Dermatology News

Approximately three-quarters of Mohs surgeons recommended nicotinamide for prevention of keratinocyte carcinoma, in a survey of members of the American College of Mohs Surgeons.

Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.

The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.

Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).

The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.

Limited safety data highlight research gaps

The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .

“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.

Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.

“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.

“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”

To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Approximately three-quarters of Mohs surgeons recommended nicotinamide for prevention of keratinocyte carcinoma, in a survey of members of the American College of Mohs Surgeons.

Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.

The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.

Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).

The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.

Limited safety data highlight research gaps

The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .

“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.

Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.

“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.

“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”

To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Approximately three-quarters of Mohs surgeons recommended nicotinamide for prevention of keratinocyte carcinoma, in a survey of members of the American College of Mohs Surgeons.

Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.

The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.

Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).

The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.

Limited safety data highlight research gaps

The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .

“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.

Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.

“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.

“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”

To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.

The study received no outside funding. The researchers had no financial conflicts to disclose.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)

He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 10⁹). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.

“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

Patients with prurigo nodularis tend to make a greater number of visits to health care specialists and are burdened by a greater number of medical comorbidities, compared with age-matched controls, as well those with atopic dermatitis and psoriasis.

Those are key findings from a retrospective analysis of claims data that was published online April 3, 2021, in the Journal of Investigative Dermatology.

“Prurigo nodularis is a tremendously understudied inflammatory skin disease,” one of the study’s cosenior authors, Shawn G. Kwatra, MD, of the department of dermatology, Johns Hopkins University, Baltimore, said in an interview. “Prurigo nodularis patients have uncontrolled itch, which leads to reduced quality of life, and the association with many disease comorbidities. We focused on better understanding in this work the unique comorbidities of prurigo nodularis, compared to other inflammatory skin diseases.”

For the study, Dr. Kwatra, cosenior author Yevgeniy R. Semenov, MD, of the department of dermatology, Massachusetts General Hospital, Boston, and colleagues evaluated nationally representative, private insurance claims data from October 2015 to December 2019 to identify prurigo nodularis (PN) patients, who were defined as individuals with two or more medical claims for PN using ICD-10-CM codes. For comparison with patients with inflammatory skin diseases, they used the same claims data to identify patients with atopic dermatitis (AD) and psoriasis as well as to select controls who were age and gender matched to PN patients. Next, they quantified the overall comorbidity burden with the Charlson Comorbidity Index (CCI).

In 2016, the claims database included 2,658 patients with PN, 21,482 patients with AD, 21,073 patients with psoriasis, and 13,290 controls. The number of patients in each category rose each subsequent year, so that by the end of 2019 there were 9,426 patients with PN, 70,298 patients with AD, 59,509 patients with psoriasis, and 47,130 controls. Between 2016 and 2019 the mean age of PN patients increased from 57.5 to 59.8 years and the percent of male patients rose from 44.5% to 46.5%.

Between 2016 and 2019, the overall PN prevalence rates rose from 18 per 100,000 to 58 per 100,000, while the PN prevalence rates among adults increased from 22 per 100,000 to 70 per 100,000, and the rates among children rose grew from 2 per 100,000 to 7 per 100,000. “Our report shows an estimated disease prevalence of around 335,000 cases of PN in the United States,” said Dr. Kwatra, who was among a group of researchers to recently report on systemic Th22-polarized inflammation in PN patients.

The researchers also found that patients with PN had the highest mean CCI in both 2016 and 2019. In 2016, their mean CCI was 1.53, compared with 0.98 among controls, 0.53 among those with AD, and 1.16 among those with psoriasis. In 2019, the mean CCI had increased in all groups of patients, to 2.32 among those with PN, 1.57 among controls, 0.75 among those with AD patients, and 1.71 among those with psoriasis.

The top five medical specialties who cared for PN patients, defined as the estimated number of visits per year per patient, were internal medicine (2.01 visits), dermatology (1.87 visits), family practice (1.60 visits), cardiology or cardiovascular disease (0.85 visits), and orthopedics or orthopedic surgery (0.49 visits).

“If you encounter a patient with prurigo nodularis, it’s important to perform a screening for chronic kidney disease, diabetes, and liver disease,” Dr. Kwatra said. “These comorbidities along with emerging studies on circulating blood biomarkers suggest prurigo nodularis is a systemic inflammatory disorder; thus systemic agents are needed for most patients as part of multimodal therapy in prurigo nodularis.”

The researchers acknowledged certain limitations of the study, including its retrospective design and the identification of patients with PN with the ICD-10-CM code, which require further validation. “Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in the study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession,” they wrote.

Dr. Kwatra disclosed that he is an advisory board member/consultant for AbbVie, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals, and has received grant funding from Galderma, Pfizer, and Kiniksa. He has also received a Dermatology Foundation Medical Dermatology Career Development Award, a research grant from the Skin of Color Society, and is supported by the National Institutes of Health. One coauthor has been funded by NIH grants.

dbrunk@mdedge.com

Patients with prurigo nodularis tend to make a greater number of visits to health care specialists and are burdened by a greater number of medical comorbidities, compared with age-matched controls, as well those with atopic dermatitis and psoriasis.

Those are key findings from a retrospective analysis of claims data that was published online April 3, 2021, in the Journal of Investigative Dermatology.

“Prurigo nodularis is a tremendously understudied inflammatory skin disease,” one of the study’s cosenior authors, Shawn G. Kwatra, MD, of the department of dermatology, Johns Hopkins University, Baltimore, said in an interview. “Prurigo nodularis patients have uncontrolled itch, which leads to reduced quality of life, and the association with many disease comorbidities. We focused on better understanding in this work the unique comorbidities of prurigo nodularis, compared to other inflammatory skin diseases.”

For the study, Dr. Kwatra, cosenior author Yevgeniy R. Semenov, MD, of the department of dermatology, Massachusetts General Hospital, Boston, and colleagues evaluated nationally representative, private insurance claims data from October 2015 to December 2019 to identify prurigo nodularis (PN) patients, who were defined as individuals with two or more medical claims for PN using ICD-10-CM codes. For comparison with patients with inflammatory skin diseases, they used the same claims data to identify patients with atopic dermatitis (AD) and psoriasis as well as to select controls who were age and gender matched to PN patients. Next, they quantified the overall comorbidity burden with the Charlson Comorbidity Index (CCI).

In 2016, the claims database included 2,658 patients with PN, 21,482 patients with AD, 21,073 patients with psoriasis, and 13,290 controls. The number of patients in each category rose each subsequent year, so that by the end of 2019 there were 9,426 patients with PN, 70,298 patients with AD, 59,509 patients with psoriasis, and 47,130 controls. Between 2016 and 2019 the mean age of PN patients increased from 57.5 to 59.8 years and the percent of male patients rose from 44.5% to 46.5%.

Between 2016 and 2019, the overall PN prevalence rates rose from 18 per 100,000 to 58 per 100,000, while the PN prevalence rates among adults increased from 22 per 100,000 to 70 per 100,000, and the rates among children rose grew from 2 per 100,000 to 7 per 100,000. “Our report shows an estimated disease prevalence of around 335,000 cases of PN in the United States,” said Dr. Kwatra, who was among a group of researchers to recently report on systemic Th22-polarized inflammation in PN patients.

The researchers also found that patients with PN had the highest mean CCI in both 2016 and 2019. In 2016, their mean CCI was 1.53, compared with 0.98 among controls, 0.53 among those with AD, and 1.16 among those with psoriasis. In 2019, the mean CCI had increased in all groups of patients, to 2.32 among those with PN, 1.57 among controls, 0.75 among those with AD patients, and 1.71 among those with psoriasis.

The top five medical specialties who cared for PN patients, defined as the estimated number of visits per year per patient, were internal medicine (2.01 visits), dermatology (1.87 visits), family practice (1.60 visits), cardiology or cardiovascular disease (0.85 visits), and orthopedics or orthopedic surgery (0.49 visits).

“If you encounter a patient with prurigo nodularis, it’s important to perform a screening for chronic kidney disease, diabetes, and liver disease,” Dr. Kwatra said. “These comorbidities along with emerging studies on circulating blood biomarkers suggest prurigo nodularis is a systemic inflammatory disorder; thus systemic agents are needed for most patients as part of multimodal therapy in prurigo nodularis.”

The researchers acknowledged certain limitations of the study, including its retrospective design and the identification of patients with PN with the ICD-10-CM code, which require further validation. “Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in the study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession,” they wrote.

Dr. Kwatra disclosed that he is an advisory board member/consultant for AbbVie, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals, and has received grant funding from Galderma, Pfizer, and Kiniksa. He has also received a Dermatology Foundation Medical Dermatology Career Development Award, a research grant from the Skin of Color Society, and is supported by the National Institutes of Health. One coauthor has been funded by NIH grants.

dbrunk@mdedge.com

Patients with prurigo nodularis tend to make a greater number of visits to health care specialists and are burdened by a greater number of medical comorbidities, compared with age-matched controls, as well those with atopic dermatitis and psoriasis.

Those are key findings from a retrospective analysis of claims data that was published online April 3, 2021, in the Journal of Investigative Dermatology.

“Prurigo nodularis is a tremendously understudied inflammatory skin disease,” one of the study’s cosenior authors, Shawn G. Kwatra, MD, of the department of dermatology, Johns Hopkins University, Baltimore, said in an interview. “Prurigo nodularis patients have uncontrolled itch, which leads to reduced quality of life, and the association with many disease comorbidities. We focused on better understanding in this work the unique comorbidities of prurigo nodularis, compared to other inflammatory skin diseases.”

For the study, Dr. Kwatra, cosenior author Yevgeniy R. Semenov, MD, of the department of dermatology, Massachusetts General Hospital, Boston, and colleagues evaluated nationally representative, private insurance claims data from October 2015 to December 2019 to identify prurigo nodularis (PN) patients, who were defined as individuals with two or more medical claims for PN using ICD-10-CM codes. For comparison with patients with inflammatory skin diseases, they used the same claims data to identify patients with atopic dermatitis (AD) and psoriasis as well as to select controls who were age and gender matched to PN patients. Next, they quantified the overall comorbidity burden with the Charlson Comorbidity Index (CCI).

In 2016, the claims database included 2,658 patients with PN, 21,482 patients with AD, 21,073 patients with psoriasis, and 13,290 controls. The number of patients in each category rose each subsequent year, so that by the end of 2019 there were 9,426 patients with PN, 70,298 patients with AD, 59,509 patients with psoriasis, and 47,130 controls. Between 2016 and 2019 the mean age of PN patients increased from 57.5 to 59.8 years and the percent of male patients rose from 44.5% to 46.5%.

Between 2016 and 2019, the overall PN prevalence rates rose from 18 per 100,000 to 58 per 100,000, while the PN prevalence rates among adults increased from 22 per 100,000 to 70 per 100,000, and the rates among children rose grew from 2 per 100,000 to 7 per 100,000. “Our report shows an estimated disease prevalence of around 335,000 cases of PN in the United States,” said Dr. Kwatra, who was among a group of researchers to recently report on systemic Th22-polarized inflammation in PN patients.

The researchers also found that patients with PN had the highest mean CCI in both 2016 and 2019. In 2016, their mean CCI was 1.53, compared with 0.98 among controls, 0.53 among those with AD, and 1.16 among those with psoriasis. In 2019, the mean CCI had increased in all groups of patients, to 2.32 among those with PN, 1.57 among controls, 0.75 among those with AD patients, and 1.71 among those with psoriasis.

The top five medical specialties who cared for PN patients, defined as the estimated number of visits per year per patient, were internal medicine (2.01 visits), dermatology (1.87 visits), family practice (1.60 visits), cardiology or cardiovascular disease (0.85 visits), and orthopedics or orthopedic surgery (0.49 visits).

“If you encounter a patient with prurigo nodularis, it’s important to perform a screening for chronic kidney disease, diabetes, and liver disease,” Dr. Kwatra said. “These comorbidities along with emerging studies on circulating blood biomarkers suggest prurigo nodularis is a systemic inflammatory disorder; thus systemic agents are needed for most patients as part of multimodal therapy in prurigo nodularis.”

The researchers acknowledged certain limitations of the study, including its retrospective design and the identification of patients with PN with the ICD-10-CM code, which require further validation. “Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in the study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession,” they wrote.

Dr. Kwatra disclosed that he is an advisory board member/consultant for AbbVie, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals, and has received grant funding from Galderma, Pfizer, and Kiniksa. He has also received a Dermatology Foundation Medical Dermatology Career Development Award, a research grant from the Skin of Color Society, and is supported by the National Institutes of Health. One coauthor has been funded by NIH grants.

dbrunk@mdedge.com

Dr. Ben-a-bo?

Nope.

Ben-nabi?

Nope.

Ben-NO-bo?

Also no.

My surname is tricky to pronounce for some people. I sometimes exaggerate to help patients get it right: “Beh-NAAH-bee-oh.” Almost daily someone will reply: “Oh, you’re Italian!” Well, no actually, my friend Enzo who was born in Sicily and lives in Milan, he’s Italian. I’m just a Rhode Islander who knows some Italian words from his grandmother. Most times though, I just answer: ‘Yep, I’m Italian.” It’s faster.

We use names as a shortcut to identify people. In clinic, it can help to find things in common quickly, similar to asking where you’re from. (East Coast patients seem to love that I’m from New England and if they’re Italian and from New York, well then, we’re paisans right from the start.)

However, using names to guess how someone identifies can be risky. In some instances, it could even be seen as microaggressive, particularly if you got it wrong.

Like most of you I’ll bet, I’m pretty good at pronouncing names – we practice thousands of times! Other than accepting a compliment for getting a tricky one right, such as Radivojevic (I think it’s Ra-di-VOI-ye-vich), I hadn’t thought much about names until I heard a great podcast on the topic. I thought I’d share a couple tips.

First, if you’re not particularly good at names or if you struggle with certain types of names, it’s better to ask than to butcher it. Like learning the wrong way to hit a golf ball, you may never be able to do it properly once you’ve done it wrong. (Trust me, I know from both.)

If I’m feeling confident, I’ll give it a try. But if unsure, I ask the patient to pronounce it for me, then I repeat it to confirm I’ve gotten it correct. Then I say it once or twice more during the visit. Lastly, for the knotty tongue-twisting ones, I write it phonetically in their chart.

It is important because mispronouncing names can alienate patients. It might make them feel like we don’t “know” them or that we don’t care about them. Making an effort to pronounce every patients’ name correctly I believe is a simple act we can all do to move us closer to mitigating racial biases and eliminating ethnic disparities in care. Just think how much harder it might be to convince skeptical patients to take their lisinopril if you can’t even get their names right.

Worse perhaps than getting the pronunciation wrong is to turn the name into an issue. Saying: “Oh, that’s hard to pronounce” could be felt as a subtly racist remark – it’s not hard for them to pronounce of course, only for you. Also, guessing a patient’s nationality from the name is risky. Asking “are you Russian?” to someone from Ukraine or “is that Chinese?” to someone from Vietnam can quickly turn a nice office visit down a road named “Awkward.” It can give the impression that they “all look the same” to you, exactly the type of exclusion we’re trying to eliminate in medicine.

Saying a patient’s name perfectly is rewarding and a super-efficient way to connect. It can make salient the truth that you care about the patient and about his or her story, even if the name happens to be Mrs. Xiomara Winyuwongse Khosrowshahi Sundararajan Ngoc. Go ahead, give it a try.

Want more on how properly pronounce names correctly? You might like this episode of NPR’s Life Kit.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com

Dr. Ben-a-bo?

Nope.

Ben-nabi?

Nope.

Ben-NO-bo?

Also no.

My surname is tricky to pronounce for some people. I sometimes exaggerate to help patients get it right: “Beh-NAAH-bee-oh.” Almost daily someone will reply: “Oh, you’re Italian!” Well, no actually, my friend Enzo who was born in Sicily and lives in Milan, he’s Italian. I’m just a Rhode Islander who knows some Italian words from his grandmother. Most times though, I just answer: ‘Yep, I’m Italian.” It’s faster.

We use names as a shortcut to identify people. In clinic, it can help to find things in common quickly, similar to asking where you’re from. (East Coast patients seem to love that I’m from New England and if they’re Italian and from New York, well then, we’re paisans right from the start.)

However, using names to guess how someone identifies can be risky. In some instances, it could even be seen as microaggressive, particularly if you got it wrong.

Like most of you I’ll bet, I’m pretty good at pronouncing names – we practice thousands of times! Other than accepting a compliment for getting a tricky one right, such as Radivojevic (I think it’s Ra-di-VOI-ye-vich), I hadn’t thought much about names until I heard a great podcast on the topic. I thought I’d share a couple tips.

First, if you’re not particularly good at names or if you struggle with certain types of names, it’s better to ask than to butcher it. Like learning the wrong way to hit a golf ball, you may never be able to do it properly once you’ve done it wrong. (Trust me, I know from both.)

If I’m feeling confident, I’ll give it a try. But if unsure, I ask the patient to pronounce it for me, then I repeat it to confirm I’ve gotten it correct. Then I say it once or twice more during the visit. Lastly, for the knotty tongue-twisting ones, I write it phonetically in their chart.

It is important because mispronouncing names can alienate patients. It might make them feel like we don’t “know” them or that we don’t care about them. Making an effort to pronounce every patients’ name correctly I believe is a simple act we can all do to move us closer to mitigating racial biases and eliminating ethnic disparities in care. Just think how much harder it might be to convince skeptical patients to take their lisinopril if you can’t even get their names right.

Worse perhaps than getting the pronunciation wrong is to turn the name into an issue. Saying: “Oh, that’s hard to pronounce” could be felt as a subtly racist remark – it’s not hard for them to pronounce of course, only for you. Also, guessing a patient’s nationality from the name is risky. Asking “are you Russian?” to someone from Ukraine or “is that Chinese?” to someone from Vietnam can quickly turn a nice office visit down a road named “Awkward.” It can give the impression that they “all look the same” to you, exactly the type of exclusion we’re trying to eliminate in medicine.

Saying a patient’s name perfectly is rewarding and a super-efficient way to connect. It can make salient the truth that you care about the patient and about his or her story, even if the name happens to be Mrs. Xiomara Winyuwongse Khosrowshahi Sundararajan Ngoc. Go ahead, give it a try.

Want more on how properly pronounce names correctly? You might like this episode of NPR’s Life Kit.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com

Dr. Ben-a-bo?

Nope.

Ben-nabi?

Nope.

Ben-NO-bo?

Also no.

My surname is tricky to pronounce for some people. I sometimes exaggerate to help patients get it right: “Beh-NAAH-bee-oh.” Almost daily someone will reply: “Oh, you’re Italian!” Well, no actually, my friend Enzo who was born in Sicily and lives in Milan, he’s Italian. I’m just a Rhode Islander who knows some Italian words from his grandmother. Most times though, I just answer: ‘Yep, I’m Italian.” It’s faster.

We use names as a shortcut to identify people. In clinic, it can help to find things in common quickly, similar to asking where you’re from. (East Coast patients seem to love that I’m from New England and if they’re Italian and from New York, well then, we’re paisans right from the start.)

However, using names to guess how someone identifies can be risky. In some instances, it could even be seen as microaggressive, particularly if you got it wrong.

Like most of you I’ll bet, I’m pretty good at pronouncing names – we practice thousands of times! Other than accepting a compliment for getting a tricky one right, such as Radivojevic (I think it’s Ra-di-VOI-ye-vich), I hadn’t thought much about names until I heard a great podcast on the topic. I thought I’d share a couple tips.

First, if you’re not particularly good at names or if you struggle with certain types of names, it’s better to ask than to butcher it. Like learning the wrong way to hit a golf ball, you may never be able to do it properly once you’ve done it wrong. (Trust me, I know from both.)

If I’m feeling confident, I’ll give it a try. But if unsure, I ask the patient to pronounce it for me, then I repeat it to confirm I’ve gotten it correct. Then I say it once or twice more during the visit. Lastly, for the knotty tongue-twisting ones, I write it phonetically in their chart.

It is important because mispronouncing names can alienate patients. It might make them feel like we don’t “know” them or that we don’t care about them. Making an effort to pronounce every patients’ name correctly I believe is a simple act we can all do to move us closer to mitigating racial biases and eliminating ethnic disparities in care. Just think how much harder it might be to convince skeptical patients to take their lisinopril if you can’t even get their names right.

Worse perhaps than getting the pronunciation wrong is to turn the name into an issue. Saying: “Oh, that’s hard to pronounce” could be felt as a subtly racist remark – it’s not hard for them to pronounce of course, only for you. Also, guessing a patient’s nationality from the name is risky. Asking “are you Russian?” to someone from Ukraine or “is that Chinese?” to someone from Vietnam can quickly turn a nice office visit down a road named “Awkward.” It can give the impression that they “all look the same” to you, exactly the type of exclusion we’re trying to eliminate in medicine.

Saying a patient’s name perfectly is rewarding and a super-efficient way to connect. It can make salient the truth that you care about the patient and about his or her story, even if the name happens to be Mrs. Xiomara Winyuwongse Khosrowshahi Sundararajan Ngoc. Go ahead, give it a try.

Want more on how properly pronounce names correctly? You might like this episode of NPR’s Life Kit.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com

An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”

“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.

Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.

For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).

Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.

“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.

In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.

Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.

Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.

The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.

At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.

“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.

Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.

“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.

It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.

“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.

The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.

A version of this article first appeared on Medscape.com.

An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”

“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.

Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.

For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).

Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.

“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.

In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.

Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.

Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.

The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.

At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.

“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.

Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.

“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.

It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.

“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.

The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.

A version of this article first appeared on Medscape.com.

An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”

“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.

Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.

For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).

Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.

“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.

In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.

Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.

Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.

The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.

At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.

“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.

Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.

“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.

It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.

“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.

The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.

A version of this article first appeared on Medscape.com.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Necrobiosis lipoidica, or Necrobiosis lipoidica diabeticorum (NLD), is an uncommon dermatologic condition that presents as plaques on the skin. Women are often more affected than men. Patients often present in their 30s and 40s. The cause of NLD is unknown. Twenty percent of patients with NLD will have glucose intolerance or a family history of diabetes.¹ The percentage of patients with NLD who have diabetes varies in reports from 11% to 65%.² NLD may progress despite the diabetes treatment. Only 0.03% of patient with diabetes will have NLD.³

Lesions most commonly occur on the extremities, with shins being affected in most cases. They vary from asymptomatic to painful. Typically, lesions begin as small, firm erythematous papules that evolve into shiny, well-defined plaques. In older plaques, the center will often appear yellow, depressed, and atrophic, with telangiectasias. The periphery appears pink to violaceous to brown. Ulceration may be present, particularly after trauma, and there may be decreased sensation in the plaques. NLD is clinically distinct from diabetic dermopathy, which appear as brown macules, often in older patients with diabetes.

Ideally, biopsy should be taken at the edge of a lesion. Histologically, the epidermis appears normal or atrophic. A diffuse palisaded and interstitial granulomatous dermatitis consisting of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells is seen in the dermis. Granulomas are often oriented parallel to the epidermis. There is no mucin at the center of the granulomas (as seen in granuloma annulare). Inflammation may extend into the subcutaneous fat. Asteroid bodies (as seen in sarcoid) are absent.

Unfortunately, treatment of NLD is often unsuccessful. Treatment includes potent topical corticosteroids for early lesions and intralesional triamcinolone to the leading edge of lesions. Care should be taken to avoid injecting centrally where atrophy and ulceration may result. Systemic steroids may be helpful in some cases, but can elevate glucose levels. Other reported medical treatments include pentoxifylline, cyclosporine, and niacinamide. Some lesions may spontaneously resolve. Ulcerations may require surgical excision with grafting.

This case and photo are provided by Dr. Bilu Martin, who is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. James WD et al. Andrews’ Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.

2. Hashemi D et al. JAMA Dermatol. 2019 Apr 1;155(4):455-9.

3. Bolognia JL et al. Dermatology. St. Louis, Mo.: Mosby Elsevier, 2008.

Necrobiosis lipoidica, or Necrobiosis lipoidica diabeticorum (NLD), is an uncommon dermatologic condition that presents as plaques on the skin. Women are often more affected than men. Patients often present in their 30s and 40s. The cause of NLD is unknown. Twenty percent of patients with NLD will have glucose intolerance or a family history of diabetes.¹ The percentage of patients with NLD who have diabetes varies in reports from 11% to 65%.² NLD may progress despite the diabetes treatment. Only 0.03% of patient with diabetes will have NLD.³

Lesions most commonly occur on the extremities, with shins being affected in most cases. They vary from asymptomatic to painful. Typically, lesions begin as small, firm erythematous papules that evolve into shiny, well-defined plaques. In older plaques, the center will often appear yellow, depressed, and atrophic, with telangiectasias. The periphery appears pink to violaceous to brown. Ulceration may be present, particularly after trauma, and there may be decreased sensation in the plaques. NLD is clinically distinct from diabetic dermopathy, which appear as brown macules, often in older patients with diabetes.

Ideally, biopsy should be taken at the edge of a lesion. Histologically, the epidermis appears normal or atrophic. A diffuse palisaded and interstitial granulomatous dermatitis consisting of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells is seen in the dermis. Granulomas are often oriented parallel to the epidermis. There is no mucin at the center of the granulomas (as seen in granuloma annulare). Inflammation may extend into the subcutaneous fat. Asteroid bodies (as seen in sarcoid) are absent.

Unfortunately, treatment of NLD is often unsuccessful. Treatment includes potent topical corticosteroids for early lesions and intralesional triamcinolone to the leading edge of lesions. Care should be taken to avoid injecting centrally where atrophy and ulceration may result. Systemic steroids may be helpful in some cases, but can elevate glucose levels. Other reported medical treatments include pentoxifylline, cyclosporine, and niacinamide. Some lesions may spontaneously resolve. Ulcerations may require surgical excision with grafting.

This case and photo are provided by Dr. Bilu Martin, who is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. James WD et al. Andrews’ Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.

2. Hashemi D et al. JAMA Dermatol. 2019 Apr 1;155(4):455-9.

3. Bolognia JL et al. Dermatology. St. Louis, Mo.: Mosby Elsevier, 2008.

Necrobiosis lipoidica, or Necrobiosis lipoidica diabeticorum (NLD), is an uncommon dermatologic condition that presents as plaques on the skin. Women are often more affected than men. Patients often present in their 30s and 40s. The cause of NLD is unknown. Twenty percent of patients with NLD will have glucose intolerance or a family history of diabetes.¹ The percentage of patients with NLD who have diabetes varies in reports from 11% to 65%.² NLD may progress despite the diabetes treatment. Only 0.03% of patient with diabetes will have NLD.³

Lesions most commonly occur on the extremities, with shins being affected in most cases. They vary from asymptomatic to painful. Typically, lesions begin as small, firm erythematous papules that evolve into shiny, well-defined plaques. In older plaques, the center will often appear yellow, depressed, and atrophic, with telangiectasias. The periphery appears pink to violaceous to brown. Ulceration may be present, particularly after trauma, and there may be decreased sensation in the plaques. NLD is clinically distinct from diabetic dermopathy, which appear as brown macules, often in older patients with diabetes.

Ideally, biopsy should be taken at the edge of a lesion. Histologically, the epidermis appears normal or atrophic. A diffuse palisaded and interstitial granulomatous dermatitis consisting of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells is seen in the dermis. Granulomas are often oriented parallel to the epidermis. There is no mucin at the center of the granulomas (as seen in granuloma annulare). Inflammation may extend into the subcutaneous fat. Asteroid bodies (as seen in sarcoid) are absent.

Unfortunately, treatment of NLD is often unsuccessful. Treatment includes potent topical corticosteroids for early lesions and intralesional triamcinolone to the leading edge of lesions. Care should be taken to avoid injecting centrally where atrophy and ulceration may result. Systemic steroids may be helpful in some cases, but can elevate glucose levels. Other reported medical treatments include pentoxifylline, cyclosporine, and niacinamide. Some lesions may spontaneously resolve. Ulcerations may require surgical excision with grafting.

This case and photo are provided by Dr. Bilu Martin, who is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. James WD et al. Andrews’ Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.

2. Hashemi D et al. JAMA Dermatol. 2019 Apr 1;155(4):455-9.

3. Bolognia JL et al. Dermatology. St. Louis, Mo.: Mosby Elsevier, 2008.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

First-line tebentafusp significantly improved overall survival (OS) when compared with immunotherapy or chemotherapy in patients with metastatic uveal melanoma in a phase 3 trial.

Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).

Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.

In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.

Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
 

Prolonged OS despite low response rate

At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.

At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).

The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.

The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.

Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.

“So this drug is slowing down developing disease,” she said.
 

‘Manageable’ adverse events

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.

While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.

The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
 

‘Practice-changing’ results

“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.

She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.

The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.

The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.