Neurosteroids may be tied to the gender differences found in the susceptibility to schizophrenia, a cross-sectional, case control study showed.

“These findings suggest that neurosteroids are involved in the pathophysiology of schizophrenia in male patients but not so much in female patients,” reported Yu-Chi Huang, MD, of the department of psychiatry at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, and associates.

To conduct the study, the researchers recruited 65 patients with schizophrenia from an outpatient department and psychiatry ward of the hospital. Eligible patients were aged 18-65 years, diagnosed with schizophrenia as defined by the DSM-IV-TR, and taking a stable dose of antipsychotics for at least 1 month before the start of the study. In addition, the participants could have no history of major physical illnesses and had to be of ethnic Han Chinese origin. Thirty-six of the patients were men.

The control group was made up of 103 healthy hospital staff and community members who were within the same age range as the patients. The controls could have no history of illicit drug use, physical illnesses, or psychiatric disorders and had to be ethnic Han Chinese. Forty-seven members of the control group were males (Psychoneuroendocrinology. 2017 Oct;84:87-93).

Participants fasted and blood samples were obtained. Dehydroepiandrosterone (DHEA) levels were measured using the DHEA ELISA [enyme-linked immunosorbent assay] – ADKI-900-093, dehydroepiandrosterone sulfate (DHEAS) levels were measured with the Architect DHEA-S reagent kit, and pregnenolone levels were measured using the pregnenolone ELISA kit. Psychiatric diagnoses were assessed for both groups using a psychiatric interview based on the Mini-International Neuropsychiatric Interview, the Positive and Negative Syndrome Scale (PANSS), and the 17-item Hamilton Depression Rating Scale. Several factors tied to schizophrenia were evaluated, including the age of onset, illness duration, and use of antipsychotics. The numbers were placed into a database and analyzed.

After controlling for age and body mass index, the researchers found that in male patients with schizophrenia, DHEA and DHEAS serum levels were positively associated with the age of onset of schizophrenia (P less than .05) and negatively associated with the duration of illness (P less than .05). In addition, they found that pregnenolone levels were associated positively with general symptoms of the PANSS in the male schizophrenia patients (P less than .05 ). Furthermore, the levels of DHEA, DHEAS, and pregnenolone were lower among the male schizophrenia patients, compared with the serum levels of the healthy male controls. No differences were found in serum levels among the female patients with schizophrenia and the healthy controls.

The findings suggest that DHEA, DHEAS, and pregnenolone could be markers of the duration of illness and the severity of general symptoms among male patients with schizophrenia. To read the entire study, click here.

[email protected]

Neurosteroids may be tied to the gender differences found in the susceptibility to schizophrenia, a cross-sectional, case control study showed.

“These findings suggest that neurosteroids are involved in the pathophysiology of schizophrenia in male patients but not so much in female patients,” reported Yu-Chi Huang, MD, of the department of psychiatry at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, and associates.

To conduct the study, the researchers recruited 65 patients with schizophrenia from an outpatient department and psychiatry ward of the hospital. Eligible patients were aged 18-65 years, diagnosed with schizophrenia as defined by the DSM-IV-TR, and taking a stable dose of antipsychotics for at least 1 month before the start of the study. In addition, the participants could have no history of major physical illnesses and had to be of ethnic Han Chinese origin. Thirty-six of the patients were men.

The control group was made up of 103 healthy hospital staff and community members who were within the same age range as the patients. The controls could have no history of illicit drug use, physical illnesses, or psychiatric disorders and had to be ethnic Han Chinese. Forty-seven members of the control group were males (Psychoneuroendocrinology. 2017 Oct;84:87-93).

Participants fasted and blood samples were obtained. Dehydroepiandrosterone (DHEA) levels were measured using the DHEA ELISA [enyme-linked immunosorbent assay] – ADKI-900-093, dehydroepiandrosterone sulfate (DHEAS) levels were measured with the Architect DHEA-S reagent kit, and pregnenolone levels were measured using the pregnenolone ELISA kit. Psychiatric diagnoses were assessed for both groups using a psychiatric interview based on the Mini-International Neuropsychiatric Interview, the Positive and Negative Syndrome Scale (PANSS), and the 17-item Hamilton Depression Rating Scale. Several factors tied to schizophrenia were evaluated, including the age of onset, illness duration, and use of antipsychotics. The numbers were placed into a database and analyzed.

After controlling for age and body mass index, the researchers found that in male patients with schizophrenia, DHEA and DHEAS serum levels were positively associated with the age of onset of schizophrenia (P less than .05) and negatively associated with the duration of illness (P less than .05). In addition, they found that pregnenolone levels were associated positively with general symptoms of the PANSS in the male schizophrenia patients (P less than .05 ). Furthermore, the levels of DHEA, DHEAS, and pregnenolone were lower among the male schizophrenia patients, compared with the serum levels of the healthy male controls. No differences were found in serum levels among the female patients with schizophrenia and the healthy controls.

The findings suggest that DHEA, DHEAS, and pregnenolone could be markers of the duration of illness and the severity of general symptoms among male patients with schizophrenia. To read the entire study, click here.

[email protected]

Neurosteroids may be tied to the gender differences found in the susceptibility to schizophrenia, a cross-sectional, case control study showed.

“These findings suggest that neurosteroids are involved in the pathophysiology of schizophrenia in male patients but not so much in female patients,” reported Yu-Chi Huang, MD, of the department of psychiatry at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan, and associates.

To conduct the study, the researchers recruited 65 patients with schizophrenia from an outpatient department and psychiatry ward of the hospital. Eligible patients were aged 18-65 years, diagnosed with schizophrenia as defined by the DSM-IV-TR, and taking a stable dose of antipsychotics for at least 1 month before the start of the study. In addition, the participants could have no history of major physical illnesses and had to be of ethnic Han Chinese origin. Thirty-six of the patients were men.

The control group was made up of 103 healthy hospital staff and community members who were within the same age range as the patients. The controls could have no history of illicit drug use, physical illnesses, or psychiatric disorders and had to be ethnic Han Chinese. Forty-seven members of the control group were males (Psychoneuroendocrinology. 2017 Oct;84:87-93).

Participants fasted and blood samples were obtained. Dehydroepiandrosterone (DHEA) levels were measured using the DHEA ELISA [enyme-linked immunosorbent assay] – ADKI-900-093, dehydroepiandrosterone sulfate (DHEAS) levels were measured with the Architect DHEA-S reagent kit, and pregnenolone levels were measured using the pregnenolone ELISA kit. Psychiatric diagnoses were assessed for both groups using a psychiatric interview based on the Mini-International Neuropsychiatric Interview, the Positive and Negative Syndrome Scale (PANSS), and the 17-item Hamilton Depression Rating Scale. Several factors tied to schizophrenia were evaluated, including the age of onset, illness duration, and use of antipsychotics. The numbers were placed into a database and analyzed.

After controlling for age and body mass index, the researchers found that in male patients with schizophrenia, DHEA and DHEAS serum levels were positively associated with the age of onset of schizophrenia (P less than .05) and negatively associated with the duration of illness (P less than .05). In addition, they found that pregnenolone levels were associated positively with general symptoms of the PANSS in the male schizophrenia patients (P less than .05 ). Furthermore, the levels of DHEA, DHEAS, and pregnenolone were lower among the male schizophrenia patients, compared with the serum levels of the healthy male controls. No differences were found in serum levels among the female patients with schizophrenia and the healthy controls.

The findings suggest that DHEA, DHEAS, and pregnenolone could be markers of the duration of illness and the severity of general symptoms among male patients with schizophrenia. To read the entire study, click here.

[email protected]

JACKSONVILLE, FLA. – An enhanced recovery protocol for colorectal surgery patients was implemented to not only limit in-hospital opioid use, but also to reduce postdischarge opioid prescriptions.

The results of the enhanced recovery after surgery (ERAS) study were reported at the Association for Academic Surgical/Society of Academic Surgeons Academic Congress by Kathryn Hudak, a fourth-year medical student at the University of Alabama at Birmingham (UAB).

Copyright thegoodphoto/Thinkstock

[email protected]

JACKSONVILLE, FLA. – An enhanced recovery protocol for colorectal surgery patients was implemented to not only limit in-hospital opioid use, but also to reduce postdischarge opioid prescriptions.

The results of the enhanced recovery after surgery (ERAS) study were reported at the Association for Academic Surgical/Society of Academic Surgeons Academic Congress by Kathryn Hudak, a fourth-year medical student at the University of Alabama at Birmingham (UAB).

Copyright thegoodphoto/Thinkstock

[email protected]

JACKSONVILLE, FLA. – An enhanced recovery protocol for colorectal surgery patients was implemented to not only limit in-hospital opioid use, but also to reduce postdischarge opioid prescriptions.

The results of the enhanced recovery after surgery (ERAS) study were reported at the Association for Academic Surgical/Society of Academic Surgeons Academic Congress by Kathryn Hudak, a fourth-year medical student at the University of Alabama at Birmingham (UAB).

Copyright thegoodphoto/Thinkstock

[email protected]

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

Endometriosis surgery on a young woman: $483,351 award

A 17-year-old woman reported cramping and heavy bleeding during her menses. Her gynecologist suspected that the patient had endometriosis and recommended laparoscopic surgery with cauterization.

During surgery, the gynecologist found 2 metal staples in the patient’s pelvic region from a prior appendectomy. He continued with the surgery as planned, using monopolar cauterization to excise the endometriosis.

The following day, the patient sought emergency treatment for pain. Physicians discovered 2 perforations in her anterior rectum and performed an emergency colectomy. She spent 18 days in the hospital. When the colectomy was reversed 3 months later, she was hospitalized for 8 days and later developed a postoperative surgical site infection requiring IV antibiotics and weeks of wound care.

The patient was in the middle of her senior year of high school when she had the colectomy and could not return to normal activities. She was unable to graduate with her class and had to relinquish a college scholarship. As a result, she completed her senior year via homeschooling and graduated a year later.

PATIENT'S CLAIM: The gynecologist’s negligent use of the cautery device within millimeters of the staples caused the bowel injury and necessitated the colectomy. The electric current from the cautery device heated the staples, injuring the rectum, which became necrotic. While she had no long-term physical limitations, wearing the colostomy bag, missing her senior year, not being able to graduate with her class, and not being able to participate in typical senior year activities left her emotionally distressed.

PHYSICIAN'S DEFENSE: The staples were not found near the rectal injury. The injury was a known complication of cauterization, not a result of negligence.

VERDICT: A $588,351 California verdict was returned but was reduced to $483,351 because of the state cap on pain and suffering.

RELATED
Surgical excision of the most severe form of endometriosis

Sigmoid colon injury during hysterectomy

A 42-year-old woman had uterine fibroids that caused such heavy bleeding that she became anemic and required a transfusion. On June 26, she underwent laparoscopic-assisted supracervical hysterectomy performed by her primary ObGyn and an assisting ObGyn.

The next day, the patient developed pain and fever and her vital signs were unstable. The primary ObGyn called in a general surgeon. A CT scan showed a tear on the underside of the sigmoid colon. The general surgeon performed a laparotomy, resected the colon, and created a temporary colostomy. The colostomy reversal took place on September 25.

PATIENT'S CLAIM: The patient sued both ObGyns, alleging that they should have found the colon injury during surgery. The primary ObGyn settled before trial and the case continued against the assisting ObGyn. It was undisputed that one or both of the physicians caused the tear, but that was not the patient’s claim. The patient alleged that negligence occurred when the injury was not intraoperatively detected. Had the injury been found during surgery, a general surgeon could have performed a primary repair, saving the patient from further surgery and colostomy. The patient claimed mental anguish and embarrassment from the colostomy. Her abdomen is still tender and she has significant scarring.

PHYSICIAN'S CLAIM: There was no negligence. Nothing was unusual about the nature of the procedure, and nothing unusual was seen intraoperatively that would have led them to search for an injury. They performed adequate and appropriate exploration before closing. The linear tear on the underside of the sigmoid colon was very inconspicuous in size, shape, and location, and was away from the operative area. The injury likely occurred during manipulation of the sigmoid colon, which generally has to be retracted before the uterus can be removed. Even if the injury had been found intraoperatively, a general surgeon would have had to convert to laparoscopy to repair the colon.

VERDICT: After a settlement was reached with the primary gynecologist, a Texas defense verdict was returned for the assisting gynecologist.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis surgery on a young woman: $483,351 award

A 17-year-old woman reported cramping and heavy bleeding during her menses. Her gynecologist suspected that the patient had endometriosis and recommended laparoscopic surgery with cauterization.

During surgery, the gynecologist found 2 metal staples in the patient’s pelvic region from a prior appendectomy. He continued with the surgery as planned, using monopolar cauterization to excise the endometriosis.

The following day, the patient sought emergency treatment for pain. Physicians discovered 2 perforations in her anterior rectum and performed an emergency colectomy. She spent 18 days in the hospital. When the colectomy was reversed 3 months later, she was hospitalized for 8 days and later developed a postoperative surgical site infection requiring IV antibiotics and weeks of wound care.

The patient was in the middle of her senior year of high school when she had the colectomy and could not return to normal activities. She was unable to graduate with her class and had to relinquish a college scholarship. As a result, she completed her senior year via homeschooling and graduated a year later.

PATIENT'S CLAIM: The gynecologist’s negligent use of the cautery device within millimeters of the staples caused the bowel injury and necessitated the colectomy. The electric current from the cautery device heated the staples, injuring the rectum, which became necrotic. While she had no long-term physical limitations, wearing the colostomy bag, missing her senior year, not being able to graduate with her class, and not being able to participate in typical senior year activities left her emotionally distressed.

PHYSICIAN'S DEFENSE: The staples were not found near the rectal injury. The injury was a known complication of cauterization, not a result of negligence.

VERDICT: A $588,351 California verdict was returned but was reduced to $483,351 because of the state cap on pain and suffering.

RELATED
Surgical excision of the most severe form of endometriosis

Sigmoid colon injury during hysterectomy

A 42-year-old woman had uterine fibroids that caused such heavy bleeding that she became anemic and required a transfusion. On June 26, she underwent laparoscopic-assisted supracervical hysterectomy performed by her primary ObGyn and an assisting ObGyn.

The next day, the patient developed pain and fever and her vital signs were unstable. The primary ObGyn called in a general surgeon. A CT scan showed a tear on the underside of the sigmoid colon. The general surgeon performed a laparotomy, resected the colon, and created a temporary colostomy. The colostomy reversal took place on September 25.

PATIENT'S CLAIM: The patient sued both ObGyns, alleging that they should have found the colon injury during surgery. The primary ObGyn settled before trial and the case continued against the assisting ObGyn. It was undisputed that one or both of the physicians caused the tear, but that was not the patient’s claim. The patient alleged that negligence occurred when the injury was not intraoperatively detected. Had the injury been found during surgery, a general surgeon could have performed a primary repair, saving the patient from further surgery and colostomy. The patient claimed mental anguish and embarrassment from the colostomy. Her abdomen is still tender and she has significant scarring.

PHYSICIAN'S CLAIM: There was no negligence. Nothing was unusual about the nature of the procedure, and nothing unusual was seen intraoperatively that would have led them to search for an injury. They performed adequate and appropriate exploration before closing. The linear tear on the underside of the sigmoid colon was very inconspicuous in size, shape, and location, and was away from the operative area. The injury likely occurred during manipulation of the sigmoid colon, which generally has to be retracted before the uterus can be removed. Even if the injury had been found intraoperatively, a general surgeon would have had to convert to laparoscopy to repair the colon.

VERDICT: After a settlement was reached with the primary gynecologist, a Texas defense verdict was returned for the assisting gynecologist.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis surgery on a young woman: $483,351 award

A 17-year-old woman reported cramping and heavy bleeding during her menses. Her gynecologist suspected that the patient had endometriosis and recommended laparoscopic surgery with cauterization.

During surgery, the gynecologist found 2 metal staples in the patient’s pelvic region from a prior appendectomy. He continued with the surgery as planned, using monopolar cauterization to excise the endometriosis.

The following day, the patient sought emergency treatment for pain. Physicians discovered 2 perforations in her anterior rectum and performed an emergency colectomy. She spent 18 days in the hospital. When the colectomy was reversed 3 months later, she was hospitalized for 8 days and later developed a postoperative surgical site infection requiring IV antibiotics and weeks of wound care.

The patient was in the middle of her senior year of high school when she had the colectomy and could not return to normal activities. She was unable to graduate with her class and had to relinquish a college scholarship. As a result, she completed her senior year via homeschooling and graduated a year later.

PATIENT'S CLAIM: The gynecologist’s negligent use of the cautery device within millimeters of the staples caused the bowel injury and necessitated the colectomy. The electric current from the cautery device heated the staples, injuring the rectum, which became necrotic. While she had no long-term physical limitations, wearing the colostomy bag, missing her senior year, not being able to graduate with her class, and not being able to participate in typical senior year activities left her emotionally distressed.

PHYSICIAN'S DEFENSE: The staples were not found near the rectal injury. The injury was a known complication of cauterization, not a result of negligence.

VERDICT: A $588,351 California verdict was returned but was reduced to $483,351 because of the state cap on pain and suffering.

RELATED
Surgical excision of the most severe form of endometriosis

Sigmoid colon injury during hysterectomy

A 42-year-old woman had uterine fibroids that caused such heavy bleeding that she became anemic and required a transfusion. On June 26, she underwent laparoscopic-assisted supracervical hysterectomy performed by her primary ObGyn and an assisting ObGyn.

The next day, the patient developed pain and fever and her vital signs were unstable. The primary ObGyn called in a general surgeon. A CT scan showed a tear on the underside of the sigmoid colon. The general surgeon performed a laparotomy, resected the colon, and created a temporary colostomy. The colostomy reversal took place on September 25.

PATIENT'S CLAIM: The patient sued both ObGyns, alleging that they should have found the colon injury during surgery. The primary ObGyn settled before trial and the case continued against the assisting ObGyn. It was undisputed that one or both of the physicians caused the tear, but that was not the patient’s claim. The patient alleged that negligence occurred when the injury was not intraoperatively detected. Had the injury been found during surgery, a general surgeon could have performed a primary repair, saving the patient from further surgery and colostomy. The patient claimed mental anguish and embarrassment from the colostomy. Her abdomen is still tender and she has significant scarring.

PHYSICIAN'S CLAIM: There was no negligence. Nothing was unusual about the nature of the procedure, and nothing unusual was seen intraoperatively that would have led them to search for an injury. They performed adequate and appropriate exploration before closing. The linear tear on the underside of the sigmoid colon was very inconspicuous in size, shape, and location, and was away from the operative area. The injury likely occurred during manipulation of the sigmoid colon, which generally has to be retracted before the uterus can be removed. Even if the injury had been found intraoperatively, a general surgeon would have had to convert to laparoscopy to repair the colon.

VERDICT: After a settlement was reached with the primary gynecologist, a Texas defense verdict was returned for the assisting gynecologist.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Stephanie M. Levine, MD, FCCP, is an expert in lung transplantation, pulmonary and critical care issues in pregnancy and women’s lung health, and eosinophilic lung disorders. She is a Professor of Medicine in the Division of Pulmonary Diseases and Critical Care Medicine at the University of Texas Health Science Center in San Antonio, Texas; the Program Director of the Pulmonary and Critical Care Fellowship at the University of Texas Health Science Center; and the Director of the Medical Intensive Care Unit and Bronchoscopy Laboratory at the University Hospital. She also is a staff physician at the Audie Murphy Veteran Administration Hospital. Dr. Levine has authored or co-authored over 270 manuscripts, chapters, reviews, editorials, and abstracts, primarily in her major field of interest, lung transplantation. She has been Editor of both Critical Care SEEK and Pulmonary SEEK.

Stephanie M. Levine, MD, FCCP, is an expert in lung transplantation, pulmonary and critical care issues in pregnancy and women’s lung health, and eosinophilic lung disorders. She is a Professor of Medicine in the Division of Pulmonary Diseases and Critical Care Medicine at the University of Texas Health Science Center in San Antonio, Texas; the Program Director of the Pulmonary and Critical Care Fellowship at the University of Texas Health Science Center; and the Director of the Medical Intensive Care Unit and Bronchoscopy Laboratory at the University Hospital. She also is a staff physician at the Audie Murphy Veteran Administration Hospital. Dr. Levine has authored or co-authored over 270 manuscripts, chapters, reviews, editorials, and abstracts, primarily in her major field of interest, lung transplantation. She has been Editor of both Critical Care SEEK and Pulmonary SEEK.

Stephanie M. Levine, MD, FCCP, is an expert in lung transplantation, pulmonary and critical care issues in pregnancy and women’s lung health, and eosinophilic lung disorders. She is a Professor of Medicine in the Division of Pulmonary Diseases and Critical Care Medicine at the University of Texas Health Science Center in San Antonio, Texas; the Program Director of the Pulmonary and Critical Care Fellowship at the University of Texas Health Science Center; and the Director of the Medical Intensive Care Unit and Bronchoscopy Laboratory at the University Hospital. She also is a staff physician at the Audie Murphy Veteran Administration Hospital. Dr. Levine has authored or co-authored over 270 manuscripts, chapters, reviews, editorials, and abstracts, primarily in her major field of interest, lung transplantation. She has been Editor of both Critical Care SEEK and Pulmonary SEEK.

The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.

“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.

Findings in context

“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”

It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.

“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
 

Study details

About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).

An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.

The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).

“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”

“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.

The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.

“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”

Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.

SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578

The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.

“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.

Findings in context

“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”

It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.

“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
 

Study details

About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).

An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.

The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).

“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”

“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.

The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.

“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”

Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.

SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578

The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.

“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.

Findings in context

“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”

It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.

“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
 

Study details

About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).

An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.

The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).

“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”

“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.

The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.

“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”

Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.

SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578

One unintended consequence of the increased attention to early sepsis identification and intervention can be unnecessary or excessive antibiotic use. Overuse of broad-spectrum antibiotics, in turn, can fuel the emergence of life-threatening infections such as antibiotic-resistant Clostridium difficile, a scourge in many hospitals.

For a sepsis quality improvement (QI) initiative at the University of Utah, Salt Lake City, the hospitalist coleaders took several precautions to lessen the risk of antibiotic overuse. Kencee K. Graves, MD, said she and her colleague Devin J. Horton, MD, designed the hospital’s order sets in collaboration with an infectious disease specialist and pharmacist so they could avoid overly broad antibiotics whenever possible. The project also included an educational effort to get pharmacists in the habit of prompting medical providers to initiate antibiotic de-escalation at 48 hours. The hospital had an antibiotic stewardship program that likely helped as well, she said. As a result of their precautions, the team found no significant difference in the amount of broad-spectrum antibiotics doled out before and after their QI pilot project.

Infection control and antimicrobial specialists also can help; they can monitor an area’s resistance profile, create a antibiogram and reevaluate sepsis pathways and order sets to adjust the recommended antibiotics as the resistance profile changes. “I think we still have a long ways to go,” said Andy Odden, MD, SFHM, patient safety officer in the department of medicine at Washington University in St. Louis. “The initial risk of mortality is so much more dramatic than the long-term risks of developing antimicrobial resistors that unless you have the antimicrobial stewardship people with a seat at the table, that voice can get drowned out very easily.”

The antimicrobial stewardship program at University of Pennsylvania, Philadelphia, has received a boost from technology. The program offers initial guidance on which broad-spectrum antibiotics to consider depending on the suspected source of the sepsis-linked infection. Software by Jackson, Wyo.–based biotech company Teqqa also synthesizes the university hospital’s resistance data based on blood, urine, and sputum cultures. “It can predict the antibiotic sensitivity of a given bug growing out of a given culture on a given unit,” said Craig A. Umscheid, MD, MSCE, of the department of epidemiology and vice chair for quality and safety in the department of medicine at the university.

The bigger issue, Dr. Umscheid said, is when and how to de-escalate antibiotic treatment. “If somebody is feeling better in 48 hours or 72 hours and no cultures have grown back, they have no more fever, and their white counts have normalized, do you start pulling off the antibiotics slowly and, if so, how do you do that?” Several trials are examining such questions, including a multicenter collaboration called DETOURS (De-Escalating Empiric Treatment: Opting-Out of Rx for Selected Patients With Suspected Sepsis). One of the trial’s chief aims is to set up a new opt-out protocol for acute care patients in the wards.

One unintended consequence of the increased attention to early sepsis identification and intervention can be unnecessary or excessive antibiotic use. Overuse of broad-spectrum antibiotics, in turn, can fuel the emergence of life-threatening infections such as antibiotic-resistant Clostridium difficile, a scourge in many hospitals.

For a sepsis quality improvement (QI) initiative at the University of Utah, Salt Lake City, the hospitalist coleaders took several precautions to lessen the risk of antibiotic overuse. Kencee K. Graves, MD, said she and her colleague Devin J. Horton, MD, designed the hospital’s order sets in collaboration with an infectious disease specialist and pharmacist so they could avoid overly broad antibiotics whenever possible. The project also included an educational effort to get pharmacists in the habit of prompting medical providers to initiate antibiotic de-escalation at 48 hours. The hospital had an antibiotic stewardship program that likely helped as well, she said. As a result of their precautions, the team found no significant difference in the amount of broad-spectrum antibiotics doled out before and after their QI pilot project.

Infection control and antimicrobial specialists also can help; they can monitor an area’s resistance profile, create a antibiogram and reevaluate sepsis pathways and order sets to adjust the recommended antibiotics as the resistance profile changes. “I think we still have a long ways to go,” said Andy Odden, MD, SFHM, patient safety officer in the department of medicine at Washington University in St. Louis. “The initial risk of mortality is so much more dramatic than the long-term risks of developing antimicrobial resistors that unless you have the antimicrobial stewardship people with a seat at the table, that voice can get drowned out very easily.”

The antimicrobial stewardship program at University of Pennsylvania, Philadelphia, has received a boost from technology. The program offers initial guidance on which broad-spectrum antibiotics to consider depending on the suspected source of the sepsis-linked infection. Software by Jackson, Wyo.–based biotech company Teqqa also synthesizes the university hospital’s resistance data based on blood, urine, and sputum cultures. “It can predict the antibiotic sensitivity of a given bug growing out of a given culture on a given unit,” said Craig A. Umscheid, MD, MSCE, of the department of epidemiology and vice chair for quality and safety in the department of medicine at the university.

The bigger issue, Dr. Umscheid said, is when and how to de-escalate antibiotic treatment. “If somebody is feeling better in 48 hours or 72 hours and no cultures have grown back, they have no more fever, and their white counts have normalized, do you start pulling off the antibiotics slowly and, if so, how do you do that?” Several trials are examining such questions, including a multicenter collaboration called DETOURS (De-Escalating Empiric Treatment: Opting-Out of Rx for Selected Patients With Suspected Sepsis). One of the trial’s chief aims is to set up a new opt-out protocol for acute care patients in the wards.

One unintended consequence of the increased attention to early sepsis identification and intervention can be unnecessary or excessive antibiotic use. Overuse of broad-spectrum antibiotics, in turn, can fuel the emergence of life-threatening infections such as antibiotic-resistant Clostridium difficile, a scourge in many hospitals.

For a sepsis quality improvement (QI) initiative at the University of Utah, Salt Lake City, the hospitalist coleaders took several precautions to lessen the risk of antibiotic overuse. Kencee K. Graves, MD, said she and her colleague Devin J. Horton, MD, designed the hospital’s order sets in collaboration with an infectious disease specialist and pharmacist so they could avoid overly broad antibiotics whenever possible. The project also included an educational effort to get pharmacists in the habit of prompting medical providers to initiate antibiotic de-escalation at 48 hours. The hospital had an antibiotic stewardship program that likely helped as well, she said. As a result of their precautions, the team found no significant difference in the amount of broad-spectrum antibiotics doled out before and after their QI pilot project.

Infection control and antimicrobial specialists also can help; they can monitor an area’s resistance profile, create a antibiogram and reevaluate sepsis pathways and order sets to adjust the recommended antibiotics as the resistance profile changes. “I think we still have a long ways to go,” said Andy Odden, MD, SFHM, patient safety officer in the department of medicine at Washington University in St. Louis. “The initial risk of mortality is so much more dramatic than the long-term risks of developing antimicrobial resistors that unless you have the antimicrobial stewardship people with a seat at the table, that voice can get drowned out very easily.”

The antimicrobial stewardship program at University of Pennsylvania, Philadelphia, has received a boost from technology. The program offers initial guidance on which broad-spectrum antibiotics to consider depending on the suspected source of the sepsis-linked infection. Software by Jackson, Wyo.–based biotech company Teqqa also synthesizes the university hospital’s resistance data based on blood, urine, and sputum cultures. “It can predict the antibiotic sensitivity of a given bug growing out of a given culture on a given unit,” said Craig A. Umscheid, MD, MSCE, of the department of epidemiology and vice chair for quality and safety in the department of medicine at the university.

The bigger issue, Dr. Umscheid said, is when and how to de-escalate antibiotic treatment. “If somebody is feeling better in 48 hours or 72 hours and no cultures have grown back, they have no more fever, and their white counts have normalized, do you start pulling off the antibiotics slowly and, if so, how do you do that?” Several trials are examining such questions, including a multicenter collaboration called DETOURS (De-Escalating Empiric Treatment: Opting-Out of Rx for Selected Patients With Suspected Sepsis). One of the trial’s chief aims is to set up a new opt-out protocol for acute care patients in the wards.

LOS ANGELES – Women with a history of preeclampsia have a significantly increased risk for an early-onset stroke, but that risk is blunted in women taking aspirin, an epidemiologic analysis of data from more than 83,000 women in the California Teachers Study showed.

Among the 4,072 women in the study with a history of preeclampsia, 3,003 were not on aspirin, and during follow-up they had a greater than 1% incidence of stroke – ischemic and hemorrhagic combined – before turning 60 years of age. Their incidence rate was 40% higher than in the roughly 60,000 women without a preeclampsia history who were not taking aspirin, a statistically significant difference after adjustment for demographics, smoking, obesity, diabetes, and hypertension, Eliza C. Miller, MD, said at the International Stroke Conference, sponsored by the American Heart Association.

Mitchel L. Zoler/Frontline Medical News

The average age of the women with preeclampsia was 44, and 46 for those without preeclampsia. The women with a history of preeclampsia also had a higher prevalence rate of obesity, hypertension, diabetes, and chronic kidney disease. Roughly a quarter of all women were regularly taking aspirin.

After adjustment of the data for demographic and clinical differences, women with a history of preeclampsia had a 20% higher overall rate of a subsequent stroke before reaching age 60 years, but this difference was not significant in an analysis that included both women taking aspirin and those not on the drug. When the analysis focused only on the women not on aspirin, the increased stroke rate linked with a preeclampsia history rose to 40% higher than in women without a preeclampsia history, a statistically significant difference. In contrast, among the quarter of women on aspirin, the two subgroups – with a preeclampsia history and without – had similar rates of incident strokes.

[email protected]

SOURCE: Miller E et al. International Stroke Conference 2018, A174 (Stroke. 2018 Jan;49[Suppl1]:A174).

LOS ANGELES – Women with a history of preeclampsia have a significantly increased risk for an early-onset stroke, but that risk is blunted in women taking aspirin, an epidemiologic analysis of data from more than 83,000 women in the California Teachers Study showed.

Among the 4,072 women in the study with a history of preeclampsia, 3,003 were not on aspirin, and during follow-up they had a greater than 1% incidence of stroke – ischemic and hemorrhagic combined – before turning 60 years of age. Their incidence rate was 40% higher than in the roughly 60,000 women without a preeclampsia history who were not taking aspirin, a statistically significant difference after adjustment for demographics, smoking, obesity, diabetes, and hypertension, Eliza C. Miller, MD, said at the International Stroke Conference, sponsored by the American Heart Association.

Mitchel L. Zoler/Frontline Medical News

The average age of the women with preeclampsia was 44, and 46 for those without preeclampsia. The women with a history of preeclampsia also had a higher prevalence rate of obesity, hypertension, diabetes, and chronic kidney disease. Roughly a quarter of all women were regularly taking aspirin.

After adjustment of the data for demographic and clinical differences, women with a history of preeclampsia had a 20% higher overall rate of a subsequent stroke before reaching age 60 years, but this difference was not significant in an analysis that included both women taking aspirin and those not on the drug. When the analysis focused only on the women not on aspirin, the increased stroke rate linked with a preeclampsia history rose to 40% higher than in women without a preeclampsia history, a statistically significant difference. In contrast, among the quarter of women on aspirin, the two subgroups – with a preeclampsia history and without – had similar rates of incident strokes.

[email protected]

SOURCE: Miller E et al. International Stroke Conference 2018, A174 (Stroke. 2018 Jan;49[Suppl1]:A174).

LOS ANGELES – Women with a history of preeclampsia have a significantly increased risk for an early-onset stroke, but that risk is blunted in women taking aspirin, an epidemiologic analysis of data from more than 83,000 women in the California Teachers Study showed.

Among the 4,072 women in the study with a history of preeclampsia, 3,003 were not on aspirin, and during follow-up they had a greater than 1% incidence of stroke – ischemic and hemorrhagic combined – before turning 60 years of age. Their incidence rate was 40% higher than in the roughly 60,000 women without a preeclampsia history who were not taking aspirin, a statistically significant difference after adjustment for demographics, smoking, obesity, diabetes, and hypertension, Eliza C. Miller, MD, said at the International Stroke Conference, sponsored by the American Heart Association.

Mitchel L. Zoler/Frontline Medical News

The average age of the women with preeclampsia was 44, and 46 for those without preeclampsia. The women with a history of preeclampsia also had a higher prevalence rate of obesity, hypertension, diabetes, and chronic kidney disease. Roughly a quarter of all women were regularly taking aspirin.

After adjustment of the data for demographic and clinical differences, women with a history of preeclampsia had a 20% higher overall rate of a subsequent stroke before reaching age 60 years, but this difference was not significant in an analysis that included both women taking aspirin and those not on the drug. When the analysis focused only on the women not on aspirin, the increased stroke rate linked with a preeclampsia history rose to 40% higher than in women without a preeclampsia history, a statistically significant difference. In contrast, among the quarter of women on aspirin, the two subgroups – with a preeclampsia history and without – had similar rates of incident strokes.

[email protected]

SOURCE: Miller E et al. International Stroke Conference 2018, A174 (Stroke. 2018 Jan;49[Suppl1]:A174).

As I sit here and write this article, it is hard to fathom that a quarter of my year as the President of CHEST has passed by. Thanks again for this incredibly humbling opportunity to serve as your President.

I hope many who read this were able to get to Toronto and experience CHEST 2017. Special thanks to our Program Chair, Peter Mazzone, and to his Co-Chair Diane Lougheed from the Canadian Thoracic Society; the Scientific Program Committee; our excellent and committed CHEST 2017 faculty, who give their valuable time to ensure we are delivering the best clinical education possible; and our incredibly talented CHEST staff for all their work to make this meeting a reality.

1. The Editor in Chief Search Task Force, under the leadership of Dr.. David Gutterman and Nicki Augustyn, is hard at work with their diverse and talented colleagues on this critically important task.



2. The Scientific Program Committee, under Dr. David Schulman’s direction, is hard at work building October’s CHEST 2018 in San Antonio. It is so exciting to watch this group plan and create, in new and innovative ways, the content for this meeting to be held October 6-10.



3. By the publication date of this article, your Board of Regents most likely will have put the finishing touches, under the leadership of Jenny Nemkovich, our Chief of Staff, on our next 5-year strategic plan.



4. The Board of Regents is also moving forward with a uniform, business-like process and approach in delivering international education offerings and meeting opportunities. Special thanks to Bob Musacchio, our COO and the SVP of Strategy and Innovation, Sue Reimbold, wearing her hat of Market Growth; and Chad Jackson, VP of Innovation and Development, for their direction in this area.



5. Thanks to the Diversity/Inclusion Task Force for their continued work to ensure that the principles of diversity of thought and inclusion permeate all of our conversations and work on the volunteer and professional sides of CHEST.



6. Thanks also to our Training and Transitions Committee and their leadership, Drs. Gabe Bosslet and Matt Miles, and the support of Dr. Richard Irwin and our CHEST® journal for the introduction of the CHEST Teaching, Education, and Career Hub in the journal, which made its debut in January.



7. Also, emphasizing the critical importance of relationships, thanks to our colleagues and partners with so many sister societies with whom we are working closely to help advance the practice of chest medicine. I am confident that we are building better relationships built on common goals, transparency, communication, and trust than we have in many years.



8. Last, and certainly not least, one of the jobs of President I am most looking forward to is serving on the Board of Trustees of the CHEST Foundation as an ex officio member. Having served on this Board for about 10 years, I am so glad to be joining my CF family once again. What an amazing group of volunteers, leaders, and staff serving CHEST and our patients in such amazing ways.

These are but a few of so many things that are transpiring at CHEST. People have asked me if it is intimidating to take on this responsibility. With the support of such diversely talented leaders in our Presidential line; an incredibly mature and engaged BOR; and a CEO, senior leadership, and diverse and talented staff that we have at CHEST, all characterized by incredible intellect and energy, it is pretty easy to be just another member of a great team.

Thanks again for your unwavering support of CHEST and our mission.

As I sit here and write this article, it is hard to fathom that a quarter of my year as the President of CHEST has passed by. Thanks again for this incredibly humbling opportunity to serve as your President.

I hope many who read this were able to get to Toronto and experience CHEST 2017. Special thanks to our Program Chair, Peter Mazzone, and to his Co-Chair Diane Lougheed from the Canadian Thoracic Society; the Scientific Program Committee; our excellent and committed CHEST 2017 faculty, who give their valuable time to ensure we are delivering the best clinical education possible; and our incredibly talented CHEST staff for all their work to make this meeting a reality.

1. The Editor in Chief Search Task Force, under the leadership of Dr.. David Gutterman and Nicki Augustyn, is hard at work with their diverse and talented colleagues on this critically important task.



2. The Scientific Program Committee, under Dr. David Schulman’s direction, is hard at work building October’s CHEST 2018 in San Antonio. It is so exciting to watch this group plan and create, in new and innovative ways, the content for this meeting to be held October 6-10.



3. By the publication date of this article, your Board of Regents most likely will have put the finishing touches, under the leadership of Jenny Nemkovich, our Chief of Staff, on our next 5-year strategic plan.



4. The Board of Regents is also moving forward with a uniform, business-like process and approach in delivering international education offerings and meeting opportunities. Special thanks to Bob Musacchio, our COO and the SVP of Strategy and Innovation, Sue Reimbold, wearing her hat of Market Growth; and Chad Jackson, VP of Innovation and Development, for their direction in this area.



5. Thanks to the Diversity/Inclusion Task Force for their continued work to ensure that the principles of diversity of thought and inclusion permeate all of our conversations and work on the volunteer and professional sides of CHEST.



6. Thanks also to our Training and Transitions Committee and their leadership, Drs. Gabe Bosslet and Matt Miles, and the support of Dr. Richard Irwin and our CHEST® journal for the introduction of the CHEST Teaching, Education, and Career Hub in the journal, which made its debut in January.



7. Also, emphasizing the critical importance of relationships, thanks to our colleagues and partners with so many sister societies with whom we are working closely to help advance the practice of chest medicine. I am confident that we are building better relationships built on common goals, transparency, communication, and trust than we have in many years.



8. Last, and certainly not least, one of the jobs of President I am most looking forward to is serving on the Board of Trustees of the CHEST Foundation as an ex officio member. Having served on this Board for about 10 years, I am so glad to be joining my CF family once again. What an amazing group of volunteers, leaders, and staff serving CHEST and our patients in such amazing ways.

These are but a few of so many things that are transpiring at CHEST. People have asked me if it is intimidating to take on this responsibility. With the support of such diversely talented leaders in our Presidential line; an incredibly mature and engaged BOR; and a CEO, senior leadership, and diverse and talented staff that we have at CHEST, all characterized by incredible intellect and energy, it is pretty easy to be just another member of a great team.

Thanks again for your unwavering support of CHEST and our mission.

As I sit here and write this article, it is hard to fathom that a quarter of my year as the President of CHEST has passed by. Thanks again for this incredibly humbling opportunity to serve as your President.

I hope many who read this were able to get to Toronto and experience CHEST 2017. Special thanks to our Program Chair, Peter Mazzone, and to his Co-Chair Diane Lougheed from the Canadian Thoracic Society; the Scientific Program Committee; our excellent and committed CHEST 2017 faculty, who give their valuable time to ensure we are delivering the best clinical education possible; and our incredibly talented CHEST staff for all their work to make this meeting a reality.

1. The Editor in Chief Search Task Force, under the leadership of Dr.. David Gutterman and Nicki Augustyn, is hard at work with their diverse and talented colleagues on this critically important task.



2. The Scientific Program Committee, under Dr. David Schulman’s direction, is hard at work building October’s CHEST 2018 in San Antonio. It is so exciting to watch this group plan and create, in new and innovative ways, the content for this meeting to be held October 6-10.



3. By the publication date of this article, your Board of Regents most likely will have put the finishing touches, under the leadership of Jenny Nemkovich, our Chief of Staff, on our next 5-year strategic plan.



4. The Board of Regents is also moving forward with a uniform, business-like process and approach in delivering international education offerings and meeting opportunities. Special thanks to Bob Musacchio, our COO and the SVP of Strategy and Innovation, Sue Reimbold, wearing her hat of Market Growth; and Chad Jackson, VP of Innovation and Development, for their direction in this area.



5. Thanks to the Diversity/Inclusion Task Force for their continued work to ensure that the principles of diversity of thought and inclusion permeate all of our conversations and work on the volunteer and professional sides of CHEST.



6. Thanks also to our Training and Transitions Committee and their leadership, Drs. Gabe Bosslet and Matt Miles, and the support of Dr. Richard Irwin and our CHEST® journal for the introduction of the CHEST Teaching, Education, and Career Hub in the journal, which made its debut in January.



7. Also, emphasizing the critical importance of relationships, thanks to our colleagues and partners with so many sister societies with whom we are working closely to help advance the practice of chest medicine. I am confident that we are building better relationships built on common goals, transparency, communication, and trust than we have in many years.



8. Last, and certainly not least, one of the jobs of President I am most looking forward to is serving on the Board of Trustees of the CHEST Foundation as an ex officio member. Having served on this Board for about 10 years, I am so glad to be joining my CF family once again. What an amazing group of volunteers, leaders, and staff serving CHEST and our patients in such amazing ways.

These are but a few of so many things that are transpiring at CHEST. People have asked me if it is intimidating to take on this responsibility. With the support of such diversely talented leaders in our Presidential line; an incredibly mature and engaged BOR; and a CEO, senior leadership, and diverse and talented staff that we have at CHEST, all characterized by incredible intellect and energy, it is pretty easy to be just another member of a great team.

Thanks again for your unwavering support of CHEST and our mission.

A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.

However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”

Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.

The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 10⁹/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.

Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.

“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.

“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.

Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Findings in context

Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.

“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.

“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”

Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.

SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413

A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.

However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”

Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.

The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 10⁹/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.

Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.

“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.

“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.

Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Findings in context

Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.

“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.

“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”

Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.

SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413

A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.

However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”

Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.

The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 10⁹/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.

Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.

“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.

“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.

Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Findings in context

Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.

“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.

“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”

Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.

SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413