LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.

“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”

Courtesy Larry Young

Better approaches by subtype?

The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.

In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).

A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.

For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
 

Timing may also matter

Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.

The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.

Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.

Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

hematologynews@frontlinemedcom.com

LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.

“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”

Courtesy Larry Young

Better approaches by subtype?

The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.

In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).

A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.

For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
 

Timing may also matter

Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.

The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.

Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.

Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

hematologynews@frontlinemedcom.com

LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.

“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”

Courtesy Larry Young

Better approaches by subtype?

The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.

In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).

A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.

For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
 

Timing may also matter

Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.

The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.

Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.

Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

hematologynews@frontlinemedcom.com

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

sworcester@frontlinemedcom.com

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

sworcester@frontlinemedcom.com

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

sworcester@frontlinemedcom.com

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

Question: Paramedics brought an unconscious 70-year-old man to a Florida hospital emergency department. The patient had the words “Do Not Resuscitate” tattooed onto his chest. No one accompanied him, and he had no identifications on his person. His blood alcohol level was elevated, and a few hours after his arrival, he lapsed into severe metabolic acidosis and hypotensive shock. The treating team decided to enter a DNR order, and the patient died shortly thereafter without benefit of cardiopulmonary resuscitation.

Which of the following is best?

A. An ethics consult may suggest honoring the patient’s DNR wishes, as it is reasonable to infer that the tattoo expressed an authentic preference.

B. It has been said, but remains debatable, that tattoos might represent “permanent reminders of regretted decisions made while the person was intoxicated.”

C. An earlier case report in the literature cautioned that the tattooed expression of a DNR request did not reflect that particular patient’s current wishes.

D. If this patient’s Florida Department of Health out-of-hospital DNR order confirms his DNR preference, then it is appropriate to withhold resuscitation.

E. All are correct.


ANSWER: E. The above hypothetical situation is modified from a recent case report in the correspondence section of the New England Journal of Medicine.¹ It can be read as offering a sharp and dramatic focus on the issue of consent surrounding decisions to withhold CPR.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine supported DNR protocols (“no code”) based on three value considerations: self-determination, well-being, and equity.²

Daisy-Daisy/Thinkstock

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at siang@hawaii.edu.

References

1. N Engl J Med. 2017 Nov 30;377(22):2192-3.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment. Washington, DC: Government Printing Office, 1983.

3. J Gen Intern Med. 2011 Jul;26(7):791-7.

4. JAMA. 1995 Nov 22-29;274(20):1591-8.

5. Hawaii Med J. 2001 Mar;60(3):64-7.

6. N Engl J Med. 1997 Jun 26;336(26):1908-10.

7. Tan SY. Futility and DNR Orders. Internal Medicine News, March 21, 2014.

8. Gilgunn v. Mass. General Hosp. No. 92-4820 (Mass. Super Ct. Apr. 21, 1995).

9. In re Baby K, 16 F.3d 590 (4th Cir. 1994).

Question: Paramedics brought an unconscious 70-year-old man to a Florida hospital emergency department. The patient had the words “Do Not Resuscitate” tattooed onto his chest. No one accompanied him, and he had no identifications on his person. His blood alcohol level was elevated, and a few hours after his arrival, he lapsed into severe metabolic acidosis and hypotensive shock. The treating team decided to enter a DNR order, and the patient died shortly thereafter without benefit of cardiopulmonary resuscitation.

Which of the following is best?

A. An ethics consult may suggest honoring the patient’s DNR wishes, as it is reasonable to infer that the tattoo expressed an authentic preference.

B. It has been said, but remains debatable, that tattoos might represent “permanent reminders of regretted decisions made while the person was intoxicated.”

C. An earlier case report in the literature cautioned that the tattooed expression of a DNR request did not reflect that particular patient’s current wishes.

D. If this patient’s Florida Department of Health out-of-hospital DNR order confirms his DNR preference, then it is appropriate to withhold resuscitation.

E. All are correct.


ANSWER: E. The above hypothetical situation is modified from a recent case report in the correspondence section of the New England Journal of Medicine.¹ It can be read as offering a sharp and dramatic focus on the issue of consent surrounding decisions to withhold CPR.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine supported DNR protocols (“no code”) based on three value considerations: self-determination, well-being, and equity.²

Daisy-Daisy/Thinkstock

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at siang@hawaii.edu.

References

1. N Engl J Med. 2017 Nov 30;377(22):2192-3.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment. Washington, DC: Government Printing Office, 1983.

3. J Gen Intern Med. 2011 Jul;26(7):791-7.

4. JAMA. 1995 Nov 22-29;274(20):1591-8.

5. Hawaii Med J. 2001 Mar;60(3):64-7.

6. N Engl J Med. 1997 Jun 26;336(26):1908-10.

7. Tan SY. Futility and DNR Orders. Internal Medicine News, March 21, 2014.

8. Gilgunn v. Mass. General Hosp. No. 92-4820 (Mass. Super Ct. Apr. 21, 1995).

9. In re Baby K, 16 F.3d 590 (4th Cir. 1994).

Question: Paramedics brought an unconscious 70-year-old man to a Florida hospital emergency department. The patient had the words “Do Not Resuscitate” tattooed onto his chest. No one accompanied him, and he had no identifications on his person. His blood alcohol level was elevated, and a few hours after his arrival, he lapsed into severe metabolic acidosis and hypotensive shock. The treating team decided to enter a DNR order, and the patient died shortly thereafter without benefit of cardiopulmonary resuscitation.

Which of the following is best?

A. An ethics consult may suggest honoring the patient’s DNR wishes, as it is reasonable to infer that the tattoo expressed an authentic preference.

B. It has been said, but remains debatable, that tattoos might represent “permanent reminders of regretted decisions made while the person was intoxicated.”

C. An earlier case report in the literature cautioned that the tattooed expression of a DNR request did not reflect that particular patient’s current wishes.

D. If this patient’s Florida Department of Health out-of-hospital DNR order confirms his DNR preference, then it is appropriate to withhold resuscitation.

E. All are correct.


ANSWER: E. The above hypothetical situation is modified from a recent case report in the correspondence section of the New England Journal of Medicine.¹ It can be read as offering a sharp and dramatic focus on the issue of consent surrounding decisions to withhold CPR.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine supported DNR protocols (“no code”) based on three value considerations: self-determination, well-being, and equity.²

Daisy-Daisy/Thinkstock

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at siang@hawaii.edu.

References

1. N Engl J Med. 2017 Nov 30;377(22):2192-3.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment. Washington, DC: Government Printing Office, 1983.

3. J Gen Intern Med. 2011 Jul;26(7):791-7.

4. JAMA. 1995 Nov 22-29;274(20):1591-8.

5. Hawaii Med J. 2001 Mar;60(3):64-7.

6. N Engl J Med. 1997 Jun 26;336(26):1908-10.

7. Tan SY. Futility and DNR Orders. Internal Medicine News, March 21, 2014.

8. Gilgunn v. Mass. General Hosp. No. 92-4820 (Mass. Super Ct. Apr. 21, 1995).

9. In re Baby K, 16 F.3d 590 (4th Cir. 1994).

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

koakes@frontlinemedcom.com

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

koakes@frontlinemedcom.com

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

koakes@frontlinemedcom.com

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

Patients admitted to medical intensive care units may be exposed to doses of radiation that are substantial and exceed federal annual occupational limits, according to results of a recent observational study.

These “substantial” radiation doses in some patients suggest that efforts are warranted to “justify, restrict and optimize” the use of radiological resources when possible, said Sudhir Krishnan, MD, of the Cleveland Clinic, and his coauthors.

Blend Images/Fotolia

SOURCE: Krishnan S et al. Chest. 2018 Feb 4. doi: 10.1016/j.chest.2018.01.019.

Patients admitted to medical intensive care units may be exposed to doses of radiation that are substantial and exceed federal annual occupational limits, according to results of a recent observational study.

These “substantial” radiation doses in some patients suggest that efforts are warranted to “justify, restrict and optimize” the use of radiological resources when possible, said Sudhir Krishnan, MD, of the Cleveland Clinic, and his coauthors.

Blend Images/Fotolia

SOURCE: Krishnan S et al. Chest. 2018 Feb 4. doi: 10.1016/j.chest.2018.01.019.

Patients admitted to medical intensive care units may be exposed to doses of radiation that are substantial and exceed federal annual occupational limits, according to results of a recent observational study.

These “substantial” radiation doses in some patients suggest that efforts are warranted to “justify, restrict and optimize” the use of radiological resources when possible, said Sudhir Krishnan, MD, of the Cleveland Clinic, and his coauthors.

Blend Images/Fotolia

SOURCE: Krishnan S et al. Chest. 2018 Feb 4. doi: 10.1016/j.chest.2018.01.019.

Colon and rectal cancer mortality is expected to be about 15.5/100,000 population in 2018, with the highest rate in West Virginia and lowest in Utah.

Approximately 50,630 deaths from colorectal cancer are predicted for the year in the United States by the American Cancer Society (ACS) in its Cancer Facts & Figures 2018, based on analysis of 2001-2015 data from the National Center for Health Statistics.

Nationally, the colorectal cancer death rate has been declining for decades, but hidden inside that long-term trend are a couple of competing ones: From 2006 to 2015, mortality dropped 2.9% a year for those aged 55 years and older but increased by 1% annually for adults aged 55 and under, the ACS said.

Incidence rates for colon cancer and rectal cancer showed a similar trend: From 2005 to 2015 they were down by 3.8% (colon) and 3.5% (rectal) a year for adults aged 55 and older but rose 1.4% and 2.4%, respectively, for adults younger than 55. Accurate statistics on colon and rectal cancer deaths are not available separately “because many deaths from rectal cancer are misclassified as colon cancer on death certificates,” the ACS said.

rfranki@frontlinemedcom.com

Colon and rectal cancer mortality is expected to be about 15.5/100,000 population in 2018, with the highest rate in West Virginia and lowest in Utah.

Approximately 50,630 deaths from colorectal cancer are predicted for the year in the United States by the American Cancer Society (ACS) in its Cancer Facts & Figures 2018, based on analysis of 2001-2015 data from the National Center for Health Statistics.

Nationally, the colorectal cancer death rate has been declining for decades, but hidden inside that long-term trend are a couple of competing ones: From 2006 to 2015, mortality dropped 2.9% a year for those aged 55 years and older but increased by 1% annually for adults aged 55 and under, the ACS said.

Incidence rates for colon cancer and rectal cancer showed a similar trend: From 2005 to 2015 they were down by 3.8% (colon) and 3.5% (rectal) a year for adults aged 55 and older but rose 1.4% and 2.4%, respectively, for adults younger than 55. Accurate statistics on colon and rectal cancer deaths are not available separately “because many deaths from rectal cancer are misclassified as colon cancer on death certificates,” the ACS said.

rfranki@frontlinemedcom.com

Colon and rectal cancer mortality is expected to be about 15.5/100,000 population in 2018, with the highest rate in West Virginia and lowest in Utah.

Approximately 50,630 deaths from colorectal cancer are predicted for the year in the United States by the American Cancer Society (ACS) in its Cancer Facts & Figures 2018, based on analysis of 2001-2015 data from the National Center for Health Statistics.

Nationally, the colorectal cancer death rate has been declining for decades, but hidden inside that long-term trend are a couple of competing ones: From 2006 to 2015, mortality dropped 2.9% a year for those aged 55 years and older but increased by 1% annually for adults aged 55 and under, the ACS said.

Incidence rates for colon cancer and rectal cancer showed a similar trend: From 2005 to 2015 they were down by 3.8% (colon) and 3.5% (rectal) a year for adults aged 55 and older but rose 1.4% and 2.4%, respectively, for adults younger than 55. Accurate statistics on colon and rectal cancer deaths are not available separately “because many deaths from rectal cancer are misclassified as colon cancer on death certificates,” the ACS said.

rfranki@frontlinemedcom.com

Veterans with posttraumatic stress disorder might benefit from therapeutic horseback riding, a small study suggests.

“Our findings provide empirical evidence that [therapeutic horseback riding] is effective at improving coping skills and in lessening one’s difficulty with emotional regulation, especially with longer riding interventions,” wrote Rebecca A. Johnson, PhD, of the University of Missouri, Columbia, and her associates.

val_shep/Thinkstock

acruz@frontlinemedcom.com

Veterans with posttraumatic stress disorder might benefit from therapeutic horseback riding, a small study suggests.

“Our findings provide empirical evidence that [therapeutic horseback riding] is effective at improving coping skills and in lessening one’s difficulty with emotional regulation, especially with longer riding interventions,” wrote Rebecca A. Johnson, PhD, of the University of Missouri, Columbia, and her associates.

val_shep/Thinkstock

acruz@frontlinemedcom.com

Veterans with posttraumatic stress disorder might benefit from therapeutic horseback riding, a small study suggests.

“Our findings provide empirical evidence that [therapeutic horseback riding] is effective at improving coping skills and in lessening one’s difficulty with emotional regulation, especially with longer riding interventions,” wrote Rebecca A. Johnson, PhD, of the University of Missouri, Columbia, and her associates.

val_shep/Thinkstock

acruz@frontlinemedcom.com

Myth: Wearing makeup causes acne breakouts

Acne breakouts caused by makeup and other skin care products, known as acne cosmetica, typically resolve when patients stop using pore-clogging products; however, the overall impact of cosmetics on the development of acne lesions is considered to be negligible. Many cosmetics are not inherently comedogenic and can be used safely by patients in combination with proper skin care techniques.

Although dermatologists may be inclined to discourage makeup use during acne treatment or breakouts due to its potential to aggravate the patient’s condition, research has shown that treatment results and quality of life (QoL) scores associated with makeup use in acne patients may improve when patients receive instruction on how to use skin care products and cosmetics effectively. In one study of 50 female acne patients, 25 participants were instructed on how to use skin care products and cosmetics, and the other 25 participants received no specific instructions from dermatologists. After 4 weeks of treatment with conventional topical and/or oral acne medications, the investigators concluded that use of skin care products did not negatively impact acne treatment, and the group that received application instructions showed more notable improvements in QoL scores versus those who did not. In another study, the overall number of acne eruptions decreased over a 2- to 4-week period in female acne patients who were trained by a makeup artist to apply cosmetics while undergoing acne treatment. These results suggest that acne patients who wear makeup may benefit from a conversation with their dermatologist about what products and skin care techniques they can use to minimize exacerbation of or even improve their condition.

When choosing makeup that will not cause or exacerbate acne breakouts, patients should look for packaging that indicates the product will not clog pores and is oil-free, noncomedogenic, and/or nonacnegenic. Some makeup products are specifically formulated to help camouflage redness and pimples, which can help improve quality of life and self-esteem in acne patients who otherwise may be self-conscious about their appearance. Mineral-based cosmetics containing powdered formulas of silica, titanium dioxide, and zinc oxide can be used to absorb oil, camouflage redness, and prevent irritation. Anti-inflammatory ingredients and antioxidants also are used in some makeup products to reduce skin irritation and promote barrier repair. Additional cosmetic ingredients that can affect the mechanisms of acne pathogenesis and may contribute to a decrease in acne lesions include nicotinamide, lactic acid, triethyl acetate/ethyllineolate, and prebiotic plant extracts.

Makeup should be applied gently to avoid irritating the skin. It also is important to remind patients not to share their makeup brushes and applicators and to clean them weekly to ensure that bacteria, dead skin cells, and oil are not spread to the skin, which can lead to new breakouts. Although patients may be compelled to scrub the skin to remove makeup, a mild cleanser should be gently applied using the fingertips and rinsed off with lukewarm water to minimize skin irritation. Any makeup remaining on the skin after washing should be gently removed with an oil-free makeup remover.
 

Myth: Wearing makeup causes acne breakouts

Acne breakouts caused by makeup and other skin care products, known as acne cosmetica, typically resolve when patients stop using pore-clogging products; however, the overall impact of cosmetics on the development of acne lesions is considered to be negligible. Many cosmetics are not inherently comedogenic and can be used safely by patients in combination with proper skin care techniques.

Although dermatologists may be inclined to discourage makeup use during acne treatment or breakouts due to its potential to aggravate the patient’s condition, research has shown that treatment results and quality of life (QoL) scores associated with makeup use in acne patients may improve when patients receive instruction on how to use skin care products and cosmetics effectively. In one study of 50 female acne patients, 25 participants were instructed on how to use skin care products and cosmetics, and the other 25 participants received no specific instructions from dermatologists. After 4 weeks of treatment with conventional topical and/or oral acne medications, the investigators concluded that use of skin care products did not negatively impact acne treatment, and the group that received application instructions showed more notable improvements in QoL scores versus those who did not. In another study, the overall number of acne eruptions decreased over a 2- to 4-week period in female acne patients who were trained by a makeup artist to apply cosmetics while undergoing acne treatment. These results suggest that acne patients who wear makeup may benefit from a conversation with their dermatologist about what products and skin care techniques they can use to minimize exacerbation of or even improve their condition.

When choosing makeup that will not cause or exacerbate acne breakouts, patients should look for packaging that indicates the product will not clog pores and is oil-free, noncomedogenic, and/or nonacnegenic. Some makeup products are specifically formulated to help camouflage redness and pimples, which can help improve quality of life and self-esteem in acne patients who otherwise may be self-conscious about their appearance. Mineral-based cosmetics containing powdered formulas of silica, titanium dioxide, and zinc oxide can be used to absorb oil, camouflage redness, and prevent irritation. Anti-inflammatory ingredients and antioxidants also are used in some makeup products to reduce skin irritation and promote barrier repair. Additional cosmetic ingredients that can affect the mechanisms of acne pathogenesis and may contribute to a decrease in acne lesions include nicotinamide, lactic acid, triethyl acetate/ethyllineolate, and prebiotic plant extracts.

Makeup should be applied gently to avoid irritating the skin. It also is important to remind patients not to share their makeup brushes and applicators and to clean them weekly to ensure that bacteria, dead skin cells, and oil are not spread to the skin, which can lead to new breakouts. Although patients may be compelled to scrub the skin to remove makeup, a mild cleanser should be gently applied using the fingertips and rinsed off with lukewarm water to minimize skin irritation. Any makeup remaining on the skin after washing should be gently removed with an oil-free makeup remover.
 

Myth: Wearing makeup causes acne breakouts

Acne breakouts caused by makeup and other skin care products, known as acne cosmetica, typically resolve when patients stop using pore-clogging products; however, the overall impact of cosmetics on the development of acne lesions is considered to be negligible. Many cosmetics are not inherently comedogenic and can be used safely by patients in combination with proper skin care techniques.

Although dermatologists may be inclined to discourage makeup use during acne treatment or breakouts due to its potential to aggravate the patient’s condition, research has shown that treatment results and quality of life (QoL) scores associated with makeup use in acne patients may improve when patients receive instruction on how to use skin care products and cosmetics effectively. In one study of 50 female acne patients, 25 participants were instructed on how to use skin care products and cosmetics, and the other 25 participants received no specific instructions from dermatologists. After 4 weeks of treatment with conventional topical and/or oral acne medications, the investigators concluded that use of skin care products did not negatively impact acne treatment, and the group that received application instructions showed more notable improvements in QoL scores versus those who did not. In another study, the overall number of acne eruptions decreased over a 2- to 4-week period in female acne patients who were trained by a makeup artist to apply cosmetics while undergoing acne treatment. These results suggest that acne patients who wear makeup may benefit from a conversation with their dermatologist about what products and skin care techniques they can use to minimize exacerbation of or even improve their condition.

When choosing makeup that will not cause or exacerbate acne breakouts, patients should look for packaging that indicates the product will not clog pores and is oil-free, noncomedogenic, and/or nonacnegenic. Some makeup products are specifically formulated to help camouflage redness and pimples, which can help improve quality of life and self-esteem in acne patients who otherwise may be self-conscious about their appearance. Mineral-based cosmetics containing powdered formulas of silica, titanium dioxide, and zinc oxide can be used to absorb oil, camouflage redness, and prevent irritation. Anti-inflammatory ingredients and antioxidants also are used in some makeup products to reduce skin irritation and promote barrier repair. Additional cosmetic ingredients that can affect the mechanisms of acne pathogenesis and may contribute to a decrease in acne lesions include nicotinamide, lactic acid, triethyl acetate/ethyllineolate, and prebiotic plant extracts.

Makeup should be applied gently to avoid irritating the skin. It also is important to remind patients not to share their makeup brushes and applicators and to clean them weekly to ensure that bacteria, dead skin cells, and oil are not spread to the skin, which can lead to new breakouts. Although patients may be compelled to scrub the skin to remove makeup, a mild cleanser should be gently applied using the fingertips and rinsed off with lukewarm water to minimize skin irritation. Any makeup remaining on the skin after washing should be gently removed with an oil-free makeup remover.
 

The chance of developing major depressive disorder (MDD) is much higher in patients who have acne, according to a retrospective cohort analysis published as a research letter.

“The onset of acne, when patients present for treatment because of active disease, is associated with a greater risk of developing depression” wrote Isabelle A. Vallerand, an MD/PhD student at the University of Calgary (Alta.), and her associates. “Although the severity of acne was not assessed directly in the current study, this finding suggests a potential dose/response relationship such that more active disease may lead to a greater risk of depression.”

© Ocskay Bence/Fotolia.com

ilacy@frontlinemedcom.com

SOURCE: Vallerand I et al. Br J Dermatol. 2018 Feb 7. doi: 10.1111/bjd.16099.

The chance of developing major depressive disorder (MDD) is much higher in patients who have acne, according to a retrospective cohort analysis published as a research letter.

“The onset of acne, when patients present for treatment because of active disease, is associated with a greater risk of developing depression” wrote Isabelle A. Vallerand, an MD/PhD student at the University of Calgary (Alta.), and her associates. “Although the severity of acne was not assessed directly in the current study, this finding suggests a potential dose/response relationship such that more active disease may lead to a greater risk of depression.”

© Ocskay Bence/Fotolia.com

ilacy@frontlinemedcom.com

SOURCE: Vallerand I et al. Br J Dermatol. 2018 Feb 7. doi: 10.1111/bjd.16099.

The chance of developing major depressive disorder (MDD) is much higher in patients who have acne, according to a retrospective cohort analysis published as a research letter.

“The onset of acne, when patients present for treatment because of active disease, is associated with a greater risk of developing depression” wrote Isabelle A. Vallerand, an MD/PhD student at the University of Calgary (Alta.), and her associates. “Although the severity of acne was not assessed directly in the current study, this finding suggests a potential dose/response relationship such that more active disease may lead to a greater risk of depression.”

© Ocskay Bence/Fotolia.com

ilacy@frontlinemedcom.com

SOURCE: Vallerand I et al. Br J Dermatol. 2018 Feb 7. doi: 10.1111/bjd.16099.

How did the experience of office visits get to be so frustrating for both patients and doctors? Let’s put it under the microscope and examine it.

To medicine’s credit, it realized the value of looking for diseases before symptoms occurred, such as using mammograms to detect breast cancer and controlling blood pressure and blood sugar to avert comorbidities.

Today, a doctor looks at the computer screen and checks off when a mammogram was done and whether blood pressure and blood sugar are controlled. “Authorities” believe that good health is achieved by performing positive checkoffs to questions like this. This definition of quality care is, in reality, “quantity care” and can be tied to physician compensation. Physicians who did not adequately meet Physician Quality Reporting System requirements have received letters informing them that their Medicare Part B payments for 2018 will be reduced by 3%.

Many seasoned clinicians recognize that practicing good medicine involves more than following a computer printout of tests and treatments based on the patient’s symptoms, more than plugging into the diagnostic and prescription mills that are part of today’s managed care system. Making the correct diagnosis requires a carefully taken history, listening to the patients’ stories of their journeys into and through illness, and using a bio-psychosocial-spiritual approach.

Getting to know the patient as a person requires that the doctor and patient take a journey together. In that journey, when the doctor empathizes with the patient and understands what makes the patient tick, the doctor can empower the patient – giving the patient a fuller understanding of their medical conditions, greater participation in the diagnostic work-up and in treatments, and hope for success – all leading to better outcomes.

Doctors are frustrated with the current medical assembly-line system. A study has shown that physicians spend 2 hours on electronic health records and clerical work for every hour they provide direct patient care (Ann Intern Med. 2016;165[11]:753-60). Nearly half of physicians now report that they are “burned out” by the demand to achieve the quantitative requirements on the one hand and their inability to minister to the needs of their patients on the other hand. Patients are also frustrated by the system as they cope with health insurance and costs, with the short time allocated for office visits, and with a fragmented and impersonal medical system. Patients feel that they are little more than a source of information for boxes to be checked off by the physician whose eyes are forced to be on the computer and the clock.

How can we begin to integrate these measures of quality into “quantity medicine” and make the experience of medical visits less frustrating for doctors and patients? How can we reward the skills that recognize that the course of an illness is influenced by patients’ emotions and thoughts related to their problems, their supportive or stressful relationships with others, and the context within which they conceptualize their lives – particularly their religious and spiritual beliefs about life’s purpose and challenges and attitudes toward death?

Caring for patients requires a more sophisticated approach than seeing patients as computer checkoffs. Office visits need to focus on the patient who has the symptoms, not just the symptoms the patient has.

Isn’t it time to make patient-centered care a reality and not just a slogan? If this speaks to you, then what should you do? Even though solutions may not be simple, we should not be deterred from finding patient-centered systems since patients and doctors are unhappy with today’s system. Why not have patients grade their office visits?

While this approach has its shortcomings, and isn’t the only solution, it does place the patient at the center of the process, answering questions about whether the doctor listened to them, heard their concerns, and presented a reasonable plan to help them get better.

In addition, all those involved with medical care should be involved in the process to replace today’s deficient system. The nation’s main organizations representing physicians should propose solutions to support patient-centered care. Individual physicians should become involved, speaking up and sending articles and letters to medical journals and the lay press.

Patients should be empowered to open up a public discussion – in print and broadcast media – on how they want to improve their own medical experiences and the quality of their health care.

It’s worth it. It’s our health.
 

Dr. Banner is a practicing internist in Philadelphia and chair emeritus of the Albert Einstein Medical Center Medical Ethics Committee. Dr. Benor is a psychiatric psychotherapist in the United States and a wholistic psychotherapist in Canada. Dr. Reiser is adjunct professor, University of Texas School of Public Health, Austin, and the UT Austin Plan II Honors Program, and teaches medical history, medical ethics, and public policy. The authors are indebted to Benjamin Sharfman, PhD, and Jane Brown, PhD, for their important roles in creating this article.
 

How did the experience of office visits get to be so frustrating for both patients and doctors? Let’s put it under the microscope and examine it.

To medicine’s credit, it realized the value of looking for diseases before symptoms occurred, such as using mammograms to detect breast cancer and controlling blood pressure and blood sugar to avert comorbidities.

Today, a doctor looks at the computer screen and checks off when a mammogram was done and whether blood pressure and blood sugar are controlled. “Authorities” believe that good health is achieved by performing positive checkoffs to questions like this. This definition of quality care is, in reality, “quantity care” and can be tied to physician compensation. Physicians who did not adequately meet Physician Quality Reporting System requirements have received letters informing them that their Medicare Part B payments for 2018 will be reduced by 3%.

Many seasoned clinicians recognize that practicing good medicine involves more than following a computer printout of tests and treatments based on the patient’s symptoms, more than plugging into the diagnostic and prescription mills that are part of today’s managed care system. Making the correct diagnosis requires a carefully taken history, listening to the patients’ stories of their journeys into and through illness, and using a bio-psychosocial-spiritual approach.

Getting to know the patient as a person requires that the doctor and patient take a journey together. In that journey, when the doctor empathizes with the patient and understands what makes the patient tick, the doctor can empower the patient – giving the patient a fuller understanding of their medical conditions, greater participation in the diagnostic work-up and in treatments, and hope for success – all leading to better outcomes.

Doctors are frustrated with the current medical assembly-line system. A study has shown that physicians spend 2 hours on electronic health records and clerical work for every hour they provide direct patient care (Ann Intern Med. 2016;165[11]:753-60). Nearly half of physicians now report that they are “burned out” by the demand to achieve the quantitative requirements on the one hand and their inability to minister to the needs of their patients on the other hand. Patients are also frustrated by the system as they cope with health insurance and costs, with the short time allocated for office visits, and with a fragmented and impersonal medical system. Patients feel that they are little more than a source of information for boxes to be checked off by the physician whose eyes are forced to be on the computer and the clock.

How can we begin to integrate these measures of quality into “quantity medicine” and make the experience of medical visits less frustrating for doctors and patients? How can we reward the skills that recognize that the course of an illness is influenced by patients’ emotions and thoughts related to their problems, their supportive or stressful relationships with others, and the context within which they conceptualize their lives – particularly their religious and spiritual beliefs about life’s purpose and challenges and attitudes toward death?

Caring for patients requires a more sophisticated approach than seeing patients as computer checkoffs. Office visits need to focus on the patient who has the symptoms, not just the symptoms the patient has.

Isn’t it time to make patient-centered care a reality and not just a slogan? If this speaks to you, then what should you do? Even though solutions may not be simple, we should not be deterred from finding patient-centered systems since patients and doctors are unhappy with today’s system. Why not have patients grade their office visits?

While this approach has its shortcomings, and isn’t the only solution, it does place the patient at the center of the process, answering questions about whether the doctor listened to them, heard their concerns, and presented a reasonable plan to help them get better.

In addition, all those involved with medical care should be involved in the process to replace today’s deficient system. The nation’s main organizations representing physicians should propose solutions to support patient-centered care. Individual physicians should become involved, speaking up and sending articles and letters to medical journals and the lay press.

Patients should be empowered to open up a public discussion – in print and broadcast media – on how they want to improve their own medical experiences and the quality of their health care.

It’s worth it. It’s our health.
 

Dr. Banner is a practicing internist in Philadelphia and chair emeritus of the Albert Einstein Medical Center Medical Ethics Committee. Dr. Benor is a psychiatric psychotherapist in the United States and a wholistic psychotherapist in Canada. Dr. Reiser is adjunct professor, University of Texas School of Public Health, Austin, and the UT Austin Plan II Honors Program, and teaches medical history, medical ethics, and public policy. The authors are indebted to Benjamin Sharfman, PhD, and Jane Brown, PhD, for their important roles in creating this article.
 

How did the experience of office visits get to be so frustrating for both patients and doctors? Let’s put it under the microscope and examine it.

To medicine’s credit, it realized the value of looking for diseases before symptoms occurred, such as using mammograms to detect breast cancer and controlling blood pressure and blood sugar to avert comorbidities.

Today, a doctor looks at the computer screen and checks off when a mammogram was done and whether blood pressure and blood sugar are controlled. “Authorities” believe that good health is achieved by performing positive checkoffs to questions like this. This definition of quality care is, in reality, “quantity care” and can be tied to physician compensation. Physicians who did not adequately meet Physician Quality Reporting System requirements have received letters informing them that their Medicare Part B payments for 2018 will be reduced by 3%.

Many seasoned clinicians recognize that practicing good medicine involves more than following a computer printout of tests and treatments based on the patient’s symptoms, more than plugging into the diagnostic and prescription mills that are part of today’s managed care system. Making the correct diagnosis requires a carefully taken history, listening to the patients’ stories of their journeys into and through illness, and using a bio-psychosocial-spiritual approach.

Getting to know the patient as a person requires that the doctor and patient take a journey together. In that journey, when the doctor empathizes with the patient and understands what makes the patient tick, the doctor can empower the patient – giving the patient a fuller understanding of their medical conditions, greater participation in the diagnostic work-up and in treatments, and hope for success – all leading to better outcomes.

Doctors are frustrated with the current medical assembly-line system. A study has shown that physicians spend 2 hours on electronic health records and clerical work for every hour they provide direct patient care (Ann Intern Med. 2016;165[11]:753-60). Nearly half of physicians now report that they are “burned out” by the demand to achieve the quantitative requirements on the one hand and their inability to minister to the needs of their patients on the other hand. Patients are also frustrated by the system as they cope with health insurance and costs, with the short time allocated for office visits, and with a fragmented and impersonal medical system. Patients feel that they are little more than a source of information for boxes to be checked off by the physician whose eyes are forced to be on the computer and the clock.

How can we begin to integrate these measures of quality into “quantity medicine” and make the experience of medical visits less frustrating for doctors and patients? How can we reward the skills that recognize that the course of an illness is influenced by patients’ emotions and thoughts related to their problems, their supportive or stressful relationships with others, and the context within which they conceptualize their lives – particularly their religious and spiritual beliefs about life’s purpose and challenges and attitudes toward death?

Caring for patients requires a more sophisticated approach than seeing patients as computer checkoffs. Office visits need to focus on the patient who has the symptoms, not just the symptoms the patient has.

Isn’t it time to make patient-centered care a reality and not just a slogan? If this speaks to you, then what should you do? Even though solutions may not be simple, we should not be deterred from finding patient-centered systems since patients and doctors are unhappy with today’s system. Why not have patients grade their office visits?

While this approach has its shortcomings, and isn’t the only solution, it does place the patient at the center of the process, answering questions about whether the doctor listened to them, heard their concerns, and presented a reasonable plan to help them get better.

In addition, all those involved with medical care should be involved in the process to replace today’s deficient system. The nation’s main organizations representing physicians should propose solutions to support patient-centered care. Individual physicians should become involved, speaking up and sending articles and letters to medical journals and the lay press.

Patients should be empowered to open up a public discussion – in print and broadcast media – on how they want to improve their own medical experiences and the quality of their health care.

It’s worth it. It’s our health.
 

Dr. Banner is a practicing internist in Philadelphia and chair emeritus of the Albert Einstein Medical Center Medical Ethics Committee. Dr. Benor is a psychiatric psychotherapist in the United States and a wholistic psychotherapist in Canada. Dr. Reiser is adjunct professor, University of Texas School of Public Health, Austin, and the UT Austin Plan II Honors Program, and teaches medical history, medical ethics, and public policy. The authors are indebted to Benjamin Sharfman, PhD, and Jane Brown, PhD, for their important roles in creating this article.