Researchers found that patients with osteoarthritis who had total knee or hip joint arthroplasty were at increased risk of myocardial infarction in the early post-operative period, according to a study published online ahead of print August 31 in Arthritis & Rheumatology. However, findings indicate that long-term risk of heart attack did not persist, while the risk for venous thromboembolism remained years after the procedure was performed.

The cohort study included 13,849 patients who underwent total knee replacement surgery and 13,849 matched controls that did not have surgery. Patients were ages 50 or older and were diagnosed with knee or hip osteoarthritis between January 2000 and December 2012.

Findings indicate that 306 patients in the arthroplasty group and 286 in the non-surgical group developed myocardial infarction during the follow-up period.

Risk of heart attack was significantly higher during the first postoperative month in those who had knee replacement surgery compared with those in the non-surgical group (hazard ratio 8.75), and gradually declined over time. Venous thromboembolism was a significant risk during the first month and over time for those who had total knee or total hip arthroplasty.

“Our findings provide the first general population-based evidence that osteoarthritis patients who have total knee or total hip replacement surgery are at increased risk of heart attack in the immediate postoperative period,” said Yuqing Zhang, DSc, Professor of Medicine and Epidemiology at Boston University School of Medicine. “The long-term risk of heart attack was insignificant, but risk of blood clots in the lung remained for years after surgery to replace a hip or knee damaged by osteoarthritis,” said Dr. Zhang.

Researchers found that patients with osteoarthritis who had total knee or hip joint arthroplasty were at increased risk of myocardial infarction in the early post-operative period, according to a study published online ahead of print August 31 in Arthritis & Rheumatology. However, findings indicate that long-term risk of heart attack did not persist, while the risk for venous thromboembolism remained years after the procedure was performed.

The cohort study included 13,849 patients who underwent total knee replacement surgery and 13,849 matched controls that did not have surgery. Patients were ages 50 or older and were diagnosed with knee or hip osteoarthritis between January 2000 and December 2012.

Findings indicate that 306 patients in the arthroplasty group and 286 in the non-surgical group developed myocardial infarction during the follow-up period.

Risk of heart attack was significantly higher during the first postoperative month in those who had knee replacement surgery compared with those in the non-surgical group (hazard ratio 8.75), and gradually declined over time. Venous thromboembolism was a significant risk during the first month and over time for those who had total knee or total hip arthroplasty.

“Our findings provide the first general population-based evidence that osteoarthritis patients who have total knee or total hip replacement surgery are at increased risk of heart attack in the immediate postoperative period,” said Yuqing Zhang, DSc, Professor of Medicine and Epidemiology at Boston University School of Medicine. “The long-term risk of heart attack was insignificant, but risk of blood clots in the lung remained for years after surgery to replace a hip or knee damaged by osteoarthritis,” said Dr. Zhang.

Researchers found that patients with osteoarthritis who had total knee or hip joint arthroplasty were at increased risk of myocardial infarction in the early post-operative period, according to a study published online ahead of print August 31 in Arthritis & Rheumatology. However, findings indicate that long-term risk of heart attack did not persist, while the risk for venous thromboembolism remained years after the procedure was performed.

The cohort study included 13,849 patients who underwent total knee replacement surgery and 13,849 matched controls that did not have surgery. Patients were ages 50 or older and were diagnosed with knee or hip osteoarthritis between January 2000 and December 2012.

Findings indicate that 306 patients in the arthroplasty group and 286 in the non-surgical group developed myocardial infarction during the follow-up period.

Risk of heart attack was significantly higher during the first postoperative month in those who had knee replacement surgery compared with those in the non-surgical group (hazard ratio 8.75), and gradually declined over time. Venous thromboembolism was a significant risk during the first month and over time for those who had total knee or total hip arthroplasty.

“Our findings provide the first general population-based evidence that osteoarthritis patients who have total knee or total hip replacement surgery are at increased risk of heart attack in the immediate postoperative period,” said Yuqing Zhang, DSc, Professor of Medicine and Epidemiology at Boston University School of Medicine. “The long-term risk of heart attack was insignificant, but risk of blood clots in the lung remained for years after surgery to replace a hip or knee damaged by osteoarthritis,” said Dr. Zhang.

One course of topical fluorouracil cream reduced the need for localized treatments and the number of actinic keratoses (AK) over a mean follow-up of 2.6 years in the Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) trial.

These results “indicate that treating a patient with a single course of fluorouracil would reduce the subsequent number of spot treatments and benefit care of patients with multiple AKs for longer than 2 years,” concluded Dr. Hyemin Pomerantz of the department of dermatoepidemiology at the Providence (R.I.) VA Medical Center and his coauthors. Previous studies on treating AKs with topical fluorouracil have followed up participants for less than 6 months, they pointed out (JAMA Dermatol. 2015;9:952-60).

©Dr-Strangelove/ThinkStockPhotos.com

In the randomized, double-blinded, placebo-controlled study, conducted from 2009 to 2011 at 12 VA dermatology clinics, participants received topical fluorouracil cream, 5%, or a vehicle control cream, applied twice a day for 4 weeks, and were followed up for a mean of 2.6 years. There were no significant differences in the baseline characteristics of the 468 participants randomized to receive fluorouracil cream and the 464 participants randomized to receive the control cream.

The mean total AK count on the face and ears in both groups was about 11. At 6 months, the mean number of AKs per participant had dropped to 3 in the fluorouracil group (a 73% reduction from baseline) vs. a mean of 8.1 in the control group, a 24% reduction from baseline (P less than .001). Over the study period, those treated with fluorouracil had significantly fewer AKs. Over the entire study, there was not a significant difference in the number of hypertrophic AKs between the two groups, although the number of hypertrophic AKs was lower in the treatment group at 6 months.

During the study period, more participants treated with fluorouracil had complete clearance of AKs on the face and ears, compared with the control group (P less than .001). Finally, the fluorouracil group required 2 spot treatments per visit per participant vs. 3.9 in the control group (P less than .001).

“Our findings highlight the long-term efficacy of topical fluorouracil cream in treating and preventing AKs. A single course of topical fluorouracil cream, 5%, treatment led to a sustained reduction of the number of AKs and subsequent AK treatments,” in the population of patients at high risk for basal cell and squamous cell carcinomas, the authors wrote.

The study was supported by the Office of Research and Development Cooperative Studies Program at the Department of Veterans Affairs. Three of the authors reported several disclosures, including serving as a consultant to several pharmaceutical companies; the others, including the lead author, had no disclosures.

One course of topical fluorouracil cream reduced the need for localized treatments and the number of actinic keratoses (AK) over a mean follow-up of 2.6 years in the Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) trial.

These results “indicate that treating a patient with a single course of fluorouracil would reduce the subsequent number of spot treatments and benefit care of patients with multiple AKs for longer than 2 years,” concluded Dr. Hyemin Pomerantz of the department of dermatoepidemiology at the Providence (R.I.) VA Medical Center and his coauthors. Previous studies on treating AKs with topical fluorouracil have followed up participants for less than 6 months, they pointed out (JAMA Dermatol. 2015;9:952-60).

©Dr-Strangelove/ThinkStockPhotos.com

In the randomized, double-blinded, placebo-controlled study, conducted from 2009 to 2011 at 12 VA dermatology clinics, participants received topical fluorouracil cream, 5%, or a vehicle control cream, applied twice a day for 4 weeks, and were followed up for a mean of 2.6 years. There were no significant differences in the baseline characteristics of the 468 participants randomized to receive fluorouracil cream and the 464 participants randomized to receive the control cream.

The mean total AK count on the face and ears in both groups was about 11. At 6 months, the mean number of AKs per participant had dropped to 3 in the fluorouracil group (a 73% reduction from baseline) vs. a mean of 8.1 in the control group, a 24% reduction from baseline (P less than .001). Over the study period, those treated with fluorouracil had significantly fewer AKs. Over the entire study, there was not a significant difference in the number of hypertrophic AKs between the two groups, although the number of hypertrophic AKs was lower in the treatment group at 6 months.

During the study period, more participants treated with fluorouracil had complete clearance of AKs on the face and ears, compared with the control group (P less than .001). Finally, the fluorouracil group required 2 spot treatments per visit per participant vs. 3.9 in the control group (P less than .001).

“Our findings highlight the long-term efficacy of topical fluorouracil cream in treating and preventing AKs. A single course of topical fluorouracil cream, 5%, treatment led to a sustained reduction of the number of AKs and subsequent AK treatments,” in the population of patients at high risk for basal cell and squamous cell carcinomas, the authors wrote.

The study was supported by the Office of Research and Development Cooperative Studies Program at the Department of Veterans Affairs. Three of the authors reported several disclosures, including serving as a consultant to several pharmaceutical companies; the others, including the lead author, had no disclosures.

One course of topical fluorouracil cream reduced the need for localized treatments and the number of actinic keratoses (AK) over a mean follow-up of 2.6 years in the Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) trial.

These results “indicate that treating a patient with a single course of fluorouracil would reduce the subsequent number of spot treatments and benefit care of patients with multiple AKs for longer than 2 years,” concluded Dr. Hyemin Pomerantz of the department of dermatoepidemiology at the Providence (R.I.) VA Medical Center and his coauthors. Previous studies on treating AKs with topical fluorouracil have followed up participants for less than 6 months, they pointed out (JAMA Dermatol. 2015;9:952-60).

©Dr-Strangelove/ThinkStockPhotos.com

In the randomized, double-blinded, placebo-controlled study, conducted from 2009 to 2011 at 12 VA dermatology clinics, participants received topical fluorouracil cream, 5%, or a vehicle control cream, applied twice a day for 4 weeks, and were followed up for a mean of 2.6 years. There were no significant differences in the baseline characteristics of the 468 participants randomized to receive fluorouracil cream and the 464 participants randomized to receive the control cream.

The mean total AK count on the face and ears in both groups was about 11. At 6 months, the mean number of AKs per participant had dropped to 3 in the fluorouracil group (a 73% reduction from baseline) vs. a mean of 8.1 in the control group, a 24% reduction from baseline (P less than .001). Over the study period, those treated with fluorouracil had significantly fewer AKs. Over the entire study, there was not a significant difference in the number of hypertrophic AKs between the two groups, although the number of hypertrophic AKs was lower in the treatment group at 6 months.

During the study period, more participants treated with fluorouracil had complete clearance of AKs on the face and ears, compared with the control group (P less than .001). Finally, the fluorouracil group required 2 spot treatments per visit per participant vs. 3.9 in the control group (P less than .001).

“Our findings highlight the long-term efficacy of topical fluorouracil cream in treating and preventing AKs. A single course of topical fluorouracil cream, 5%, treatment led to a sustained reduction of the number of AKs and subsequent AK treatments,” in the population of patients at high risk for basal cell and squamous cell carcinomas, the authors wrote.

The study was supported by the Office of Research and Development Cooperative Studies Program at the Department of Veterans Affairs. Three of the authors reported several disclosures, including serving as a consultant to several pharmaceutical companies; the others, including the lead author, had no disclosures.

Background: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. According to a Surveillance, Epidemiology, and End Results (SEER) database analysis, the 5-year survival rates for clinical stages IA, IB, IIA, and IIB NSCLC are 50%, 43%, 36%, and 25%, respectively. Even with advances in therapies in both the surgical and medical fields, patient outcomes remain suboptimal. Our aim was to assess the role of various demographic and insurance characteristics on patient survival in early stage (stage I and II) NSCLC.

Methods: This is a retrospective study of patients diagnosed with stage I and stage II NSCLC between 1998 and 2012 utilizing the National Cancer Database (NCDB) participant user file (PUF). The NCDB is a nationwide oncology outcomes database for more than 1,500 American College of Surgeons Commission on Cancer-accredited cancer programs. The impact of various factors on survival was analyzed using the Cox proportional hazards model.

Results: A total of 304,092 patients with early stage NSCLC were analyzed for this study. On multivariate analysis, the factors associated with decreased survival were male (hazard ratio [HR] 1.32, P < .0001) compared with female, increasing age (HR 1.036, P < .0001), African American (HR 1.15, P < .0001) compared with white, and rural residency (HR 1.146, P < .0001) compared with metro areas. Privately insured patients had better survival when compared with uninsured patients (HR 0.674, P < .0001), whereas Medicaid patients had the worst survival (HR 1.076, P < .0001). Also, the patients who were diagnosed between 2008 and 2012 had a higher survival than those diagnosed earlier (HR 0.645, P < .0001).

Discussion: The above data suggest that there is a disparity in outcomes among patients with early stage NSCLC based on various demographic and health system factors. Despite an overall increase in survival due to improved therapies from 1998 to 2012, significant differences exist in terms of patient age, gender, race, residency, and insurance status. This could be secondary to decreased receipt of appropriate treatment in certain subgroups or due to a difference in cancer biology in some of these groups. Nevertheless, this study suggests room for improvement in health care delivery to all patients for optimal outcomes.

Background: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. According to a Surveillance, Epidemiology, and End Results (SEER) database analysis, the 5-year survival rates for clinical stages IA, IB, IIA, and IIB NSCLC are 50%, 43%, 36%, and 25%, respectively. Even with advances in therapies in both the surgical and medical fields, patient outcomes remain suboptimal. Our aim was to assess the role of various demographic and insurance characteristics on patient survival in early stage (stage I and II) NSCLC.

Methods: This is a retrospective study of patients diagnosed with stage I and stage II NSCLC between 1998 and 2012 utilizing the National Cancer Database (NCDB) participant user file (PUF). The NCDB is a nationwide oncology outcomes database for more than 1,500 American College of Surgeons Commission on Cancer-accredited cancer programs. The impact of various factors on survival was analyzed using the Cox proportional hazards model.

Results: A total of 304,092 patients with early stage NSCLC were analyzed for this study. On multivariate analysis, the factors associated with decreased survival were male (hazard ratio [HR] 1.32, P < .0001) compared with female, increasing age (HR 1.036, P < .0001), African American (HR 1.15, P < .0001) compared with white, and rural residency (HR 1.146, P < .0001) compared with metro areas. Privately insured patients had better survival when compared with uninsured patients (HR 0.674, P < .0001), whereas Medicaid patients had the worst survival (HR 1.076, P < .0001). Also, the patients who were diagnosed between 2008 and 2012 had a higher survival than those diagnosed earlier (HR 0.645, P < .0001).

Discussion: The above data suggest that there is a disparity in outcomes among patients with early stage NSCLC based on various demographic and health system factors. Despite an overall increase in survival due to improved therapies from 1998 to 2012, significant differences exist in terms of patient age, gender, race, residency, and insurance status. This could be secondary to decreased receipt of appropriate treatment in certain subgroups or due to a difference in cancer biology in some of these groups. Nevertheless, this study suggests room for improvement in health care delivery to all patients for optimal outcomes.

Background: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. According to a Surveillance, Epidemiology, and End Results (SEER) database analysis, the 5-year survival rates for clinical stages IA, IB, IIA, and IIB NSCLC are 50%, 43%, 36%, and 25%, respectively. Even with advances in therapies in both the surgical and medical fields, patient outcomes remain suboptimal. Our aim was to assess the role of various demographic and insurance characteristics on patient survival in early stage (stage I and II) NSCLC.

Methods: This is a retrospective study of patients diagnosed with stage I and stage II NSCLC between 1998 and 2012 utilizing the National Cancer Database (NCDB) participant user file (PUF). The NCDB is a nationwide oncology outcomes database for more than 1,500 American College of Surgeons Commission on Cancer-accredited cancer programs. The impact of various factors on survival was analyzed using the Cox proportional hazards model.

Results: A total of 304,092 patients with early stage NSCLC were analyzed for this study. On multivariate analysis, the factors associated with decreased survival were male (hazard ratio [HR] 1.32, P < .0001) compared with female, increasing age (HR 1.036, P < .0001), African American (HR 1.15, P < .0001) compared with white, and rural residency (HR 1.146, P < .0001) compared with metro areas. Privately insured patients had better survival when compared with uninsured patients (HR 0.674, P < .0001), whereas Medicaid patients had the worst survival (HR 1.076, P < .0001). Also, the patients who were diagnosed between 2008 and 2012 had a higher survival than those diagnosed earlier (HR 0.645, P < .0001).

Discussion: The above data suggest that there is a disparity in outcomes among patients with early stage NSCLC based on various demographic and health system factors. Despite an overall increase in survival due to improved therapies from 1998 to 2012, significant differences exist in terms of patient age, gender, race, residency, and insurance status. This could be secondary to decreased receipt of appropriate treatment in certain subgroups or due to a difference in cancer biology in some of these groups. Nevertheless, this study suggests room for improvement in health care delivery to all patients for optimal outcomes.

An 80-year-old man is brought in by family for evaluation of a lesion on his nose. It manifested several years ago, at a smaller size, but has recently and abruptly grown. Although asymptomatic, the lesion is disturbing to the patient, who can now see it out of the corner of his eye.

The patient worked all of his adult life in the outdoors, as a farm and ranch hand. He has an extensive history of nonmelanoma skin cancer; several lesions have been removed from his face and arm.

Since the patient lives alone and rarely has visitors, it has been months since anyone has seen him. But as soon as his son-in-law saw the patient, he was sufficiently alarmed by the lesion to insist that care be sought.

EXAMINATION
The patient’s facial skin shows abundant evidence of chronic, severe sun damage: a whitish, spongy look to the skin on his forehead and upper cheeks and a great deal of discoloration and scaling.

The lesion in question is a 3 x 1.5–cm, round, bulbous, smooth mass covering the right alar bulb. The surface is glassy-looking, with multiple telangiectasias. It is very firm but nontender on palpation. Shave biopsy is performed.

What is the diagnosis?

DISCUSSION
The biopsy results confirmed the suspicion of basal cell carcinoma (BCC). BCCs typically grow very slowly, often taking years to become noticeable, although not every BCC follows the rules. Some are more aggressive than others, both in terms of growth and clinical behavior.

It’s quite likely that in this case, the patient’s social isolation created the impression that his lesion grew abruptly and dramatically. (A subsequent eye exam revealed a number of problems, including severe presbyopia and advanced cataracts, so the patient himself might not have noticed the lesion for a while.) However, due to the large size and aggressive nature of the lesion—and the fact that the patient lives more than two hours from the nearest city, rendering his other treatment option, radiation, impractical—he was referred for Mohs surgery.

This process will establish clear surgical margins and provide acceptable closure. The latter may require reconstruction of the nose, depending on the depth of the cancer. Mohs surgeons often co-manage such cases with their counterparts in ENT or plastic surgery.

The differential for this lesion included keratoacanthoma , squamous cell carcinoma, and cyst.

TAKE-HOME LEARNING POINTS
• Basal cell carcinoma (BCC) is typically very slow growing, but there are exceptions.

• Social isolation can allow lesions and conditions to advance before they’re detected.

• Shave biopsy is indicated only for possible nonmelanoma skin cancers. Possible melanomas require excision, multiple punches, or deep shave to establish depth (a key prognostic factor).

• Rapid growth of BCCs suggests more aggressive clinical behavior, which in turn suggests the need for controlled margins to ensure complete removal. 

An 80-year-old man is brought in by family for evaluation of a lesion on his nose. It manifested several years ago, at a smaller size, but has recently and abruptly grown. Although asymptomatic, the lesion is disturbing to the patient, who can now see it out of the corner of his eye.

The patient worked all of his adult life in the outdoors, as a farm and ranch hand. He has an extensive history of nonmelanoma skin cancer; several lesions have been removed from his face and arm.

Since the patient lives alone and rarely has visitors, it has been months since anyone has seen him. But as soon as his son-in-law saw the patient, he was sufficiently alarmed by the lesion to insist that care be sought.

EXAMINATION
The patient’s facial skin shows abundant evidence of chronic, severe sun damage: a whitish, spongy look to the skin on his forehead and upper cheeks and a great deal of discoloration and scaling.

The lesion in question is a 3 x 1.5–cm, round, bulbous, smooth mass covering the right alar bulb. The surface is glassy-looking, with multiple telangiectasias. It is very firm but nontender on palpation. Shave biopsy is performed.

What is the diagnosis?

DISCUSSION
The biopsy results confirmed the suspicion of basal cell carcinoma (BCC). BCCs typically grow very slowly, often taking years to become noticeable, although not every BCC follows the rules. Some are more aggressive than others, both in terms of growth and clinical behavior.

It’s quite likely that in this case, the patient’s social isolation created the impression that his lesion grew abruptly and dramatically. (A subsequent eye exam revealed a number of problems, including severe presbyopia and advanced cataracts, so the patient himself might not have noticed the lesion for a while.) However, due to the large size and aggressive nature of the lesion—and the fact that the patient lives more than two hours from the nearest city, rendering his other treatment option, radiation, impractical—he was referred for Mohs surgery.

This process will establish clear surgical margins and provide acceptable closure. The latter may require reconstruction of the nose, depending on the depth of the cancer. Mohs surgeons often co-manage such cases with their counterparts in ENT or plastic surgery.

The differential for this lesion included keratoacanthoma , squamous cell carcinoma, and cyst.

TAKE-HOME LEARNING POINTS
• Basal cell carcinoma (BCC) is typically very slow growing, but there are exceptions.

• Social isolation can allow lesions and conditions to advance before they’re detected.

• Shave biopsy is indicated only for possible nonmelanoma skin cancers. Possible melanomas require excision, multiple punches, or deep shave to establish depth (a key prognostic factor).

• Rapid growth of BCCs suggests more aggressive clinical behavior, which in turn suggests the need for controlled margins to ensure complete removal. 

An 80-year-old man is brought in by family for evaluation of a lesion on his nose. It manifested several years ago, at a smaller size, but has recently and abruptly grown. Although asymptomatic, the lesion is disturbing to the patient, who can now see it out of the corner of his eye.

The patient worked all of his adult life in the outdoors, as a farm and ranch hand. He has an extensive history of nonmelanoma skin cancer; several lesions have been removed from his face and arm.

Since the patient lives alone and rarely has visitors, it has been months since anyone has seen him. But as soon as his son-in-law saw the patient, he was sufficiently alarmed by the lesion to insist that care be sought.

EXAMINATION
The patient’s facial skin shows abundant evidence of chronic, severe sun damage: a whitish, spongy look to the skin on his forehead and upper cheeks and a great deal of discoloration and scaling.

The lesion in question is a 3 x 1.5–cm, round, bulbous, smooth mass covering the right alar bulb. The surface is glassy-looking, with multiple telangiectasias. It is very firm but nontender on palpation. Shave biopsy is performed.

What is the diagnosis?

DISCUSSION
The biopsy results confirmed the suspicion of basal cell carcinoma (BCC). BCCs typically grow very slowly, often taking years to become noticeable, although not every BCC follows the rules. Some are more aggressive than others, both in terms of growth and clinical behavior.

It’s quite likely that in this case, the patient’s social isolation created the impression that his lesion grew abruptly and dramatically. (A subsequent eye exam revealed a number of problems, including severe presbyopia and advanced cataracts, so the patient himself might not have noticed the lesion for a while.) However, due to the large size and aggressive nature of the lesion—and the fact that the patient lives more than two hours from the nearest city, rendering his other treatment option, radiation, impractical—he was referred for Mohs surgery.

This process will establish clear surgical margins and provide acceptable closure. The latter may require reconstruction of the nose, depending on the depth of the cancer. Mohs surgeons often co-manage such cases with their counterparts in ENT or plastic surgery.

The differential for this lesion included keratoacanthoma , squamous cell carcinoma, and cyst.

TAKE-HOME LEARNING POINTS
• Basal cell carcinoma (BCC) is typically very slow growing, but there are exceptions.

• Social isolation can allow lesions and conditions to advance before they’re detected.

• Shave biopsy is indicated only for possible nonmelanoma skin cancers. Possible melanomas require excision, multiple punches, or deep shave to establish depth (a key prognostic factor).

• Rapid growth of BCCs suggests more aggressive clinical behavior, which in turn suggests the need for controlled margins to ensure complete removal. 

Anatomical connectivity in discreet frontal regions of the brain is disrupted in bipolar I disorder patients, but not in mentally healthy relatives of such patients, according to a study.

©Purestock/thinkstockphotos.com

The researchers looked for connectivity abnormalities in the brains of multiply affected bipolar I disorder families “to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential.” Tractography was done on magnetic resonance diffusion images of the brains of 19 bipolar I patients in remission, 21 of the patients’ first-degree relatives who did not have bipolar I, and 18 unrelated controls who also did not have bipolar I. A connectivity matrix was generated for each patient, and the Brain Connectivity Toolbox was used to extract neural network metrics.

“Whole brain analysis revealed no differences between groups,” according to Natalie J. Forde, a PhD candidate at the University Medical Centre Gronigen (the Netherlands) and her colleagues. “Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced [organization] in [bipolar I] patients, compared with controls.”

Read the full study in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.08.004).

klennon@frontlinemedcom.com

Anatomical connectivity in discreet frontal regions of the brain is disrupted in bipolar I disorder patients, but not in mentally healthy relatives of such patients, according to a study.

©Purestock/thinkstockphotos.com

The researchers looked for connectivity abnormalities in the brains of multiply affected bipolar I disorder families “to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential.” Tractography was done on magnetic resonance diffusion images of the brains of 19 bipolar I patients in remission, 21 of the patients’ first-degree relatives who did not have bipolar I, and 18 unrelated controls who also did not have bipolar I. A connectivity matrix was generated for each patient, and the Brain Connectivity Toolbox was used to extract neural network metrics.

“Whole brain analysis revealed no differences between groups,” according to Natalie J. Forde, a PhD candidate at the University Medical Centre Gronigen (the Netherlands) and her colleagues. “Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced [organization] in [bipolar I] patients, compared with controls.”

Read the full study in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.08.004).

klennon@frontlinemedcom.com

Anatomical connectivity in discreet frontal regions of the brain is disrupted in bipolar I disorder patients, but not in mentally healthy relatives of such patients, according to a study.

©Purestock/thinkstockphotos.com

The researchers looked for connectivity abnormalities in the brains of multiply affected bipolar I disorder families “to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential.” Tractography was done on magnetic resonance diffusion images of the brains of 19 bipolar I patients in remission, 21 of the patients’ first-degree relatives who did not have bipolar I, and 18 unrelated controls who also did not have bipolar I. A connectivity matrix was generated for each patient, and the Brain Connectivity Toolbox was used to extract neural network metrics.

“Whole brain analysis revealed no differences between groups,” according to Natalie J. Forde, a PhD candidate at the University Medical Centre Gronigen (the Netherlands) and her colleagues. “Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced [organization] in [bipolar I] patients, compared with controls.”

Read the full study in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.08.004).

klennon@frontlinemedcom.com

Wendell Lim, PhD

Photo courtesy of UCSF

Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.

The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.

This system effectively targeted leukemia and lymphoma cells in preclinical experiments.

But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.

Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.

Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.

“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”

To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”

ON-switch CAR

The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.

Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.

Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.

The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”

The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).

The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.

The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.

Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.

Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.

The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.

“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”

Wendell Lim, PhD

Photo courtesy of UCSF

Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.

The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.

This system effectively targeted leukemia and lymphoma cells in preclinical experiments.

But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.

Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.

Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.

“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”

To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”

ON-switch CAR

The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.

Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.

Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.

The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”

The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).

The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.

The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.

Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.

Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.

The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.

“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”

Wendell Lim, PhD

Photo courtesy of UCSF

Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.

The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.

This system effectively targeted leukemia and lymphoma cells in preclinical experiments.

But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.

Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.

Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.

“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”

To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”

ON-switch CAR

The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.

Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.

Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.

The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”

The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).

The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.

The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.

Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.

Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.

The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.

“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Young cancer patient

Photo by Bill Branson

Results of a small study reveal the material hardships families experience when a child is undergoing cancer treatment.

Researchers surveyed 99 families of children with cancer.

Six months after the child’s diagnosis, 29% of the families reported having at least one household material hardship, such as food, housing, or energy insecurity.

Twenty percent of the families had reported having such hardships at the time of the child’s diagnosis.

Kira Bona, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and her colleagues reported results from this survey in Pediatric Blood & Cancer.

The researchers surveyed 99 families of pediatric cancer patients treated at Dana-Farber/Boston Children’s, first within a month of diagnosis and then 6 months later.

At diagnosis, 20% of the families were low-income, which was defined as 200% of the federal poverty level. Six months later, an additional 12% suffered income losses that pushed them into the low-income group.

At 6 months, 25% of the families said they had lost more than 40% of their household income due to treatment-related work disruptions. A total of 56% of adults who supported their families experienced a disruption of their work.

This included 15% of parents who either quit their jobs or were laid off as a result of their child’s illness, as well as 37% of respondents who cut their hours or took a leave of absence. Thirty-four percent of these individuals were paid during their leave.

At 6 months, 29% of families said they had at least one material hardship. Twenty percent reported food insecurity, 17% reported energy insecurity, and 8% reported housing insecurity.*

These findings surprised researchers, who said they expected lower levels of need at their center because it provides psychosocial support for patients and has resource specialists to help families facing financial difficulties.

“What it says is that even at a well-resourced, large referral center, about a third of families are reporting food, housing, or energy insecurity 6 months into treatment,” Dr Bona said. “If anything, the numbers in our study are an underestimate of what might be seen at less well-resourced institutions, which was somewhat surprising to us.”

By focusing on specific material hardships, which can be addressed through governmental or philanthropic support, the researchers hope they have identified variables that are easier for clinicians to ameliorate than overall income.

Dr Bona said subsequent research will examine whether material hardship has the same effect on patient outcomes as low-income status.

“If household material hardship is linked to poorer outcomes in pediatric oncology, just like income is, then we can design interventions to fix food, housing, and energy insecurity,” she said. “It’s not clear what you do about income in a clinical setting.”

*Definitions for household material hardships were as follows.

Food insecurity was measured via the US Household Food Security Survey Module: Six-Item Short Form, which includes questions to asses if respondents:

• sometimes/often do not have enough food to eat
• sometimes/often cannot afford to eat balanced meals
• sometimes/often worry about having enough money to buy food, etc.

Families met the definition for housing insecurity if they reported any of the following:

• crowding (defined as >2 people per bedroom in the home)
• multiple moves (>1 move in the prior year)
• doubling up (having to live with other people, even temporarily, because of financial difficulties in the past 6 months).

Families met the definition for energy insecurity if, in the prior 6 months, they had experienced any of the following:

• received a letter threatening to shut off the gas/electricity/oil to their house because they had not paid the bills
• had the gas/electric/oil company shut off electricity or refused to deliver oil/gas because they had not paid the bills
• had any days that their home was not heated/cooled because they couldn’t pay the bills
• had ever used a cooking stove to heat their home because they couldn’t pay the bills.

Young cancer patient

Photo by Bill Branson

Results of a small study reveal the material hardships families experience when a child is undergoing cancer treatment.

Researchers surveyed 99 families of children with cancer.

Six months after the child’s diagnosis, 29% of the families reported having at least one household material hardship, such as food, housing, or energy insecurity.

Twenty percent of the families had reported having such hardships at the time of the child’s diagnosis.

Kira Bona, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and her colleagues reported results from this survey in Pediatric Blood & Cancer.

The researchers surveyed 99 families of pediatric cancer patients treated at Dana-Farber/Boston Children’s, first within a month of diagnosis and then 6 months later.

At diagnosis, 20% of the families were low-income, which was defined as 200% of the federal poverty level. Six months later, an additional 12% suffered income losses that pushed them into the low-income group.

At 6 months, 25% of the families said they had lost more than 40% of their household income due to treatment-related work disruptions. A total of 56% of adults who supported their families experienced a disruption of their work.

This included 15% of parents who either quit their jobs or were laid off as a result of their child’s illness, as well as 37% of respondents who cut their hours or took a leave of absence. Thirty-four percent of these individuals were paid during their leave.

At 6 months, 29% of families said they had at least one material hardship. Twenty percent reported food insecurity, 17% reported energy insecurity, and 8% reported housing insecurity.*

These findings surprised researchers, who said they expected lower levels of need at their center because it provides psychosocial support for patients and has resource specialists to help families facing financial difficulties.

“What it says is that even at a well-resourced, large referral center, about a third of families are reporting food, housing, or energy insecurity 6 months into treatment,” Dr Bona said. “If anything, the numbers in our study are an underestimate of what might be seen at less well-resourced institutions, which was somewhat surprising to us.”

By focusing on specific material hardships, which can be addressed through governmental or philanthropic support, the researchers hope they have identified variables that are easier for clinicians to ameliorate than overall income.

Dr Bona said subsequent research will examine whether material hardship has the same effect on patient outcomes as low-income status.

“If household material hardship is linked to poorer outcomes in pediatric oncology, just like income is, then we can design interventions to fix food, housing, and energy insecurity,” she said. “It’s not clear what you do about income in a clinical setting.”

*Definitions for household material hardships were as follows.

Food insecurity was measured via the US Household Food Security Survey Module: Six-Item Short Form, which includes questions to asses if respondents:

• sometimes/often do not have enough food to eat
• sometimes/often cannot afford to eat balanced meals
• sometimes/often worry about having enough money to buy food, etc.

Families met the definition for housing insecurity if they reported any of the following:

• crowding (defined as >2 people per bedroom in the home)
• multiple moves (>1 move in the prior year)
• doubling up (having to live with other people, even temporarily, because of financial difficulties in the past 6 months).

Families met the definition for energy insecurity if, in the prior 6 months, they had experienced any of the following:

• received a letter threatening to shut off the gas/electricity/oil to their house because they had not paid the bills
• had the gas/electric/oil company shut off electricity or refused to deliver oil/gas because they had not paid the bills
• had any days that their home was not heated/cooled because they couldn’t pay the bills
• had ever used a cooking stove to heat their home because they couldn’t pay the bills.

Young cancer patient

Photo by Bill Branson

Results of a small study reveal the material hardships families experience when a child is undergoing cancer treatment.

Researchers surveyed 99 families of children with cancer.

Six months after the child’s diagnosis, 29% of the families reported having at least one household material hardship, such as food, housing, or energy insecurity.

Twenty percent of the families had reported having such hardships at the time of the child’s diagnosis.

Kira Bona, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and her colleagues reported results from this survey in Pediatric Blood & Cancer.

The researchers surveyed 99 families of pediatric cancer patients treated at Dana-Farber/Boston Children’s, first within a month of diagnosis and then 6 months later.

At diagnosis, 20% of the families were low-income, which was defined as 200% of the federal poverty level. Six months later, an additional 12% suffered income losses that pushed them into the low-income group.

At 6 months, 25% of the families said they had lost more than 40% of their household income due to treatment-related work disruptions. A total of 56% of adults who supported their families experienced a disruption of their work.

This included 15% of parents who either quit their jobs or were laid off as a result of their child’s illness, as well as 37% of respondents who cut their hours or took a leave of absence. Thirty-four percent of these individuals were paid during their leave.

At 6 months, 29% of families said they had at least one material hardship. Twenty percent reported food insecurity, 17% reported energy insecurity, and 8% reported housing insecurity.*

These findings surprised researchers, who said they expected lower levels of need at their center because it provides psychosocial support for patients and has resource specialists to help families facing financial difficulties.

“What it says is that even at a well-resourced, large referral center, about a third of families are reporting food, housing, or energy insecurity 6 months into treatment,” Dr Bona said. “If anything, the numbers in our study are an underestimate of what might be seen at less well-resourced institutions, which was somewhat surprising to us.”

By focusing on specific material hardships, which can be addressed through governmental or philanthropic support, the researchers hope they have identified variables that are easier for clinicians to ameliorate than overall income.

Dr Bona said subsequent research will examine whether material hardship has the same effect on patient outcomes as low-income status.

“If household material hardship is linked to poorer outcomes in pediatric oncology, just like income is, then we can design interventions to fix food, housing, and energy insecurity,” she said. “It’s not clear what you do about income in a clinical setting.”

*Definitions for household material hardships were as follows.

Food insecurity was measured via the US Household Food Security Survey Module: Six-Item Short Form, which includes questions to asses if respondents:

• sometimes/often do not have enough food to eat
• sometimes/often cannot afford to eat balanced meals
• sometimes/often worry about having enough money to buy food, etc.

Families met the definition for housing insecurity if they reported any of the following:

• crowding (defined as >2 people per bedroom in the home)
• multiple moves (>1 move in the prior year)
• doubling up (having to live with other people, even temporarily, because of financial difficulties in the past 6 months).

Families met the definition for energy insecurity if, in the prior 6 months, they had experienced any of the following:

• received a letter threatening to shut off the gas/electricity/oil to their house because they had not paid the bills
• had the gas/electric/oil company shut off electricity or refused to deliver oil/gas because they had not paid the bills
• had any days that their home was not heated/cooled because they couldn’t pay the bills
• had ever used a cooking stove to heat their home because they couldn’t pay the bills.