Nonmelanoma Skin Cancer

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

To the Editor:

Kaposi sarcoma (KS) is a rare angioproliferative disorder associated with human herpesvirus 8 (HHV-8) infection.¹ There are 4 main recognized epidemiologic forms of KS: classic, endemic, epidemic, and iatrogenic (Table). Nonepidemic KS is a recently described rare fifth type of KS that occurs in a subset of patients who do not fit the other classifications—HIV-negative patients without detectable cellular or humoral immune deficiency. This subset has been described as clinically similar to classic KS with limited disease but occurring in younger men.^2,3 We describe a case of nonepidemic KS in a Middle Eastern heterosexual immunocompetent man.

A 30-year-old man presented for evaluation of a growth on the nose of 3 months’ duration. The patient reported being otherwise healthy and was not taking long-term medications. He denied a history of malignancy, organ transplant, or immunosuppressive therapy. He was born in Syria and lived in Thailand for several years prior to moving to the United States. HIV testing 6 months prior to presentation was negative. He denied fever, chills, lymphadenopathy, shortness of breath, hemoptysis, melena, hematochezia, and intravenous drug use.

Physical examination revealed a solitary shiny, 7-mm, pink-red papule on the nasal dorsum (Figure 1). No other skin or mucosal lesions were identified. There was no cervical, axillary, or inguinal lymphadenopathy. A laboratory workup consisting of serum immunoglobulins and serum protein electrophoresis was unremarkable. Tests for HIV-1 and HIV-2 as well as human T-lymphotropic virus 1 and 2 were negative. The CD4 and CD8 counts were within reference range. Histopathology of a shave biopsy revealed a dermal spindle cell proliferation arranged in short intersecting fascicles and admixed with plasma cells and occasional mitotic figures. Immunohistochemistry showed that the spindle cells stained positive for CD34, CD31, and HHV-8 (Figure 2). The lesion resolved after treatment with cryotherapy. Repeat HIV testing 3 months later was negative. No recurrence or new lesions were identified at 3-month follow-up.

Similar to the other subtypes of KS, the nonepidemic form is dependent on HHV-8 infection, which is more commonly transmitted via saliva and sexual contact.^3,4 After infecting endothelial cells, HHV-8 is believed to activate the mammalian target of rapamycin and nuclear factor κB pathways, resulting in aberrant cellular differentiation and neoangiogenesis through upregulation of vascular endothelial growth factor and basic fibroblast growth factor.^2,4 Similar to what is seen with other herpesviruses, HHV-8 infection typically is lifelong due to the virus’s ability to establish latency within human B cells and endothelial cells as well as undergo sporadic bouts of lytic reactivation during its life cycle.⁴

Nonepidemic KS resembles other variants clinically, manifesting as erythematous or violaceous, painless, nonblanchable macules, papules, and nodules.¹ Early lesions often are asymptomatic and can manifest as pigmented macules or small papules that vary from pale pink to vivid purple. Nodules also can occur and be exophytic and ulcerated with bleeding.¹ Secondary lymphoproliferative disorders including Castleman disease and lymphoma have been reported.^2,5

In contrast to other types of KS in which pulmonary or gastrointestinal tract lesions can develop with hemoptysis or hematochezia, mucocutaneous and visceral lesions rarely are reported in nonepidemic KS.³ Lymphedema, a feature associated with endemic KS, is notably absent in nonepidemic KS.^1,3

The differential diagnosis applicable to all KS subtypes includes other vascular lesions such as angiomatosis and angiosarcoma. Histopathologic analysis is critical to differentiate KS from these conditions; visual diagnosis alone has only an 80% positive predictive value for KS.⁴ The histopathologic presentation of KS is a vascular proliferation in the dermis accompanied by an increased number of vessels without an endothelial cell lining.⁴ Spindle cell proliferation also is a common feature and is considered to be the KS tumor cell. Immunostaining for HHV-8 antigen as well as for CD31 and CD34 can be used to confirm the diagnosis.⁴

The management and prognosis of KS depends on the epidemiologic subtype. Classic and nonepidemic KS generally are indolent with a good prognosis. Periodic follow-up is recommended because of an increased risk for secondary malignancy such as lymphoma. The treatment of epidemic KS is highly active antiretroviral therapy. Similarly, reduction of immunosuppression is warranted for iatrogenic KS. For all types, cutaneous lesions can be treated with local excision, cryosurgery, radiation, chemotherapy, intralesional vincristine, or a topical agent such as imiquimod or alitretinoin.⁶

To the Editor:

Kaposi sarcoma (KS) is a rare angioproliferative disorder associated with human herpesvirus 8 (HHV-8) infection.¹ There are 4 main recognized epidemiologic forms of KS: classic, endemic, epidemic, and iatrogenic (Table). Nonepidemic KS is a recently described rare fifth type of KS that occurs in a subset of patients who do not fit the other classifications—HIV-negative patients without detectable cellular or humoral immune deficiency. This subset has been described as clinically similar to classic KS with limited disease but occurring in younger men.^2,3 We describe a case of nonepidemic KS in a Middle Eastern heterosexual immunocompetent man.

A 30-year-old man presented for evaluation of a growth on the nose of 3 months’ duration. The patient reported being otherwise healthy and was not taking long-term medications. He denied a history of malignancy, organ transplant, or immunosuppressive therapy. He was born in Syria and lived in Thailand for several years prior to moving to the United States. HIV testing 6 months prior to presentation was negative. He denied fever, chills, lymphadenopathy, shortness of breath, hemoptysis, melena, hematochezia, and intravenous drug use.

Physical examination revealed a solitary shiny, 7-mm, pink-red papule on the nasal dorsum (Figure 1). No other skin or mucosal lesions were identified. There was no cervical, axillary, or inguinal lymphadenopathy. A laboratory workup consisting of serum immunoglobulins and serum protein electrophoresis was unremarkable. Tests for HIV-1 and HIV-2 as well as human T-lymphotropic virus 1 and 2 were negative. The CD4 and CD8 counts were within reference range. Histopathology of a shave biopsy revealed a dermal spindle cell proliferation arranged in short intersecting fascicles and admixed with plasma cells and occasional mitotic figures. Immunohistochemistry showed that the spindle cells stained positive for CD34, CD31, and HHV-8 (Figure 2). The lesion resolved after treatment with cryotherapy. Repeat HIV testing 3 months later was negative. No recurrence or new lesions were identified at 3-month follow-up.

Similar to the other subtypes of KS, the nonepidemic form is dependent on HHV-8 infection, which is more commonly transmitted via saliva and sexual contact.^3,4 After infecting endothelial cells, HHV-8 is believed to activate the mammalian target of rapamycin and nuclear factor κB pathways, resulting in aberrant cellular differentiation and neoangiogenesis through upregulation of vascular endothelial growth factor and basic fibroblast growth factor.^2,4 Similar to what is seen with other herpesviruses, HHV-8 infection typically is lifelong due to the virus’s ability to establish latency within human B cells and endothelial cells as well as undergo sporadic bouts of lytic reactivation during its life cycle.⁴

Nonepidemic KS resembles other variants clinically, manifesting as erythematous or violaceous, painless, nonblanchable macules, papules, and nodules.¹ Early lesions often are asymptomatic and can manifest as pigmented macules or small papules that vary from pale pink to vivid purple. Nodules also can occur and be exophytic and ulcerated with bleeding.¹ Secondary lymphoproliferative disorders including Castleman disease and lymphoma have been reported.^2,5

In contrast to other types of KS in which pulmonary or gastrointestinal tract lesions can develop with hemoptysis or hematochezia, mucocutaneous and visceral lesions rarely are reported in nonepidemic KS.³ Lymphedema, a feature associated with endemic KS, is notably absent in nonepidemic KS.^1,3

The differential diagnosis applicable to all KS subtypes includes other vascular lesions such as angiomatosis and angiosarcoma. Histopathologic analysis is critical to differentiate KS from these conditions; visual diagnosis alone has only an 80% positive predictive value for KS.⁴ The histopathologic presentation of KS is a vascular proliferation in the dermis accompanied by an increased number of vessels without an endothelial cell lining.⁴ Spindle cell proliferation also is a common feature and is considered to be the KS tumor cell. Immunostaining for HHV-8 antigen as well as for CD31 and CD34 can be used to confirm the diagnosis.⁴

The management and prognosis of KS depends on the epidemiologic subtype. Classic and nonepidemic KS generally are indolent with a good prognosis. Periodic follow-up is recommended because of an increased risk for secondary malignancy such as lymphoma. The treatment of epidemic KS is highly active antiretroviral therapy. Similarly, reduction of immunosuppression is warranted for iatrogenic KS. For all types, cutaneous lesions can be treated with local excision, cryosurgery, radiation, chemotherapy, intralesional vincristine, or a topical agent such as imiquimod or alitretinoin.⁶

To the Editor:

Kaposi sarcoma (KS) is a rare angioproliferative disorder associated with human herpesvirus 8 (HHV-8) infection.¹ There are 4 main recognized epidemiologic forms of KS: classic, endemic, epidemic, and iatrogenic (Table). Nonepidemic KS is a recently described rare fifth type of KS that occurs in a subset of patients who do not fit the other classifications—HIV-negative patients without detectable cellular or humoral immune deficiency. This subset has been described as clinically similar to classic KS with limited disease but occurring in younger men.^2,3 We describe a case of nonepidemic KS in a Middle Eastern heterosexual immunocompetent man.

A 30-year-old man presented for evaluation of a growth on the nose of 3 months’ duration. The patient reported being otherwise healthy and was not taking long-term medications. He denied a history of malignancy, organ transplant, or immunosuppressive therapy. He was born in Syria and lived in Thailand for several years prior to moving to the United States. HIV testing 6 months prior to presentation was negative. He denied fever, chills, lymphadenopathy, shortness of breath, hemoptysis, melena, hematochezia, and intravenous drug use.

Physical examination revealed a solitary shiny, 7-mm, pink-red papule on the nasal dorsum (Figure 1). No other skin or mucosal lesions were identified. There was no cervical, axillary, or inguinal lymphadenopathy. A laboratory workup consisting of serum immunoglobulins and serum protein electrophoresis was unremarkable. Tests for HIV-1 and HIV-2 as well as human T-lymphotropic virus 1 and 2 were negative. The CD4 and CD8 counts were within reference range. Histopathology of a shave biopsy revealed a dermal spindle cell proliferation arranged in short intersecting fascicles and admixed with plasma cells and occasional mitotic figures. Immunohistochemistry showed that the spindle cells stained positive for CD34, CD31, and HHV-8 (Figure 2). The lesion resolved after treatment with cryotherapy. Repeat HIV testing 3 months later was negative. No recurrence or new lesions were identified at 3-month follow-up.

Similar to the other subtypes of KS, the nonepidemic form is dependent on HHV-8 infection, which is more commonly transmitted via saliva and sexual contact.^3,4 After infecting endothelial cells, HHV-8 is believed to activate the mammalian target of rapamycin and nuclear factor κB pathways, resulting in aberrant cellular differentiation and neoangiogenesis through upregulation of vascular endothelial growth factor and basic fibroblast growth factor.^2,4 Similar to what is seen with other herpesviruses, HHV-8 infection typically is lifelong due to the virus’s ability to establish latency within human B cells and endothelial cells as well as undergo sporadic bouts of lytic reactivation during its life cycle.⁴

Nonepidemic KS resembles other variants clinically, manifesting as erythematous or violaceous, painless, nonblanchable macules, papules, and nodules.¹ Early lesions often are asymptomatic and can manifest as pigmented macules or small papules that vary from pale pink to vivid purple. Nodules also can occur and be exophytic and ulcerated with bleeding.¹ Secondary lymphoproliferative disorders including Castleman disease and lymphoma have been reported.^2,5

In contrast to other types of KS in which pulmonary or gastrointestinal tract lesions can develop with hemoptysis or hematochezia, mucocutaneous and visceral lesions rarely are reported in nonepidemic KS.³ Lymphedema, a feature associated with endemic KS, is notably absent in nonepidemic KS.^1,3

The differential diagnosis applicable to all KS subtypes includes other vascular lesions such as angiomatosis and angiosarcoma. Histopathologic analysis is critical to differentiate KS from these conditions; visual diagnosis alone has only an 80% positive predictive value for KS.⁴ The histopathologic presentation of KS is a vascular proliferation in the dermis accompanied by an increased number of vessels without an endothelial cell lining.⁴ Spindle cell proliferation also is a common feature and is considered to be the KS tumor cell. Immunostaining for HHV-8 antigen as well as for CD31 and CD34 can be used to confirm the diagnosis.⁴

The management and prognosis of KS depends on the epidemiologic subtype. Classic and nonepidemic KS generally are indolent with a good prognosis. Periodic follow-up is recommended because of an increased risk for secondary malignancy such as lymphoma. The treatment of epidemic KS is highly active antiretroviral therapy. Similarly, reduction of immunosuppression is warranted for iatrogenic KS. For all types, cutaneous lesions can be treated with local excision, cryosurgery, radiation, chemotherapy, intralesional vincristine, or a topical agent such as imiquimod or alitretinoin.⁶

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

To the Editor:

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon peripheral T-cell lymphoma that accounts for 1% to 2% of all forms of non-Hodgkin lymphoma and usually affects middle-aged individuals.¹ It primarily appears on the skin and mimics an inflammatory dermatosis, leading to diagnostic and therapeutic delays.² No gold-standard treatment has been identified for AITL; the prognosis often remains poor, with a 5-year progression-free survival rate of approximately 25%.³ Because of the rarity of AITL and the unmet need of a standard-of-care treatment regimen, relapsing and remitting disease is common and continues to challenge clinicians.

Methotrexate (MTX), a dihydrofolate reductase inhibitor used to treat many autoimmune diseases, is prescribed at a higher dosage (>500 mg/m²) to manage cancers, including refractory AITL.⁴ In blocking dihydrofolate reductase, MTX reduces the folate pool, with the possible adverse effect of bone marrow suppression. Another important toxic effect is acute kidney injury, which may be due to an overdose of MTX or a patient’s predisposition to chronic kidney failure.⁴

A 50-year-old man was admitted to our inpatient clinic for evaluation of acute oral and genital mucositis. He had a 5-year history of AITL. He was previously treated by hematology with 3 lines of chemotherapy for multiple supradiaphragmatic and subdiaphragmatic localizations of lymphoma, without success. Six days prior to the current presentation, the hematologist started high-dose (3.5 g/m²) intravenous MTX therapy. Five days later, the patient developed transfusion-resistant pancytopenia and fever (maximum body temperature, 102.7°F [39.3°C]).

Physical examination at the current presentation revealed massive necrosis of the lower lip (Figure, A) and partial necrosis of the upper lip. Severe purulent balanoposthitis, causing penile edema and phimosis, complicated the clinical condition. Analysis of a specimen from a cutaneous swab of the penis showed infection with Pseudomonas aeruginosa and Enterococcus faecalis. Considering the clinical presentation and time of onset of signs and symptoms, a diagnosis of acute MTX-induced mucositis was made.

Rescue therapy was started immediately, including high-dose intravenous leucovorin (120 mg 4 times daily), oral sulfamethoxazole-trimethoprim (800 mg/160 mg 3 times daily for 3 days per week), and oral levofloxacin (500 mg/d). After 4 days of treatment, the patient was afebrile. Mucositis of the lips had almost resolved (Figure, B), and balanoposthitis also improved after this rescue therapy. Methotrexate was not resumed because rituximab had been started.

To the Editor:

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon peripheral T-cell lymphoma that accounts for 1% to 2% of all forms of non-Hodgkin lymphoma and usually affects middle-aged individuals.¹ It primarily appears on the skin and mimics an inflammatory dermatosis, leading to diagnostic and therapeutic delays.² No gold-standard treatment has been identified for AITL; the prognosis often remains poor, with a 5-year progression-free survival rate of approximately 25%.³ Because of the rarity of AITL and the unmet need of a standard-of-care treatment regimen, relapsing and remitting disease is common and continues to challenge clinicians.

Methotrexate (MTX), a dihydrofolate reductase inhibitor used to treat many autoimmune diseases, is prescribed at a higher dosage (>500 mg/m²) to manage cancers, including refractory AITL.⁴ In blocking dihydrofolate reductase, MTX reduces the folate pool, with the possible adverse effect of bone marrow suppression. Another important toxic effect is acute kidney injury, which may be due to an overdose of MTX or a patient’s predisposition to chronic kidney failure.⁴

A 50-year-old man was admitted to our inpatient clinic for evaluation of acute oral and genital mucositis. He had a 5-year history of AITL. He was previously treated by hematology with 3 lines of chemotherapy for multiple supradiaphragmatic and subdiaphragmatic localizations of lymphoma, without success. Six days prior to the current presentation, the hematologist started high-dose (3.5 g/m²) intravenous MTX therapy. Five days later, the patient developed transfusion-resistant pancytopenia and fever (maximum body temperature, 102.7°F [39.3°C]).

Physical examination at the current presentation revealed massive necrosis of the lower lip (Figure, A) and partial necrosis of the upper lip. Severe purulent balanoposthitis, causing penile edema and phimosis, complicated the clinical condition. Analysis of a specimen from a cutaneous swab of the penis showed infection with Pseudomonas aeruginosa and Enterococcus faecalis. Considering the clinical presentation and time of onset of signs and symptoms, a diagnosis of acute MTX-induced mucositis was made.

Rescue therapy was started immediately, including high-dose intravenous leucovorin (120 mg 4 times daily), oral sulfamethoxazole-trimethoprim (800 mg/160 mg 3 times daily for 3 days per week), and oral levofloxacin (500 mg/d). After 4 days of treatment, the patient was afebrile. Mucositis of the lips had almost resolved (Figure, B), and balanoposthitis also improved after this rescue therapy. Methotrexate was not resumed because rituximab had been started.

To the Editor:

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon peripheral T-cell lymphoma that accounts for 1% to 2% of all forms of non-Hodgkin lymphoma and usually affects middle-aged individuals.¹ It primarily appears on the skin and mimics an inflammatory dermatosis, leading to diagnostic and therapeutic delays.² No gold-standard treatment has been identified for AITL; the prognosis often remains poor, with a 5-year progression-free survival rate of approximately 25%.³ Because of the rarity of AITL and the unmet need of a standard-of-care treatment regimen, relapsing and remitting disease is common and continues to challenge clinicians.

Methotrexate (MTX), a dihydrofolate reductase inhibitor used to treat many autoimmune diseases, is prescribed at a higher dosage (>500 mg/m²) to manage cancers, including refractory AITL.⁴ In blocking dihydrofolate reductase, MTX reduces the folate pool, with the possible adverse effect of bone marrow suppression. Another important toxic effect is acute kidney injury, which may be due to an overdose of MTX or a patient’s predisposition to chronic kidney failure.⁴

A 50-year-old man was admitted to our inpatient clinic for evaluation of acute oral and genital mucositis. He had a 5-year history of AITL. He was previously treated by hematology with 3 lines of chemotherapy for multiple supradiaphragmatic and subdiaphragmatic localizations of lymphoma, without success. Six days prior to the current presentation, the hematologist started high-dose (3.5 g/m²) intravenous MTX therapy. Five days later, the patient developed transfusion-resistant pancytopenia and fever (maximum body temperature, 102.7°F [39.3°C]).

Physical examination at the current presentation revealed massive necrosis of the lower lip (Figure, A) and partial necrosis of the upper lip. Severe purulent balanoposthitis, causing penile edema and phimosis, complicated the clinical condition. Analysis of a specimen from a cutaneous swab of the penis showed infection with Pseudomonas aeruginosa and Enterococcus faecalis. Considering the clinical presentation and time of onset of signs and symptoms, a diagnosis of acute MTX-induced mucositis was made.

Rescue therapy was started immediately, including high-dose intravenous leucovorin (120 mg 4 times daily), oral sulfamethoxazole-trimethoprim (800 mg/160 mg 3 times daily for 3 days per week), and oral levofloxacin (500 mg/d). After 4 days of treatment, the patient was afebrile. Mucositis of the lips had almost resolved (Figure, B), and balanoposthitis also improved after this rescue therapy. Methotrexate was not resumed because rituximab had been started.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Radiation oncologists from the largest professional societies have come together to lobby for Medicare payment reform.

The American Society for Radiation Oncology (ASTRO) recently announced its partnership with three other groups — the American College of Radiation Oncology, the American College of Radiology, and the American Society of Clinical Oncology — to change how the specialty is paid for services. 

Over the past decade, radiation oncologists have seen a 23% drop in Medicare reimbursement for radiation therapy services, with more cuts to come, according to a press release from ASTRO.

Traditionally, Medicare has reimbursed on the basis of the fraction of radiation delivered. But with moves toward hypofractionated regimens, deescalated therapy, and other changes in the field, reimbursement has continued to dwindle. 

The cuts have led to practice consolidation and closures that threaten patient access especially in rural and underserved areas, a spokesperson for the group told this news organization.

To reverse this trend, ASTRO recently proposed the Radiation Oncology Case Rate program, a legislative initiative to base reimbursements on patient volumes instead of fractions delivered. 

ASTRO is currently drafting a congressional bill to change the current payment structure, which “has become untenable,” the spokesperson said. 

A version of this article appeared on Medscape.com.

Radiation oncologists from the largest professional societies have come together to lobby for Medicare payment reform.

The American Society for Radiation Oncology (ASTRO) recently announced its partnership with three other groups — the American College of Radiation Oncology, the American College of Radiology, and the American Society of Clinical Oncology — to change how the specialty is paid for services. 

Over the past decade, radiation oncologists have seen a 23% drop in Medicare reimbursement for radiation therapy services, with more cuts to come, according to a press release from ASTRO.

Traditionally, Medicare has reimbursed on the basis of the fraction of radiation delivered. But with moves toward hypofractionated regimens, deescalated therapy, and other changes in the field, reimbursement has continued to dwindle. 

The cuts have led to practice consolidation and closures that threaten patient access especially in rural and underserved areas, a spokesperson for the group told this news organization.

To reverse this trend, ASTRO recently proposed the Radiation Oncology Case Rate program, a legislative initiative to base reimbursements on patient volumes instead of fractions delivered. 

ASTRO is currently drafting a congressional bill to change the current payment structure, which “has become untenable,” the spokesperson said. 

A version of this article appeared on Medscape.com.

Radiation oncologists from the largest professional societies have come together to lobby for Medicare payment reform.

The American Society for Radiation Oncology (ASTRO) recently announced its partnership with three other groups — the American College of Radiation Oncology, the American College of Radiology, and the American Society of Clinical Oncology — to change how the specialty is paid for services. 

Over the past decade, radiation oncologists have seen a 23% drop in Medicare reimbursement for radiation therapy services, with more cuts to come, according to a press release from ASTRO.

Traditionally, Medicare has reimbursed on the basis of the fraction of radiation delivered. But with moves toward hypofractionated regimens, deescalated therapy, and other changes in the field, reimbursement has continued to dwindle. 

The cuts have led to practice consolidation and closures that threaten patient access especially in rural and underserved areas, a spokesperson for the group told this news organization.

To reverse this trend, ASTRO recently proposed the Radiation Oncology Case Rate program, a legislative initiative to base reimbursements on patient volumes instead of fractions delivered. 

ASTRO is currently drafting a congressional bill to change the current payment structure, which “has become untenable,” the spokesperson said. 

A version of this article appeared on Medscape.com.