and his team performed a series of sentinel lymph node biopsies that ruled out metastasis. “What is also interesting is the father had ocular melanoma, which is what got us to thinking about BAP1 mutations in this family.” A sister who developed melanoma and a brother who also was diagnosed with melanoma plus kidney cancer at age 45 years were further clues to the germline mutation.
 

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

Dr. Hensin Tsao
A BAP1-associated skin lesion
In someone with a relevant mutation that destroys this BAP1 function, the ubiquitin compounds fail to be removed. “In the case of BAP1 protein loss, cancers can proliferate. “All the families described so far [with inherited BAP1 alterations] have a harmful mutations that kill this protein somehow,” Dr. Tsao said.

Once a dermatologist suspects a BAP1 mutation–associated cancer, they can order a BAP1 nuclear stain to confirm diagnosis. Formal documentation of a germline mutation, however, requires genetic testing of blood DNA.
 

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.
 

 

 

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

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MIAMI – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy James Dick
Dr. Hensin Tsao
“And melanoma becomes a window and opportunity to screen and identify these other mutations. And as with all cancer syndromes, we want to screen earlier.”

The BAP1-associated skin lesions can emerge when patients are relatively young, even as teenagers. The melanoma and renal cell cancers also can have an early onset, said Dr. Tsao, director of the melanoma genetics program at Massachusetts General Hospital, Boston. The skin lesion itself can be a tipoff for a BAP1 germline mutation. In general, they are small, dome shaped – not flat like a superficial basal cell – rarely pigmented and appear “orangey translucent.” Dr. Tsao added: “When you start seeing them, you’ll recognize them. However, to be sure, you’re going to have to biopsy to know what is going on.”

In one patient he described, the pattern of malignancies in the patient’s family was a hint that she had a BAP1 mutation, Dr. Tsao said. The proband had melanoma starting at age 31 years, a squamous cell carcinoma at 35 years, and basal cell carcinoma at age 40 years. “She had nine ‘nevoid melanomas’ over the years. Nevoid melanomas are rare, and with nine in a row, you know something odd is going on.” Dr. Tsao and his team performed a series of sentinel lymph node biopsies that ruled out metastasis. “What is also interesting is the father had ocular melanoma, which is what got us to thinking about BAP1 mutations in this family.” A sister who developed melanoma and a brother who also was diagnosed with melanoma plus kidney cancer at age 45 years were further clues to the germline mutation.
 

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

Dr. Hensin Tsao
A BAP1-associated skin lesion
In someone with a relevant mutation that destroys this BAP1 function, the ubiquitin compounds fail to be removed. “In the case of BAP1 protein loss, cancers can proliferate. “All the families described so far [with inherited BAP1 alterations] have a harmful mutations that kill this protein somehow,” Dr. Tsao said.

Once a dermatologist suspects a BAP1 mutation–associated cancer, they can order a BAP1 nuclear stain to confirm diagnosis. Formal documentation of a germline mutation, however, requires genetic testing of blood DNA.
 

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.
 

 

 

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

 

MIAMI – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy James Dick
Dr. Hensin Tsao
“And melanoma becomes a window and opportunity to screen and identify these other mutations. And as with all cancer syndromes, we want to screen earlier.”

The BAP1-associated skin lesions can emerge when patients are relatively young, even as teenagers. The melanoma and renal cell cancers also can have an early onset, said Dr. Tsao, director of the melanoma genetics program at Massachusetts General Hospital, Boston. The skin lesion itself can be a tipoff for a BAP1 germline mutation. In general, they are small, dome shaped – not flat like a superficial basal cell – rarely pigmented and appear “orangey translucent.” Dr. Tsao added: “When you start seeing them, you’ll recognize them. However, to be sure, you’re going to have to biopsy to know what is going on.”

In one patient he described, the pattern of malignancies in the patient’s family was a hint that she had a BAP1 mutation, Dr. Tsao said. The proband had melanoma starting at age 31 years, a squamous cell carcinoma at 35 years, and basal cell carcinoma at age 40 years. “She had nine ‘nevoid melanomas’ over the years. Nevoid melanomas are rare, and with nine in a row, you know something odd is going on.” Dr. Tsao and his team performed a series of sentinel lymph node biopsies that ruled out metastasis. “What is also interesting is the father had ocular melanoma, which is what got us to thinking about BAP1 mutations in this family.” A sister who developed melanoma and a brother who also was diagnosed with melanoma plus kidney cancer at age 45 years were further clues to the germline mutation.
 

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

Dr. Hensin Tsao
A BAP1-associated skin lesion
In someone with a relevant mutation that destroys this BAP1 function, the ubiquitin compounds fail to be removed. “In the case of BAP1 protein loss, cancers can proliferate. “All the families described so far [with inherited BAP1 alterations] have a harmful mutations that kill this protein somehow,” Dr. Tsao said.

Once a dermatologist suspects a BAP1 mutation–associated cancer, they can order a BAP1 nuclear stain to confirm diagnosis. Formal documentation of a germline mutation, however, requires genetic testing of blood DNA.
 

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.
 

 

 

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

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Mobile Medical Apps for Patient Education: A Graded Review of Available Dermatology Apps

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Mobile Medical Apps for Patient Education: A Graded Review of Available Dermatology Apps

According to industry estimates, roughly 64% of US adults were smartphone users in 2015.1 Smartphones enable users to utilize mobile applications (apps) that can perform a variety of functions in many categories, including business, music, photography, entertainment, education, social networking, travel, and lifestyle. The widespread adoption and use of mobile apps has implications for medical practice. Mobile apps have the capability to serve as information sources for patients, educational tools for students, and diagnostic aids for physicians.2 Consequently, a number of medical and health care–oriented apps have already been developed3 and are increasingly utilized by patients and providers.4

Given its visual nature, dermatology is particularly amenable to the integration of mobile medical apps. A study by Brewer et al5 identified more than 229 dermatology-related apps in categories ranging from general dermatology reference, self-surveillance and diagnosis, disease guides, educational aids, sunscreen and UV recommendations, and teledermatology. Patients served as the target audience and principal consumers of more than half of these dermatology apps.5

Mobile medical and health care apps demonstrate great potential for serving as valuable information sources for patients with dermatologic conditions; however, the content, functions, accuracy, and educational value of dermatology mobile apps are not well characterized, making it difficult for patients and health care providers to select and recommend appropriate apps.6 In this study, we created a rubric to objectively grade 44 publicly available mobile dermatology apps with the primary focus of patient education.

Methods

We conducted a search of dermatology-related educational mobile apps that were publicly available via the App Store (Apple Inc) from January 2016 to November 2016. (The pricing, availability, and other features of these apps may have changed since the study period.) The following search terms were used: dermatology, dermoscopy, melanoma, skin cancer, psoriasis, rosacea, acne, eczema, dermal fillers, and Mohs surgery. We excluded apps that were not in English; had a solely commercial focus; were mobile textbooks or scientific journals; were used to provide teledermatology services with no educational purpose; were solely focused on homeopathic, alternative, and/or complementary medicine; or were intended primarily as a reference for students or health care professionals. Our search yielded 44 apps with patient education as a primary objective. The apps were divided into 6 categories based on their focus: general dermatology, cosmetic dermatology, acne, eczema, psoriasis, and skin cancer.

Each app was reviewed using a quantified grading rubric developed by the researchers. In a prior evaluation, Handel7 reviewed 35 health and wellness mobile apps utilizing the categories of ease of use, reliability, quality, scope of information, and aesthetics.4 These criteria were modified and adapted for the purposes of this study, and a 4-point scale was applied to each criterion. The final criteria were (1) educational objectives, (2) content, (3) accuracy, (4) design, and (5) conflict of interest. The quantified grading rubric is described in Table 1.

Results

The possible range of scores based on the grading rubric was 5 to 20. The actual range of scores was 8 to 19 (Table 2). The 44 reviewed apps were categorized by topic as acne, cosmetic dermatology, eczema, general dermatology, psoriasis, or skin cancer. A sample of 15 apps selected to represent the distribution of scores and their grading on the rubric are presented in Table 3.

Comment

The number of dermatology-related apps available to mobile users continues to grow at an increasing rate.8 The apps vary in many aspects, including their purpose, scope, intended audience, and goals of the app publisher. In turn, more individuals are turning to mobile apps for medical information,4 especially in dermatology, thus it is necessary to create a systematic way to evaluate the quality and utility of each app to assist users in making informed decisions about which apps will best meet their needs in the midst of a wide array of choices.

For the purpose of this study, an objective rubric was created that can be used to evaluate the quality of medical apps for patient education in dermatology. An app’s adequacy and usefulness for patient education was thought to depend on 3 possible score ranges into which the app could fall based on the grading rubric. An app with a total score in the range of 5 to 10 was not thought to be useful and may even be detrimental to patients. An app with a total score in the range of 11 to 15 may be used for patient education with some reservations based on shortcomings for certain criteria. An app with a score in the range of 16 to 20 was thought to be valuable and adequate for patient education. For example, the How to Treat Acne app received a total score of 8 and therefore would not be recommended to patients based on the grading rubric used in this study. This particular app provided sparse and sometimes inaccurate information, had a confusing user interface, and contained many obstructive advertisements. In contrast, the Eczema Doc app received a total score of 19, which indicates a quality app deemed to be useful for patient information based on the established rubric. This app met all the objectives that it advertised, contained accurate information with verified citation of sources, and was very easy for users to navigate.

Of the 44 graded apps, only 9 (20.5%) received scores in the highest range of 16 to 20, which indicates a need for improvements in mobile dermatology apps intended for patient education. Adopting the grading rubric developed in this study as a standard in the creation of medical apps could have beneficial implications in disseminating accurate, safe, unbiased, and easy-to-understand information to patients.

References
  1. Smith A. U.S. smartphone use in 2015. Pew Research Center website. http://www.pewinternet.org/2015/04/01/us-smartphone-use-in-2015. Published April 1, 2015. Accessed August 29, 2017.
  2. Nilsen W, Kumar S, Shar A, et al. Advancing the science of mHealth. J Health Commun. 2012;17(suppl 1):5-10.
  3. West DM. How mobile devices are transforming healthcare issues in technology innovation. Issues Technol Innov. 2012;18:1-14.
  4. Boudreaux ED, Waring ME, Hayes RB, et al. Evaluating and selecting mobile health apps: strategies for healthcare providers and healthcare organizations. Transl Behav Med. 2014;4:363-371.
  5. Brewer AC, Endly DC, Henley J, et al. Mobile applications in dermatology. JAMA Dermatol. 2013;149:1300-1304.
  6. Cummings E, Borycki E, Roehrer E. Issues and considerations for healthcare consumers using mobile applications. Stud Health Technol Inform. 2013;183:227-231.
  7. Handel MJ. mHealth (mobile health)-using apps for health and wellness. Explore. 2011;7:256-261.
  8. Boulos MN, Brewer AC, Karimkhani C, et al. Mobile medical and health apps: state of the art, concerns, regulatory control and certification. Online J Public Health Inform. 2014;5:229.
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Ms. Masud and Drs. Shafi and Rao are from the Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. Dr. Rao also is from the Department of Dermatology, Weill Cornell Medicine, New York, New York.

The authors report no conflict of interest.

Correspondence: Babar K. Rao, MD, 1 World's Fair Dr, Somerset, NJ 08873 (babarrao@gmail.com).

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Ms. Masud and Drs. Shafi and Rao are from the Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. Dr. Rao also is from the Department of Dermatology, Weill Cornell Medicine, New York, New York.

The authors report no conflict of interest.

Correspondence: Babar K. Rao, MD, 1 World's Fair Dr, Somerset, NJ 08873 (babarrao@gmail.com).

Author and Disclosure Information

Ms. Masud and Drs. Shafi and Rao are from the Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. Dr. Rao also is from the Department of Dermatology, Weill Cornell Medicine, New York, New York.

The authors report no conflict of interest.

Correspondence: Babar K. Rao, MD, 1 World's Fair Dr, Somerset, NJ 08873 (babarrao@gmail.com).

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According to industry estimates, roughly 64% of US adults were smartphone users in 2015.1 Smartphones enable users to utilize mobile applications (apps) that can perform a variety of functions in many categories, including business, music, photography, entertainment, education, social networking, travel, and lifestyle. The widespread adoption and use of mobile apps has implications for medical practice. Mobile apps have the capability to serve as information sources for patients, educational tools for students, and diagnostic aids for physicians.2 Consequently, a number of medical and health care–oriented apps have already been developed3 and are increasingly utilized by patients and providers.4

Given its visual nature, dermatology is particularly amenable to the integration of mobile medical apps. A study by Brewer et al5 identified more than 229 dermatology-related apps in categories ranging from general dermatology reference, self-surveillance and diagnosis, disease guides, educational aids, sunscreen and UV recommendations, and teledermatology. Patients served as the target audience and principal consumers of more than half of these dermatology apps.5

Mobile medical and health care apps demonstrate great potential for serving as valuable information sources for patients with dermatologic conditions; however, the content, functions, accuracy, and educational value of dermatology mobile apps are not well characterized, making it difficult for patients and health care providers to select and recommend appropriate apps.6 In this study, we created a rubric to objectively grade 44 publicly available mobile dermatology apps with the primary focus of patient education.

Methods

We conducted a search of dermatology-related educational mobile apps that were publicly available via the App Store (Apple Inc) from January 2016 to November 2016. (The pricing, availability, and other features of these apps may have changed since the study period.) The following search terms were used: dermatology, dermoscopy, melanoma, skin cancer, psoriasis, rosacea, acne, eczema, dermal fillers, and Mohs surgery. We excluded apps that were not in English; had a solely commercial focus; were mobile textbooks or scientific journals; were used to provide teledermatology services with no educational purpose; were solely focused on homeopathic, alternative, and/or complementary medicine; or were intended primarily as a reference for students or health care professionals. Our search yielded 44 apps with patient education as a primary objective. The apps were divided into 6 categories based on their focus: general dermatology, cosmetic dermatology, acne, eczema, psoriasis, and skin cancer.

Each app was reviewed using a quantified grading rubric developed by the researchers. In a prior evaluation, Handel7 reviewed 35 health and wellness mobile apps utilizing the categories of ease of use, reliability, quality, scope of information, and aesthetics.4 These criteria were modified and adapted for the purposes of this study, and a 4-point scale was applied to each criterion. The final criteria were (1) educational objectives, (2) content, (3) accuracy, (4) design, and (5) conflict of interest. The quantified grading rubric is described in Table 1.

Results

The possible range of scores based on the grading rubric was 5 to 20. The actual range of scores was 8 to 19 (Table 2). The 44 reviewed apps were categorized by topic as acne, cosmetic dermatology, eczema, general dermatology, psoriasis, or skin cancer. A sample of 15 apps selected to represent the distribution of scores and their grading on the rubric are presented in Table 3.

Comment

The number of dermatology-related apps available to mobile users continues to grow at an increasing rate.8 The apps vary in many aspects, including their purpose, scope, intended audience, and goals of the app publisher. In turn, more individuals are turning to mobile apps for medical information,4 especially in dermatology, thus it is necessary to create a systematic way to evaluate the quality and utility of each app to assist users in making informed decisions about which apps will best meet their needs in the midst of a wide array of choices.

For the purpose of this study, an objective rubric was created that can be used to evaluate the quality of medical apps for patient education in dermatology. An app’s adequacy and usefulness for patient education was thought to depend on 3 possible score ranges into which the app could fall based on the grading rubric. An app with a total score in the range of 5 to 10 was not thought to be useful and may even be detrimental to patients. An app with a total score in the range of 11 to 15 may be used for patient education with some reservations based on shortcomings for certain criteria. An app with a score in the range of 16 to 20 was thought to be valuable and adequate for patient education. For example, the How to Treat Acne app received a total score of 8 and therefore would not be recommended to patients based on the grading rubric used in this study. This particular app provided sparse and sometimes inaccurate information, had a confusing user interface, and contained many obstructive advertisements. In contrast, the Eczema Doc app received a total score of 19, which indicates a quality app deemed to be useful for patient information based on the established rubric. This app met all the objectives that it advertised, contained accurate information with verified citation of sources, and was very easy for users to navigate.

Of the 44 graded apps, only 9 (20.5%) received scores in the highest range of 16 to 20, which indicates a need for improvements in mobile dermatology apps intended for patient education. Adopting the grading rubric developed in this study as a standard in the creation of medical apps could have beneficial implications in disseminating accurate, safe, unbiased, and easy-to-understand information to patients.

According to industry estimates, roughly 64% of US adults were smartphone users in 2015.1 Smartphones enable users to utilize mobile applications (apps) that can perform a variety of functions in many categories, including business, music, photography, entertainment, education, social networking, travel, and lifestyle. The widespread adoption and use of mobile apps has implications for medical practice. Mobile apps have the capability to serve as information sources for patients, educational tools for students, and diagnostic aids for physicians.2 Consequently, a number of medical and health care–oriented apps have already been developed3 and are increasingly utilized by patients and providers.4

Given its visual nature, dermatology is particularly amenable to the integration of mobile medical apps. A study by Brewer et al5 identified more than 229 dermatology-related apps in categories ranging from general dermatology reference, self-surveillance and diagnosis, disease guides, educational aids, sunscreen and UV recommendations, and teledermatology. Patients served as the target audience and principal consumers of more than half of these dermatology apps.5

Mobile medical and health care apps demonstrate great potential for serving as valuable information sources for patients with dermatologic conditions; however, the content, functions, accuracy, and educational value of dermatology mobile apps are not well characterized, making it difficult for patients and health care providers to select and recommend appropriate apps.6 In this study, we created a rubric to objectively grade 44 publicly available mobile dermatology apps with the primary focus of patient education.

Methods

We conducted a search of dermatology-related educational mobile apps that were publicly available via the App Store (Apple Inc) from January 2016 to November 2016. (The pricing, availability, and other features of these apps may have changed since the study period.) The following search terms were used: dermatology, dermoscopy, melanoma, skin cancer, psoriasis, rosacea, acne, eczema, dermal fillers, and Mohs surgery. We excluded apps that were not in English; had a solely commercial focus; were mobile textbooks or scientific journals; were used to provide teledermatology services with no educational purpose; were solely focused on homeopathic, alternative, and/or complementary medicine; or were intended primarily as a reference for students or health care professionals. Our search yielded 44 apps with patient education as a primary objective. The apps were divided into 6 categories based on their focus: general dermatology, cosmetic dermatology, acne, eczema, psoriasis, and skin cancer.

Each app was reviewed using a quantified grading rubric developed by the researchers. In a prior evaluation, Handel7 reviewed 35 health and wellness mobile apps utilizing the categories of ease of use, reliability, quality, scope of information, and aesthetics.4 These criteria were modified and adapted for the purposes of this study, and a 4-point scale was applied to each criterion. The final criteria were (1) educational objectives, (2) content, (3) accuracy, (4) design, and (5) conflict of interest. The quantified grading rubric is described in Table 1.

Results

The possible range of scores based on the grading rubric was 5 to 20. The actual range of scores was 8 to 19 (Table 2). The 44 reviewed apps were categorized by topic as acne, cosmetic dermatology, eczema, general dermatology, psoriasis, or skin cancer. A sample of 15 apps selected to represent the distribution of scores and their grading on the rubric are presented in Table 3.

Comment

The number of dermatology-related apps available to mobile users continues to grow at an increasing rate.8 The apps vary in many aspects, including their purpose, scope, intended audience, and goals of the app publisher. In turn, more individuals are turning to mobile apps for medical information,4 especially in dermatology, thus it is necessary to create a systematic way to evaluate the quality and utility of each app to assist users in making informed decisions about which apps will best meet their needs in the midst of a wide array of choices.

For the purpose of this study, an objective rubric was created that can be used to evaluate the quality of medical apps for patient education in dermatology. An app’s adequacy and usefulness for patient education was thought to depend on 3 possible score ranges into which the app could fall based on the grading rubric. An app with a total score in the range of 5 to 10 was not thought to be useful and may even be detrimental to patients. An app with a total score in the range of 11 to 15 may be used for patient education with some reservations based on shortcomings for certain criteria. An app with a score in the range of 16 to 20 was thought to be valuable and adequate for patient education. For example, the How to Treat Acne app received a total score of 8 and therefore would not be recommended to patients based on the grading rubric used in this study. This particular app provided sparse and sometimes inaccurate information, had a confusing user interface, and contained many obstructive advertisements. In contrast, the Eczema Doc app received a total score of 19, which indicates a quality app deemed to be useful for patient information based on the established rubric. This app met all the objectives that it advertised, contained accurate information with verified citation of sources, and was very easy for users to navigate.

Of the 44 graded apps, only 9 (20.5%) received scores in the highest range of 16 to 20, which indicates a need for improvements in mobile dermatology apps intended for patient education. Adopting the grading rubric developed in this study as a standard in the creation of medical apps could have beneficial implications in disseminating accurate, safe, unbiased, and easy-to-understand information to patients.

References
  1. Smith A. U.S. smartphone use in 2015. Pew Research Center website. http://www.pewinternet.org/2015/04/01/us-smartphone-use-in-2015. Published April 1, 2015. Accessed August 29, 2017.
  2. Nilsen W, Kumar S, Shar A, et al. Advancing the science of mHealth. J Health Commun. 2012;17(suppl 1):5-10.
  3. West DM. How mobile devices are transforming healthcare issues in technology innovation. Issues Technol Innov. 2012;18:1-14.
  4. Boudreaux ED, Waring ME, Hayes RB, et al. Evaluating and selecting mobile health apps: strategies for healthcare providers and healthcare organizations. Transl Behav Med. 2014;4:363-371.
  5. Brewer AC, Endly DC, Henley J, et al. Mobile applications in dermatology. JAMA Dermatol. 2013;149:1300-1304.
  6. Cummings E, Borycki E, Roehrer E. Issues and considerations for healthcare consumers using mobile applications. Stud Health Technol Inform. 2013;183:227-231.
  7. Handel MJ. mHealth (mobile health)-using apps for health and wellness. Explore. 2011;7:256-261.
  8. Boulos MN, Brewer AC, Karimkhani C, et al. Mobile medical and health apps: state of the art, concerns, regulatory control and certification. Online J Public Health Inform. 2014;5:229.
References
  1. Smith A. U.S. smartphone use in 2015. Pew Research Center website. http://www.pewinternet.org/2015/04/01/us-smartphone-use-in-2015. Published April 1, 2015. Accessed August 29, 2017.
  2. Nilsen W, Kumar S, Shar A, et al. Advancing the science of mHealth. J Health Commun. 2012;17(suppl 1):5-10.
  3. West DM. How mobile devices are transforming healthcare issues in technology innovation. Issues Technol Innov. 2012;18:1-14.
  4. Boudreaux ED, Waring ME, Hayes RB, et al. Evaluating and selecting mobile health apps: strategies for healthcare providers and healthcare organizations. Transl Behav Med. 2014;4:363-371.
  5. Brewer AC, Endly DC, Henley J, et al. Mobile applications in dermatology. JAMA Dermatol. 2013;149:1300-1304.
  6. Cummings E, Borycki E, Roehrer E. Issues and considerations for healthcare consumers using mobile applications. Stud Health Technol Inform. 2013;183:227-231.
  7. Handel MJ. mHealth (mobile health)-using apps for health and wellness. Explore. 2011;7:256-261.
  8. Boulos MN, Brewer AC, Karimkhani C, et al. Mobile medical and health apps: state of the art, concerns, regulatory control and certification. Online J Public Health Inform. 2014;5:229.
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  • Mobile dermatology apps for educational purposes should be objectively reviewed before being used by patients.
  • In our study, only 9 (20.5%) of the 44 dermatology apps evaluated were considered adequate for patient information based on our grading criteria.
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Neoadjuvant dabrafenib and trametinib improves event-free survival in resectable melanoma

Neoadjuvant data promising, role unclear
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For patients with surgically resectable, BRAF-mutated melanoma, neoadjuvant and adjuvant treatment with the combination of dabrafenib and trametinib resulted in significantly longer event-free survival compared with standard care, according to results of a randomized study.

The trial was closed early because of the “large difference” in event-free survival favoring the neoadjuvant approach, the authors wrote (Lancet Oncol. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9.

While early closure limits interpretation of results, they do provide important proof-of-concept and data for future studies, wrote the authors, led by Rodabe N Amaria, MD, of the department of medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The clinical and translational results strongly support the rationale for further assessment of neoadjuvant therapy in patients with high-risk, surgically resectable melanoma,” Dr. Amaria and colleagues said in the report on the randomized trial, believed to be the first to evaluate the role of neoadjuvant therapy versus standard care in BRAF-mutated melanoma.

Dabrafenib and trametinib combination therapy is approved as a treatment for patients with unresectable or metastatic stage IV melanoma and a BRAFV600 mutation, which is found in about half of cutaneous melanomas, authors said.

To evaluate the combination in earlier stage disease, Dr. Amaria and coinvestigators conducted a single-center, open-label, randomized, phase 2 trial of 21 patients with surgically resectable clinical stage III or oligometastatic stage IV melanoma with BRAFV600E or BRAFV600K mutations.

Patients were randomized 2:1 to receive the neoadjuvant/adjuvant treatment or to standard of care, which consisted of standard surgery plus consideration for adjuvant therapy, the authors said. Those patients assigned to the targeted therapy arm received 8 weeks of neoadjuvant dabrafenib and trametinib followed by surgery, then adjuvant dabrafenib and trametinib for up to 44 weeks.

Event-free survival, the primary endpoint of the trial, was a median of 19.7 months for neoadjuvant plus adjuvant dabrafenib and trametinib, versus 2.9 months for standard care (P less than .0001), the investigators reported.

Dabrafenib and trametinib combination therapy was well tolerated as neoadjuvant and adjuvant therapy, with no grade 4 adverse events or treatment related deaths, according to the investigators. The most common grade 3 adverse event seen with the combination was diarrhea, occurring in 2 patients (15%).

The trial is continuing as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.

Dr. Amaria and colleagues reported individual disclosures related to Merck, Bristol-Myers Squibb, Array Biopharma, and others, including Novartis Pharmaceuticals Corp., which supplied drugs and funded clinical aspects of the study.

SOURCE: Amaria et al. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9

Body

 

Although results of the study by Amaria et al. are “promising,” the role of neoadjuvant therapy in treatment of stage III–IV oligometastatic melanoma in clinical practice “is unclear for now,” melanoma specialists Paolo A. Ascierto, MD, and Alexander M. M. Eggermont, MD, PhD, wrote in an editorial.

Amaria et al. have presented results of the first randomized trial to evaluate neoadjuvant therapy versus standard care in patients with high-risk resectable BRAF-mutated melanoma.

Patients who received both neoadjuvant and adjuvant treatment with the dabrafenib/trametinib combination had superior event-free survival versus standard surgery and consideration for adjuvant therapy, published results show.

However, previous studies have already shown good results on this, that adjuvant dabrafenib plus trametinib (as well as nivolumab monotherapy) in this setting, “raising the question of whether a neoadjuvant approach is really needed, especially given a possible reduction of the role of surgery in the future,” Dr. Ascierto and Dr. Eggermont wrote.

Alternatively, adjuvant therapy with newer, more effective agents may be a “better way forward,” they said, noting that three patients in the trial by Amaria et al. who progressed after neoadjuvant/adjuvant dabrafenib and trametinib relapsed at first with brain metastases, raising the question of whether the treatment “might induce a resistant phenotype predisposed to the development of CNS metastases.”

That said, effectively combining neoadjuvant with adjuvant therapy could reduce the extent of surgery, make radiotherapy redundant, or increase distant metastasis-free survival and overall survival, among other benefits.

“The next generation of adjuvant trials should aim to address these outstanding questions,” they concluded.
 

Dr. Ascierto is with Istituto Nazionale Tumori Fondazione “G Pascale,” Napoli, Italy, and Dr. Eggermont is with Cancer Institute Gustave Roussy, University Paris-Sud, France. This commentary is based on their editorial appearing in The Lancet Oncology (2018 Jan 17. doi: 10.1016/S1470-2045[18]30016-0). The authors reported disclosures related to Novartis, Merck Serono, Bristol-Myers Squibb, Amgen, and others.

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Although results of the study by Amaria et al. are “promising,” the role of neoadjuvant therapy in treatment of stage III–IV oligometastatic melanoma in clinical practice “is unclear for now,” melanoma specialists Paolo A. Ascierto, MD, and Alexander M. M. Eggermont, MD, PhD, wrote in an editorial.

Amaria et al. have presented results of the first randomized trial to evaluate neoadjuvant therapy versus standard care in patients with high-risk resectable BRAF-mutated melanoma.

Patients who received both neoadjuvant and adjuvant treatment with the dabrafenib/trametinib combination had superior event-free survival versus standard surgery and consideration for adjuvant therapy, published results show.

However, previous studies have already shown good results on this, that adjuvant dabrafenib plus trametinib (as well as nivolumab monotherapy) in this setting, “raising the question of whether a neoadjuvant approach is really needed, especially given a possible reduction of the role of surgery in the future,” Dr. Ascierto and Dr. Eggermont wrote.

Alternatively, adjuvant therapy with newer, more effective agents may be a “better way forward,” they said, noting that three patients in the trial by Amaria et al. who progressed after neoadjuvant/adjuvant dabrafenib and trametinib relapsed at first with brain metastases, raising the question of whether the treatment “might induce a resistant phenotype predisposed to the development of CNS metastases.”

That said, effectively combining neoadjuvant with adjuvant therapy could reduce the extent of surgery, make radiotherapy redundant, or increase distant metastasis-free survival and overall survival, among other benefits.

“The next generation of adjuvant trials should aim to address these outstanding questions,” they concluded.
 

Dr. Ascierto is with Istituto Nazionale Tumori Fondazione “G Pascale,” Napoli, Italy, and Dr. Eggermont is with Cancer Institute Gustave Roussy, University Paris-Sud, France. This commentary is based on their editorial appearing in The Lancet Oncology (2018 Jan 17. doi: 10.1016/S1470-2045[18]30016-0). The authors reported disclosures related to Novartis, Merck Serono, Bristol-Myers Squibb, Amgen, and others.

Body

 

Although results of the study by Amaria et al. are “promising,” the role of neoadjuvant therapy in treatment of stage III–IV oligometastatic melanoma in clinical practice “is unclear for now,” melanoma specialists Paolo A. Ascierto, MD, and Alexander M. M. Eggermont, MD, PhD, wrote in an editorial.

Amaria et al. have presented results of the first randomized trial to evaluate neoadjuvant therapy versus standard care in patients with high-risk resectable BRAF-mutated melanoma.

Patients who received both neoadjuvant and adjuvant treatment with the dabrafenib/trametinib combination had superior event-free survival versus standard surgery and consideration for adjuvant therapy, published results show.

However, previous studies have already shown good results on this, that adjuvant dabrafenib plus trametinib (as well as nivolumab monotherapy) in this setting, “raising the question of whether a neoadjuvant approach is really needed, especially given a possible reduction of the role of surgery in the future,” Dr. Ascierto and Dr. Eggermont wrote.

Alternatively, adjuvant therapy with newer, more effective agents may be a “better way forward,” they said, noting that three patients in the trial by Amaria et al. who progressed after neoadjuvant/adjuvant dabrafenib and trametinib relapsed at first with brain metastases, raising the question of whether the treatment “might induce a resistant phenotype predisposed to the development of CNS metastases.”

That said, effectively combining neoadjuvant with adjuvant therapy could reduce the extent of surgery, make radiotherapy redundant, or increase distant metastasis-free survival and overall survival, among other benefits.

“The next generation of adjuvant trials should aim to address these outstanding questions,” they concluded.
 

Dr. Ascierto is with Istituto Nazionale Tumori Fondazione “G Pascale,” Napoli, Italy, and Dr. Eggermont is with Cancer Institute Gustave Roussy, University Paris-Sud, France. This commentary is based on their editorial appearing in The Lancet Oncology (2018 Jan 17. doi: 10.1016/S1470-2045[18]30016-0). The authors reported disclosures related to Novartis, Merck Serono, Bristol-Myers Squibb, Amgen, and others.

Title
Neoadjuvant data promising, role unclear
Neoadjuvant data promising, role unclear

 

For patients with surgically resectable, BRAF-mutated melanoma, neoadjuvant and adjuvant treatment with the combination of dabrafenib and trametinib resulted in significantly longer event-free survival compared with standard care, according to results of a randomized study.

The trial was closed early because of the “large difference” in event-free survival favoring the neoadjuvant approach, the authors wrote (Lancet Oncol. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9.

While early closure limits interpretation of results, they do provide important proof-of-concept and data for future studies, wrote the authors, led by Rodabe N Amaria, MD, of the department of medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The clinical and translational results strongly support the rationale for further assessment of neoadjuvant therapy in patients with high-risk, surgically resectable melanoma,” Dr. Amaria and colleagues said in the report on the randomized trial, believed to be the first to evaluate the role of neoadjuvant therapy versus standard care in BRAF-mutated melanoma.

Dabrafenib and trametinib combination therapy is approved as a treatment for patients with unresectable or metastatic stage IV melanoma and a BRAFV600 mutation, which is found in about half of cutaneous melanomas, authors said.

To evaluate the combination in earlier stage disease, Dr. Amaria and coinvestigators conducted a single-center, open-label, randomized, phase 2 trial of 21 patients with surgically resectable clinical stage III or oligometastatic stage IV melanoma with BRAFV600E or BRAFV600K mutations.

Patients were randomized 2:1 to receive the neoadjuvant/adjuvant treatment or to standard of care, which consisted of standard surgery plus consideration for adjuvant therapy, the authors said. Those patients assigned to the targeted therapy arm received 8 weeks of neoadjuvant dabrafenib and trametinib followed by surgery, then adjuvant dabrafenib and trametinib for up to 44 weeks.

Event-free survival, the primary endpoint of the trial, was a median of 19.7 months for neoadjuvant plus adjuvant dabrafenib and trametinib, versus 2.9 months for standard care (P less than .0001), the investigators reported.

Dabrafenib and trametinib combination therapy was well tolerated as neoadjuvant and adjuvant therapy, with no grade 4 adverse events or treatment related deaths, according to the investigators. The most common grade 3 adverse event seen with the combination was diarrhea, occurring in 2 patients (15%).

The trial is continuing as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.

Dr. Amaria and colleagues reported individual disclosures related to Merck, Bristol-Myers Squibb, Array Biopharma, and others, including Novartis Pharmaceuticals Corp., which supplied drugs and funded clinical aspects of the study.

SOURCE: Amaria et al. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9

 

For patients with surgically resectable, BRAF-mutated melanoma, neoadjuvant and adjuvant treatment with the combination of dabrafenib and trametinib resulted in significantly longer event-free survival compared with standard care, according to results of a randomized study.

The trial was closed early because of the “large difference” in event-free survival favoring the neoadjuvant approach, the authors wrote (Lancet Oncol. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9.

While early closure limits interpretation of results, they do provide important proof-of-concept and data for future studies, wrote the authors, led by Rodabe N Amaria, MD, of the department of medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The clinical and translational results strongly support the rationale for further assessment of neoadjuvant therapy in patients with high-risk, surgically resectable melanoma,” Dr. Amaria and colleagues said in the report on the randomized trial, believed to be the first to evaluate the role of neoadjuvant therapy versus standard care in BRAF-mutated melanoma.

Dabrafenib and trametinib combination therapy is approved as a treatment for patients with unresectable or metastatic stage IV melanoma and a BRAFV600 mutation, which is found in about half of cutaneous melanomas, authors said.

To evaluate the combination in earlier stage disease, Dr. Amaria and coinvestigators conducted a single-center, open-label, randomized, phase 2 trial of 21 patients with surgically resectable clinical stage III or oligometastatic stage IV melanoma with BRAFV600E or BRAFV600K mutations.

Patients were randomized 2:1 to receive the neoadjuvant/adjuvant treatment or to standard of care, which consisted of standard surgery plus consideration for adjuvant therapy, the authors said. Those patients assigned to the targeted therapy arm received 8 weeks of neoadjuvant dabrafenib and trametinib followed by surgery, then adjuvant dabrafenib and trametinib for up to 44 weeks.

Event-free survival, the primary endpoint of the trial, was a median of 19.7 months for neoadjuvant plus adjuvant dabrafenib and trametinib, versus 2.9 months for standard care (P less than .0001), the investigators reported.

Dabrafenib and trametinib combination therapy was well tolerated as neoadjuvant and adjuvant therapy, with no grade 4 adverse events or treatment related deaths, according to the investigators. The most common grade 3 adverse event seen with the combination was diarrhea, occurring in 2 patients (15%).

The trial is continuing as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.

Dr. Amaria and colleagues reported individual disclosures related to Merck, Bristol-Myers Squibb, Array Biopharma, and others, including Novartis Pharmaceuticals Corp., which supplied drugs and funded clinical aspects of the study.

SOURCE: Amaria et al. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9

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Key clinical point: In patients with high-risk, surgically resectable, clinical stage III-IV melanoma, dabrafenib and trametinib given in both the neoadjuvant and adjuvant setting improved event-free survival compared with standard care.

Major finding: Median event-free survival was 19.7 months for neoadjuvant/adjuvant dabrafenib and trametinib versus 2.9 months for standard upfront surgery including consideration for standard adjuvant therapy (P less than .0001).

Data source: A single-center, open-label, randomized, phase 2 trial including 21 patients with surgically resectable clinical stage III or oligometastatic stage IV BRAF-mutated melanoma.

Disclosures: Investigators reported ties to Novartis Pharmaceuticals Corp., which supplied drugs and funded clinical aspects of the study, and disclosures related to Merck, Bristol-Myers Squibb, Array Biopharma, and others.

Source: Amaria et al. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9.

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Supportive oncodermatology: Cancer advances spawn new subspecialty

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Not too long ago at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, a woman with widely metastatic melanoma, who had been planning her own funeral, was surprised when she had a phenomenal response to immunotherapy.

She was shocked to learn that her cancer was almost completely gone after 12 weeks, but she was stunned when she developed a rash that made her oncologist think she needed to stop treatment.

Courtesy Dr. Jennifer Choi
To be certain, though, he paged a dermatologist working in the cancer center who quickly determined that the rash was treatment-related psoriasis and not life threatening. Phototherapy, topical steroids, and apremilast (Otezla) did the trick. “We got her psoriasis under control so that she was able to stay on her immunotherapy, which had saved her life,” said dermatologist Nicole LeBoeuf, MD, who is the director the Skin Toxicities from Anticancer Therapies Clinic at the cancer center and was involved with the case. Stories like that are why a new subspecialty – supportive oncodermatology – is emerging within the field of dermatology and why oncodermatologists are likely to become more common in cancer centers nationwide in the not-too-distant future.

With traditional cytotoxic chemotherapies, there were a few well-defined skin side effects that oncologists were comfortable managing on their own with steroids or by reducing or stopping treatment for a bit.

But over the last decade, new cancer options have become available, most notably immunotherapies and targeted biologics, which are keeping some people alive longer but also causing cutaneous side effects that have never been seen before in oncology and are being reported frequently.
 

An urgent need

Dr. Nicole LeBoeuf
As cancer treatment becomes more complex, oncologists are discovering that it helps to have a dermatologist on hand who can recognize and manage these problems and decide whether treatment needs to be stopped.

Currently in the United States, there’s only a handful of dedicated supportive oncodermatology services, which can be found at major academic cancer centers such as Dana-Farber/Brigham and Women’s, but the residents and fellows being trained at these centers are starting to fan out across the country and set up new services.

One day, it’s likely that every major cancer institution will have “a toxicities team with expert dermatologists,” said Dr. LeBoeuf, who launched the supportive oncodermatology program at Dana-Farber in 2014 and who now runs it with a team of dermatologists and clinics every week. Dr. LeBoeuf is a leader in the field, like the other dermatologists interviewed for this story.

With all the new treatments and with even more on the way, “there’s an urgent need for dermatologists to be involved in care of cancer patients,” Dr. LeBoeuf said.
 

The problem

Dr. Bernice Kwong
Newer treatments have made cancer less lethal in some cases, but almost all of their targets also play a role in the skin, and that causes problems.

Immunotherapies like the PD-1 blocking agents pembrolizumab (Keytruda) and nivolumab (Opdivo) – both used for an ever-expanding list of tumors – amp up the immune system to fight cancer, but they also tend to cause adverse events that mimic autoimmune diseases such as lupus, psoriasis, lichen planus, and vitiligo. Dermatologists are familiar with those problems and how to manage them, but oncologists generally are not.

Meanwhile, the many targeted therapies approved over the past decade interfere with specific molecules needed for tumor growth, but they also are associated with a wide range of skin, hair, and nail side effects that include skin growths, itching, paronychia, and more.

Agents that target vascular endothelial growth factors, such as sorafenib (Nexavar) and bevacizumab (Avastin), can trigger a painful hand-foot skin reaction that’s different from the hand-foot syndrome reported with older cytotoxic agents.

Epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib (Tarceva) or gefitinib (Iressa), often cause miserable acne-like eruptions, but that can mean the drug is working.

It’s hard for oncologists to know what’s life-threatening and what isn’t; that’s where dermatologists come in.

A solution

Dr. Jennifer Choi
“There needs to be specialists who recognize what is happening. It’s not just about helping patients feel better, although that’s a huge component; it’s also about helping decide what their future care will be. Unless you see these reactions a lot, you will not have any idea what you are looking at,” said Jennifer Choi, MD chief of the division of oncodermatology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

When problems come up, oncologists and patients need answers right away, she said. There’s no time to wait a month or two for a dermatology appointment to find out whether, for instance, a new mouth ulcer is a minor inconvenience or the first sign of Stevens-Johnson syndrome, and the last thing an exhausted cancer patient needs is to be told to go to yet another clinic for a dermatology consult.

For supportive oncodermatology, that means being where the patients are: in the cancer centers. “Our clinic is situated on the same cancer floor as all the other oncology clinics,” which means easy access for both patients and oncologists, Dr. Choi said. “They just come down the hall.”
 

 

Build it, and they will come

The Stanford (Calif.) Cancer Center is a good example of what happens once a supportive oncodermatology service is up and running.

The program there was the brainchild of dermatologist Bernice Kwong, MD, who helped launch it in 2012 with 2 half-day outpatient clinics per week.

“Once people knew we were there seeing patients, we needed to expand it to 3 half days, and within 6 months, we knew we had to be” in the cancer center daily, she said. “The oncologists felt we were helping them keep their patients on treatment longer; they didn’t have to stop therapy to sort out a rash.”

Currently, the clinic sees about 15 to 20 patients a day, but “we have more need than that,” said Dr. Kwong, who is trying to recruit more dermatologists to help.

“The need is huge. There’s so much room for growth,” she noted, but first, “you need the oncologists to be on board.”

Dermatologist Adam Friedman, MD, director of supportive oncodermatology at the George Washington University Cancer Center, Washington, says his program is on the other end of the growth curve since it was only launched in the spring of 2017. Only about 80 patients have been treated so far, and there’s one dedicated clinic day a month, although he is on call for urgent cases, as is the case for many of the other dermatologists interviewed for this story.

Dr. Adam Friedman
“The struggle has been getting oncologists to remember to send us their patients,” Dr. Friedman said. It would be preferable to do referrals before treatment, too, he added, because “we are starting to see that if we pretreat these patients, we can limit or even prevent their rashes altogether.” The acne-like eruptions with EGFR inhibitors are a good example. “If you pretreat a week or two beforehand with doxycycline, a topical steroid, moisturizer, and sun protection, you can actually prevent them,” he noted.

Dr. Friedman expects business will pick up soon once word gets out, just like at Dana-Farber/Brigham and Women’s, Stanford, and elsewhere. “The places with the greatest need are going to have these services first, and then you’ll see them pop up elsewhere. I think we are going to see more,” he said.
 

The birth of supportive oncodermatology

Dermatologist Mario Lacouture, MD, director of the oncodermatology program at Memorial Sloan Kettering Cancer Center, New York, is considered by many oncodermatologists to be the father of the field.

He started the very first program in 2005 at Northwestern University, Chicago, followed by the program at Sloan Kettering a few years later. He has helped train many of the leaders in the field and coined the phrase “supportive oncodermatology” as the senior author in the field’s seminal paper, published in 2011 (J Am Acad Dermatol. 2011 Sep;65[3]:624-35). That article, in turn, inspired at least a few young dermatologists to make supportive oncodermatology their career choice. Dr. Lacouture speaks regularly at oncology and dermatology meetings to raise awareness about how dermatologists can improve cancer care.

Dr. Mario Lacouture
His own awareness started when he was a dermatology resident at the University of Chicago; a mentor took him on oncology calls to see cancer patients with skin problems. “In many cases, the anticancer drugs keeping these people alive were being stopped because of skin problems that we, as dermatologists, could have treated relatively easily. I realized that there had to be something we could do so these patients could stay on their drugs and also have a better quality of life,” he said.

Cancer survivors were also a concern. “Cancer treatment has improved so much that people are living longer, but the majority of survivors have either temporary or permanent cutaneous problems that would benefit from dermatologic care. However, the oncology community and patients are usually not aware that there are things we can do to help,” Dr. Lacouture said.

The message seems to have gotten out, however, among the hundreds of oncologists affiliated with Sloan Kettering. Dr. Lacouture needs a team of supportive oncodermatologists to meet the demand, with walk-in clinics every day and round-the-clock call.

He anticipates a day when visiting a supportive oncodermatologist will be routine, even before the start of cancer treatment, just as people visit a dentist before bone marrow transplants or radiation treatment to the head and neck. The idea would be to prevent cutaneous toxicity, something Dr. Lacouture and his team are already doing at Sloan Kettering. In time, supportive oncodermatology “is something that is going to be instituted early on” in treatment, he said.

“It’s important for dermatologists to reach out to their local oncologists; they will see there are many, many cancer patients and survivors who would benefit immensely from their care,” he said.

Dr. Lacouture is a consultant for Galderma, Janssen, and Johnson & Johnson. The other dermatologists interviewed for this story had no relevant industry disclosures. La Roche-Posay, a subsidiary of L’Oreal, is helping fund the supportive oncodermatology program at George Washington University. The company is interested in using cosmetics to camouflage cancer treatment skin lesions, Dr. Friedman said. Dr. Friedman is a member of the Dermatology News advisory board.

aotto@frontlinemedcom.com






 
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Not too long ago at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, a woman with widely metastatic melanoma, who had been planning her own funeral, was surprised when she had a phenomenal response to immunotherapy.

She was shocked to learn that her cancer was almost completely gone after 12 weeks, but she was stunned when she developed a rash that made her oncologist think she needed to stop treatment.

Courtesy Dr. Jennifer Choi
To be certain, though, he paged a dermatologist working in the cancer center who quickly determined that the rash was treatment-related psoriasis and not life threatening. Phototherapy, topical steroids, and apremilast (Otezla) did the trick. “We got her psoriasis under control so that she was able to stay on her immunotherapy, which had saved her life,” said dermatologist Nicole LeBoeuf, MD, who is the director the Skin Toxicities from Anticancer Therapies Clinic at the cancer center and was involved with the case. Stories like that are why a new subspecialty – supportive oncodermatology – is emerging within the field of dermatology and why oncodermatologists are likely to become more common in cancer centers nationwide in the not-too-distant future.

With traditional cytotoxic chemotherapies, there were a few well-defined skin side effects that oncologists were comfortable managing on their own with steroids or by reducing or stopping treatment for a bit.

But over the last decade, new cancer options have become available, most notably immunotherapies and targeted biologics, which are keeping some people alive longer but also causing cutaneous side effects that have never been seen before in oncology and are being reported frequently.
 

An urgent need

Dr. Nicole LeBoeuf
As cancer treatment becomes more complex, oncologists are discovering that it helps to have a dermatologist on hand who can recognize and manage these problems and decide whether treatment needs to be stopped.

Currently in the United States, there’s only a handful of dedicated supportive oncodermatology services, which can be found at major academic cancer centers such as Dana-Farber/Brigham and Women’s, but the residents and fellows being trained at these centers are starting to fan out across the country and set up new services.

One day, it’s likely that every major cancer institution will have “a toxicities team with expert dermatologists,” said Dr. LeBoeuf, who launched the supportive oncodermatology program at Dana-Farber in 2014 and who now runs it with a team of dermatologists and clinics every week. Dr. LeBoeuf is a leader in the field, like the other dermatologists interviewed for this story.

With all the new treatments and with even more on the way, “there’s an urgent need for dermatologists to be involved in care of cancer patients,” Dr. LeBoeuf said.
 

The problem

Dr. Bernice Kwong
Newer treatments have made cancer less lethal in some cases, but almost all of their targets also play a role in the skin, and that causes problems.

Immunotherapies like the PD-1 blocking agents pembrolizumab (Keytruda) and nivolumab (Opdivo) – both used for an ever-expanding list of tumors – amp up the immune system to fight cancer, but they also tend to cause adverse events that mimic autoimmune diseases such as lupus, psoriasis, lichen planus, and vitiligo. Dermatologists are familiar with those problems and how to manage them, but oncologists generally are not.

Meanwhile, the many targeted therapies approved over the past decade interfere with specific molecules needed for tumor growth, but they also are associated with a wide range of skin, hair, and nail side effects that include skin growths, itching, paronychia, and more.

Agents that target vascular endothelial growth factors, such as sorafenib (Nexavar) and bevacizumab (Avastin), can trigger a painful hand-foot skin reaction that’s different from the hand-foot syndrome reported with older cytotoxic agents.

Epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib (Tarceva) or gefitinib (Iressa), often cause miserable acne-like eruptions, but that can mean the drug is working.

It’s hard for oncologists to know what’s life-threatening and what isn’t; that’s where dermatologists come in.

A solution

Dr. Jennifer Choi
“There needs to be specialists who recognize what is happening. It’s not just about helping patients feel better, although that’s a huge component; it’s also about helping decide what their future care will be. Unless you see these reactions a lot, you will not have any idea what you are looking at,” said Jennifer Choi, MD chief of the division of oncodermatology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

When problems come up, oncologists and patients need answers right away, she said. There’s no time to wait a month or two for a dermatology appointment to find out whether, for instance, a new mouth ulcer is a minor inconvenience or the first sign of Stevens-Johnson syndrome, and the last thing an exhausted cancer patient needs is to be told to go to yet another clinic for a dermatology consult.

For supportive oncodermatology, that means being where the patients are: in the cancer centers. “Our clinic is situated on the same cancer floor as all the other oncology clinics,” which means easy access for both patients and oncologists, Dr. Choi said. “They just come down the hall.”
 

 

Build it, and they will come

The Stanford (Calif.) Cancer Center is a good example of what happens once a supportive oncodermatology service is up and running.

The program there was the brainchild of dermatologist Bernice Kwong, MD, who helped launch it in 2012 with 2 half-day outpatient clinics per week.

“Once people knew we were there seeing patients, we needed to expand it to 3 half days, and within 6 months, we knew we had to be” in the cancer center daily, she said. “The oncologists felt we were helping them keep their patients on treatment longer; they didn’t have to stop therapy to sort out a rash.”

Currently, the clinic sees about 15 to 20 patients a day, but “we have more need than that,” said Dr. Kwong, who is trying to recruit more dermatologists to help.

“The need is huge. There’s so much room for growth,” she noted, but first, “you need the oncologists to be on board.”

Dermatologist Adam Friedman, MD, director of supportive oncodermatology at the George Washington University Cancer Center, Washington, says his program is on the other end of the growth curve since it was only launched in the spring of 2017. Only about 80 patients have been treated so far, and there’s one dedicated clinic day a month, although he is on call for urgent cases, as is the case for many of the other dermatologists interviewed for this story.

Dr. Adam Friedman
“The struggle has been getting oncologists to remember to send us their patients,” Dr. Friedman said. It would be preferable to do referrals before treatment, too, he added, because “we are starting to see that if we pretreat these patients, we can limit or even prevent their rashes altogether.” The acne-like eruptions with EGFR inhibitors are a good example. “If you pretreat a week or two beforehand with doxycycline, a topical steroid, moisturizer, and sun protection, you can actually prevent them,” he noted.

Dr. Friedman expects business will pick up soon once word gets out, just like at Dana-Farber/Brigham and Women’s, Stanford, and elsewhere. “The places with the greatest need are going to have these services first, and then you’ll see them pop up elsewhere. I think we are going to see more,” he said.
 

The birth of supportive oncodermatology

Dermatologist Mario Lacouture, MD, director of the oncodermatology program at Memorial Sloan Kettering Cancer Center, New York, is considered by many oncodermatologists to be the father of the field.

He started the very first program in 2005 at Northwestern University, Chicago, followed by the program at Sloan Kettering a few years later. He has helped train many of the leaders in the field and coined the phrase “supportive oncodermatology” as the senior author in the field’s seminal paper, published in 2011 (J Am Acad Dermatol. 2011 Sep;65[3]:624-35). That article, in turn, inspired at least a few young dermatologists to make supportive oncodermatology their career choice. Dr. Lacouture speaks regularly at oncology and dermatology meetings to raise awareness about how dermatologists can improve cancer care.

Dr. Mario Lacouture
His own awareness started when he was a dermatology resident at the University of Chicago; a mentor took him on oncology calls to see cancer patients with skin problems. “In many cases, the anticancer drugs keeping these people alive were being stopped because of skin problems that we, as dermatologists, could have treated relatively easily. I realized that there had to be something we could do so these patients could stay on their drugs and also have a better quality of life,” he said.

Cancer survivors were also a concern. “Cancer treatment has improved so much that people are living longer, but the majority of survivors have either temporary or permanent cutaneous problems that would benefit from dermatologic care. However, the oncology community and patients are usually not aware that there are things we can do to help,” Dr. Lacouture said.

The message seems to have gotten out, however, among the hundreds of oncologists affiliated with Sloan Kettering. Dr. Lacouture needs a team of supportive oncodermatologists to meet the demand, with walk-in clinics every day and round-the-clock call.

He anticipates a day when visiting a supportive oncodermatologist will be routine, even before the start of cancer treatment, just as people visit a dentist before bone marrow transplants or radiation treatment to the head and neck. The idea would be to prevent cutaneous toxicity, something Dr. Lacouture and his team are already doing at Sloan Kettering. In time, supportive oncodermatology “is something that is going to be instituted early on” in treatment, he said.

“It’s important for dermatologists to reach out to their local oncologists; they will see there are many, many cancer patients and survivors who would benefit immensely from their care,” he said.

Dr. Lacouture is a consultant for Galderma, Janssen, and Johnson & Johnson. The other dermatologists interviewed for this story had no relevant industry disclosures. La Roche-Posay, a subsidiary of L’Oreal, is helping fund the supportive oncodermatology program at George Washington University. The company is interested in using cosmetics to camouflage cancer treatment skin lesions, Dr. Friedman said. Dr. Friedman is a member of the Dermatology News advisory board.

aotto@frontlinemedcom.com






 

 

Not too long ago at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, a woman with widely metastatic melanoma, who had been planning her own funeral, was surprised when she had a phenomenal response to immunotherapy.

She was shocked to learn that her cancer was almost completely gone after 12 weeks, but she was stunned when she developed a rash that made her oncologist think she needed to stop treatment.

Courtesy Dr. Jennifer Choi
To be certain, though, he paged a dermatologist working in the cancer center who quickly determined that the rash was treatment-related psoriasis and not life threatening. Phototherapy, topical steroids, and apremilast (Otezla) did the trick. “We got her psoriasis under control so that she was able to stay on her immunotherapy, which had saved her life,” said dermatologist Nicole LeBoeuf, MD, who is the director the Skin Toxicities from Anticancer Therapies Clinic at the cancer center and was involved with the case. Stories like that are why a new subspecialty – supportive oncodermatology – is emerging within the field of dermatology and why oncodermatologists are likely to become more common in cancer centers nationwide in the not-too-distant future.

With traditional cytotoxic chemotherapies, there were a few well-defined skin side effects that oncologists were comfortable managing on their own with steroids or by reducing or stopping treatment for a bit.

But over the last decade, new cancer options have become available, most notably immunotherapies and targeted biologics, which are keeping some people alive longer but also causing cutaneous side effects that have never been seen before in oncology and are being reported frequently.
 

An urgent need

Dr. Nicole LeBoeuf
As cancer treatment becomes more complex, oncologists are discovering that it helps to have a dermatologist on hand who can recognize and manage these problems and decide whether treatment needs to be stopped.

Currently in the United States, there’s only a handful of dedicated supportive oncodermatology services, which can be found at major academic cancer centers such as Dana-Farber/Brigham and Women’s, but the residents and fellows being trained at these centers are starting to fan out across the country and set up new services.

One day, it’s likely that every major cancer institution will have “a toxicities team with expert dermatologists,” said Dr. LeBoeuf, who launched the supportive oncodermatology program at Dana-Farber in 2014 and who now runs it with a team of dermatologists and clinics every week. Dr. LeBoeuf is a leader in the field, like the other dermatologists interviewed for this story.

With all the new treatments and with even more on the way, “there’s an urgent need for dermatologists to be involved in care of cancer patients,” Dr. LeBoeuf said.
 

The problem

Dr. Bernice Kwong
Newer treatments have made cancer less lethal in some cases, but almost all of their targets also play a role in the skin, and that causes problems.

Immunotherapies like the PD-1 blocking agents pembrolizumab (Keytruda) and nivolumab (Opdivo) – both used for an ever-expanding list of tumors – amp up the immune system to fight cancer, but they also tend to cause adverse events that mimic autoimmune diseases such as lupus, psoriasis, lichen planus, and vitiligo. Dermatologists are familiar with those problems and how to manage them, but oncologists generally are not.

Meanwhile, the many targeted therapies approved over the past decade interfere with specific molecules needed for tumor growth, but they also are associated with a wide range of skin, hair, and nail side effects that include skin growths, itching, paronychia, and more.

Agents that target vascular endothelial growth factors, such as sorafenib (Nexavar) and bevacizumab (Avastin), can trigger a painful hand-foot skin reaction that’s different from the hand-foot syndrome reported with older cytotoxic agents.

Epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib (Tarceva) or gefitinib (Iressa), often cause miserable acne-like eruptions, but that can mean the drug is working.

It’s hard for oncologists to know what’s life-threatening and what isn’t; that’s where dermatologists come in.

A solution

Dr. Jennifer Choi
“There needs to be specialists who recognize what is happening. It’s not just about helping patients feel better, although that’s a huge component; it’s also about helping decide what their future care will be. Unless you see these reactions a lot, you will not have any idea what you are looking at,” said Jennifer Choi, MD chief of the division of oncodermatology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

When problems come up, oncologists and patients need answers right away, she said. There’s no time to wait a month or two for a dermatology appointment to find out whether, for instance, a new mouth ulcer is a minor inconvenience or the first sign of Stevens-Johnson syndrome, and the last thing an exhausted cancer patient needs is to be told to go to yet another clinic for a dermatology consult.

For supportive oncodermatology, that means being where the patients are: in the cancer centers. “Our clinic is situated on the same cancer floor as all the other oncology clinics,” which means easy access for both patients and oncologists, Dr. Choi said. “They just come down the hall.”
 

 

Build it, and they will come

The Stanford (Calif.) Cancer Center is a good example of what happens once a supportive oncodermatology service is up and running.

The program there was the brainchild of dermatologist Bernice Kwong, MD, who helped launch it in 2012 with 2 half-day outpatient clinics per week.

“Once people knew we were there seeing patients, we needed to expand it to 3 half days, and within 6 months, we knew we had to be” in the cancer center daily, she said. “The oncologists felt we were helping them keep their patients on treatment longer; they didn’t have to stop therapy to sort out a rash.”

Currently, the clinic sees about 15 to 20 patients a day, but “we have more need than that,” said Dr. Kwong, who is trying to recruit more dermatologists to help.

“The need is huge. There’s so much room for growth,” she noted, but first, “you need the oncologists to be on board.”

Dermatologist Adam Friedman, MD, director of supportive oncodermatology at the George Washington University Cancer Center, Washington, says his program is on the other end of the growth curve since it was only launched in the spring of 2017. Only about 80 patients have been treated so far, and there’s one dedicated clinic day a month, although he is on call for urgent cases, as is the case for many of the other dermatologists interviewed for this story.

Dr. Adam Friedman
“The struggle has been getting oncologists to remember to send us their patients,” Dr. Friedman said. It would be preferable to do referrals before treatment, too, he added, because “we are starting to see that if we pretreat these patients, we can limit or even prevent their rashes altogether.” The acne-like eruptions with EGFR inhibitors are a good example. “If you pretreat a week or two beforehand with doxycycline, a topical steroid, moisturizer, and sun protection, you can actually prevent them,” he noted.

Dr. Friedman expects business will pick up soon once word gets out, just like at Dana-Farber/Brigham and Women’s, Stanford, and elsewhere. “The places with the greatest need are going to have these services first, and then you’ll see them pop up elsewhere. I think we are going to see more,” he said.
 

The birth of supportive oncodermatology

Dermatologist Mario Lacouture, MD, director of the oncodermatology program at Memorial Sloan Kettering Cancer Center, New York, is considered by many oncodermatologists to be the father of the field.

He started the very first program in 2005 at Northwestern University, Chicago, followed by the program at Sloan Kettering a few years later. He has helped train many of the leaders in the field and coined the phrase “supportive oncodermatology” as the senior author in the field’s seminal paper, published in 2011 (J Am Acad Dermatol. 2011 Sep;65[3]:624-35). That article, in turn, inspired at least a few young dermatologists to make supportive oncodermatology their career choice. Dr. Lacouture speaks regularly at oncology and dermatology meetings to raise awareness about how dermatologists can improve cancer care.

Dr. Mario Lacouture
His own awareness started when he was a dermatology resident at the University of Chicago; a mentor took him on oncology calls to see cancer patients with skin problems. “In many cases, the anticancer drugs keeping these people alive were being stopped because of skin problems that we, as dermatologists, could have treated relatively easily. I realized that there had to be something we could do so these patients could stay on their drugs and also have a better quality of life,” he said.

Cancer survivors were also a concern. “Cancer treatment has improved so much that people are living longer, but the majority of survivors have either temporary or permanent cutaneous problems that would benefit from dermatologic care. However, the oncology community and patients are usually not aware that there are things we can do to help,” Dr. Lacouture said.

The message seems to have gotten out, however, among the hundreds of oncologists affiliated with Sloan Kettering. Dr. Lacouture needs a team of supportive oncodermatologists to meet the demand, with walk-in clinics every day and round-the-clock call.

He anticipates a day when visiting a supportive oncodermatologist will be routine, even before the start of cancer treatment, just as people visit a dentist before bone marrow transplants or radiation treatment to the head and neck. The idea would be to prevent cutaneous toxicity, something Dr. Lacouture and his team are already doing at Sloan Kettering. In time, supportive oncodermatology “is something that is going to be instituted early on” in treatment, he said.

“It’s important for dermatologists to reach out to their local oncologists; they will see there are many, many cancer patients and survivors who would benefit immensely from their care,” he said.

Dr. Lacouture is a consultant for Galderma, Janssen, and Johnson & Johnson. The other dermatologists interviewed for this story had no relevant industry disclosures. La Roche-Posay, a subsidiary of L’Oreal, is helping fund the supportive oncodermatology program at George Washington University. The company is interested in using cosmetics to camouflage cancer treatment skin lesions, Dr. Friedman said. Dr. Friedman is a member of the Dermatology News advisory board.

aotto@frontlinemedcom.com






 
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Sentinel node biopsy: Who needs it?

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More than 17 years ago, I published an article that was largely ignored, predicating that patient benefit from the sentinel node biopsy procedure was unlikely.

I asserted that the lymph nodes are not a reliable filter for melanoma cells, lymphatic drainage is capricious, and many individuals (especially younger ones) have benign neval rests in their lymph nodes that cannot be distinguished from melanoma deposits, since they are both positive for the S100 protein (Int J Dermatol. 2000 Nov;39[11]:807-11). In addition, multiple uncontrolled studies had shown that locating sentinel nodes, followed by a complete lymph node dissection, had no survival benefit. At the time, I argued that sentinel node biopsy should be performed only if the patient was going to be enrolled in a clinical study.

Dr. Brett M. Coldiron
The sentinel node biopsy train roared on, justified by adjunctive interferon therapy. But after 15 years of studies, the adverse effects of interferon, and the lack of benefit from biopsy for melanoma patients have become apparent. A few months ago, it was definitively shown that completion lymph node dissection after a positive sentinel node finding added no survival benefit (N Engl J Med. 2017 Jun 8;376[23]:2211-22).

Many surgical oncologists have built their careers around the flawed premise that removing the draining nodes would cure melanoma. It doesn’t. It is past time to admit it and move on.

So, if completion node dissection does not save lives, why do a sentinel node biopsy? I recently asked a dermatologist friend, who is a committed acolyte of the sentinel node biopsy school, why he continues to recommend sentinel node biopsy if there is no benefit from complete node dissection. His quick response was that patients want to know if they are at higher risk of metastatic disease so that they can be followed closely with high-resolution ultrasound at a major cancer center and can be eligible for clinical trials. His reply gave me pause, so I asked why completion node dissection was still being recommended. I was told that some patients with positive sentinel nodes lived far away, and if they would not make regular follow-up visits for high-resolution ultrasound, the surgical oncologists do completion node dissection to ensure “local nodal control.” Yipes! You’re going to rip my groin out because I like quiet county living?

I doubt that patients would be enthusiastic if told beforehand that sentinel node biopsies costs $14,000-$18,000, and has a 9% complication rate, and one-third of those patients who have complications end up with permanent lymphedema. I wondered if the patients were told they could have a genetic test done on their already excised melanoma tissue that would tell them if they were in a high-risk group without having an additional invasive surgical procedure. I wondered if they were told that 10%-30% of people with negative sentinel nodes go on to develop metastatic disease. I also wondered if they had been told they would have to walk around with their melanoma, which could spread at any time, for several additional weeks, while waiting for the results of their sentinel node biopsy, instead of having the melanoma immediately removed by their dermatologist. I also wondered if they had been told that high-resolution ultrasound has not definitively been shown to be superior to clinical palpation of the lymph nodes.

I looked into the possibility of clinical trials for patients with positive sentinel nodes, as well. Based on my search of clinical trials.gov in January, there are 33 trials in the United States studying patients with stage 3 (positive sentinel node) or greater disease. If I had a positive sentinel node, I would look for a study in which I had a chance of getting nivolumab, which recently has been shown to be superior to ipilimumab in the phase 3 Checkmate 238 trial published in 2017 (N Engl J Med 2017 Nov 9; 377:1824-35).

But I am getting ahead of myself.

As a thinking man, if I had a thick melanoma (that was less than 2 mm), I would opt for a genetic test of my already excised melanoma tissue. If the results of that genetic test (which has near identical sensitivity and specificity for developing metastatic disease as a sentinel node) put me in the low-risk group, I would pass on the sentinel node biopsy. This would eliminate a lot of unnecessary surgery. If I fell into the high-risk group, I would consider a sentinel node biopsy so I could get into a study, or determine if I needed to find a way to get my insurance to pay, or if I could personally afford nivolumab. Even if I opted not to take the drug, because of the potential risk of high-grade side effects, the high-risk genetic profile tells me I would still need more frequent follow-up.

These are exciting times. I am looking forward to clinical trials that allow a patient with a high-risk genetic profile to go directly into a trial. We are moving into the realm of individualized genomic medicine in which metastatic melanoma truly becomes a curable disease.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Dr. Coldiron has no financial or other conflicts of interest with Castle Biosciences, the manufacturer of the DecisionDx-Melanoma genetic expression profile test. Email him at dermnews@frontlinemedcom.com.

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More than 17 years ago, I published an article that was largely ignored, predicating that patient benefit from the sentinel node biopsy procedure was unlikely.

I asserted that the lymph nodes are not a reliable filter for melanoma cells, lymphatic drainage is capricious, and many individuals (especially younger ones) have benign neval rests in their lymph nodes that cannot be distinguished from melanoma deposits, since they are both positive for the S100 protein (Int J Dermatol. 2000 Nov;39[11]:807-11). In addition, multiple uncontrolled studies had shown that locating sentinel nodes, followed by a complete lymph node dissection, had no survival benefit. At the time, I argued that sentinel node biopsy should be performed only if the patient was going to be enrolled in a clinical study.

Dr. Brett M. Coldiron
The sentinel node biopsy train roared on, justified by adjunctive interferon therapy. But after 15 years of studies, the adverse effects of interferon, and the lack of benefit from biopsy for melanoma patients have become apparent. A few months ago, it was definitively shown that completion lymph node dissection after a positive sentinel node finding added no survival benefit (N Engl J Med. 2017 Jun 8;376[23]:2211-22).

Many surgical oncologists have built their careers around the flawed premise that removing the draining nodes would cure melanoma. It doesn’t. It is past time to admit it and move on.

So, if completion node dissection does not save lives, why do a sentinel node biopsy? I recently asked a dermatologist friend, who is a committed acolyte of the sentinel node biopsy school, why he continues to recommend sentinel node biopsy if there is no benefit from complete node dissection. His quick response was that patients want to know if they are at higher risk of metastatic disease so that they can be followed closely with high-resolution ultrasound at a major cancer center and can be eligible for clinical trials. His reply gave me pause, so I asked why completion node dissection was still being recommended. I was told that some patients with positive sentinel nodes lived far away, and if they would not make regular follow-up visits for high-resolution ultrasound, the surgical oncologists do completion node dissection to ensure “local nodal control.” Yipes! You’re going to rip my groin out because I like quiet county living?

I doubt that patients would be enthusiastic if told beforehand that sentinel node biopsies costs $14,000-$18,000, and has a 9% complication rate, and one-third of those patients who have complications end up with permanent lymphedema. I wondered if the patients were told they could have a genetic test done on their already excised melanoma tissue that would tell them if they were in a high-risk group without having an additional invasive surgical procedure. I wondered if they were told that 10%-30% of people with negative sentinel nodes go on to develop metastatic disease. I also wondered if they had been told they would have to walk around with their melanoma, which could spread at any time, for several additional weeks, while waiting for the results of their sentinel node biopsy, instead of having the melanoma immediately removed by their dermatologist. I also wondered if they had been told that high-resolution ultrasound has not definitively been shown to be superior to clinical palpation of the lymph nodes.

I looked into the possibility of clinical trials for patients with positive sentinel nodes, as well. Based on my search of clinical trials.gov in January, there are 33 trials in the United States studying patients with stage 3 (positive sentinel node) or greater disease. If I had a positive sentinel node, I would look for a study in which I had a chance of getting nivolumab, which recently has been shown to be superior to ipilimumab in the phase 3 Checkmate 238 trial published in 2017 (N Engl J Med 2017 Nov 9; 377:1824-35).

But I am getting ahead of myself.

As a thinking man, if I had a thick melanoma (that was less than 2 mm), I would opt for a genetic test of my already excised melanoma tissue. If the results of that genetic test (which has near identical sensitivity and specificity for developing metastatic disease as a sentinel node) put me in the low-risk group, I would pass on the sentinel node biopsy. This would eliminate a lot of unnecessary surgery. If I fell into the high-risk group, I would consider a sentinel node biopsy so I could get into a study, or determine if I needed to find a way to get my insurance to pay, or if I could personally afford nivolumab. Even if I opted not to take the drug, because of the potential risk of high-grade side effects, the high-risk genetic profile tells me I would still need more frequent follow-up.

These are exciting times. I am looking forward to clinical trials that allow a patient with a high-risk genetic profile to go directly into a trial. We are moving into the realm of individualized genomic medicine in which metastatic melanoma truly becomes a curable disease.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Dr. Coldiron has no financial or other conflicts of interest with Castle Biosciences, the manufacturer of the DecisionDx-Melanoma genetic expression profile test. Email him at dermnews@frontlinemedcom.com.

 

More than 17 years ago, I published an article that was largely ignored, predicating that patient benefit from the sentinel node biopsy procedure was unlikely.

I asserted that the lymph nodes are not a reliable filter for melanoma cells, lymphatic drainage is capricious, and many individuals (especially younger ones) have benign neval rests in their lymph nodes that cannot be distinguished from melanoma deposits, since they are both positive for the S100 protein (Int J Dermatol. 2000 Nov;39[11]:807-11). In addition, multiple uncontrolled studies had shown that locating sentinel nodes, followed by a complete lymph node dissection, had no survival benefit. At the time, I argued that sentinel node biopsy should be performed only if the patient was going to be enrolled in a clinical study.

Dr. Brett M. Coldiron
The sentinel node biopsy train roared on, justified by adjunctive interferon therapy. But after 15 years of studies, the adverse effects of interferon, and the lack of benefit from biopsy for melanoma patients have become apparent. A few months ago, it was definitively shown that completion lymph node dissection after a positive sentinel node finding added no survival benefit (N Engl J Med. 2017 Jun 8;376[23]:2211-22).

Many surgical oncologists have built their careers around the flawed premise that removing the draining nodes would cure melanoma. It doesn’t. It is past time to admit it and move on.

So, if completion node dissection does not save lives, why do a sentinel node biopsy? I recently asked a dermatologist friend, who is a committed acolyte of the sentinel node biopsy school, why he continues to recommend sentinel node biopsy if there is no benefit from complete node dissection. His quick response was that patients want to know if they are at higher risk of metastatic disease so that they can be followed closely with high-resolution ultrasound at a major cancer center and can be eligible for clinical trials. His reply gave me pause, so I asked why completion node dissection was still being recommended. I was told that some patients with positive sentinel nodes lived far away, and if they would not make regular follow-up visits for high-resolution ultrasound, the surgical oncologists do completion node dissection to ensure “local nodal control.” Yipes! You’re going to rip my groin out because I like quiet county living?

I doubt that patients would be enthusiastic if told beforehand that sentinel node biopsies costs $14,000-$18,000, and has a 9% complication rate, and one-third of those patients who have complications end up with permanent lymphedema. I wondered if the patients were told they could have a genetic test done on their already excised melanoma tissue that would tell them if they were in a high-risk group without having an additional invasive surgical procedure. I wondered if they were told that 10%-30% of people with negative sentinel nodes go on to develop metastatic disease. I also wondered if they had been told they would have to walk around with their melanoma, which could spread at any time, for several additional weeks, while waiting for the results of their sentinel node biopsy, instead of having the melanoma immediately removed by their dermatologist. I also wondered if they had been told that high-resolution ultrasound has not definitively been shown to be superior to clinical palpation of the lymph nodes.

I looked into the possibility of clinical trials for patients with positive sentinel nodes, as well. Based on my search of clinical trials.gov in January, there are 33 trials in the United States studying patients with stage 3 (positive sentinel node) or greater disease. If I had a positive sentinel node, I would look for a study in which I had a chance of getting nivolumab, which recently has been shown to be superior to ipilimumab in the phase 3 Checkmate 238 trial published in 2017 (N Engl J Med 2017 Nov 9; 377:1824-35).

But I am getting ahead of myself.

As a thinking man, if I had a thick melanoma (that was less than 2 mm), I would opt for a genetic test of my already excised melanoma tissue. If the results of that genetic test (which has near identical sensitivity and specificity for developing metastatic disease as a sentinel node) put me in the low-risk group, I would pass on the sentinel node biopsy. This would eliminate a lot of unnecessary surgery. If I fell into the high-risk group, I would consider a sentinel node biopsy so I could get into a study, or determine if I needed to find a way to get my insurance to pay, or if I could personally afford nivolumab. Even if I opted not to take the drug, because of the potential risk of high-grade side effects, the high-risk genetic profile tells me I would still need more frequent follow-up.

These are exciting times. I am looking forward to clinical trials that allow a patient with a high-risk genetic profile to go directly into a trial. We are moving into the realm of individualized genomic medicine in which metastatic melanoma truly becomes a curable disease.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Dr. Coldiron has no financial or other conflicts of interest with Castle Biosciences, the manufacturer of the DecisionDx-Melanoma genetic expression profile test. Email him at dermnews@frontlinemedcom.com.

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Desmoplastic melanoma yields to checkpoint inhibitors

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Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.

Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas, MD, PhD, of the University of California, Los Angeles, and colleagues.

Dr. Antoni Ribas
“Our data suggest that DM, and probably the non-DM NF1 subtype arising from sun-exposed areas, have a high response rate to PD-1 blockade therapy because they have a more dynamic preexisting adaptive immune response,” they wrote in Nature.

Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.

Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.

“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.

To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.

Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.

The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.

When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”

The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.

Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.

“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.

The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
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Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.

Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas, MD, PhD, of the University of California, Los Angeles, and colleagues.

Dr. Antoni Ribas
“Our data suggest that DM, and probably the non-DM NF1 subtype arising from sun-exposed areas, have a high response rate to PD-1 blockade therapy because they have a more dynamic preexisting adaptive immune response,” they wrote in Nature.

Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.

Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.

“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.

To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.

Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.

The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.

When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”

The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.

Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.

“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.

The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.

 

Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.

Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas, MD, PhD, of the University of California, Los Angeles, and colleagues.

Dr. Antoni Ribas
“Our data suggest that DM, and probably the non-DM NF1 subtype arising from sun-exposed areas, have a high response rate to PD-1 blockade therapy because they have a more dynamic preexisting adaptive immune response,” they wrote in Nature.

Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.

Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.

“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.

To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.

Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.

The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.

When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”

The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.

Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.

“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.

The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
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Key clinical point: Desmoplastic melanoma (DM) has a high mutational load that may make it susceptible to anti–PD-1 and PD-L1 therapy.

Major finding: The objective response rate was 70%, including 32% complete and 38% partial responses.

Data source: A retrospective review of data on 60 patients with desmoplastic melanoma treated with immune checkpoint inhibitors.

Disclosures: The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.

Source: Ribas A et al. Nature. 2018 Jan 10. doi: 10.1038/nature25187.

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