Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report.

INTRODUCTION: The increased availability of immunotherapeutic agents for the treatment of a wide array of cancer in the general oncology practice setting will reveal rare and unique toxicities. MATERIALS AND METHODS: The mechanism of cardiac allograft rejection in the context of PD-1 antibody therapy was explored in a patient with cutaneous squamous cell cancer complicating long-standing cardiac allograft. Immune cell infiltrate in the myocardium and peripheral blood lymphocyte repertoire were assessed using myocardial biopsy and temporal analysis of peripheral blood samples. The efficacy of high-intensity immunosuppression to reverse graft rejection was explored. RESULTS: Endomyocardial biopsy showed acute moderate diffuse cellular rejection with a predominant population of CD3+, CD8+ and CD4+ infiltrating lymphocytes; peripheral blood circulating lymphocytes showed a high frequency of proliferating and activated CD8+ T cells expressing PD-1 compared to a normal control. There was no difference in the activation and proliferation of CD4+ T cells compared to a normal control. Cardiac function improved following high-intensity immunosuppression and patient survived for up to 7 months after discontinuation of nivolumab. CONCLUSIONS: Immune checkpoint inhibitors should be avoided in allograft recipients but high-intensity immunosuppression is effective to salvage allograft rejection induced by these agents.

Revisiting mechanisms of resistance to immunotherapies in metastatic clear-cell renal-cell carcinoma.

Renal-cell carcinoma (RCC) remains a leading cause of cancer-related mortality worldwide. Though newer therapeutic combinations of immune checkpoint inhibitors and targeted therapies have greatly improved outcomes, resistance to these therapies is becoming a challenge for long-term control. Mechanisms of resistance have been explored in a variety of solid tumors, including RCC. Based upon our review of the current literature on the mechanisms of resistance to immunotherapies for the management of metastatic clear-cell renal cell carcinomas (mccRCC), the ensuing conclusions have been made: The management of mccRCC has progressed substantially with the advent of checkpoint inhibitors and targeted oral therapies, alone and/or in combination. Nevertheless, innate or developed resistance to these therapies remains an ongoing challenge, particularly to immune checkpoint inhibitors (ICIs). Several of the known mechanisms of resistance have been well defined, but recent progression in cellular therapies helps to expand the armamentarium of potential combination options that may overcome these modes of resistance and improve long-term disease control and survival for an otherwise dismal disease. In the ensuing review and update of the literature on the mechanisms of resistance to immunotherapies in mccRCC, we have revisited the known resistance mechanisms of immunotherapies in metastatic clear-cell RCC and explored ongoing and future strategies to overcome them.

Fear of Saying No (FOSNO): Setting Boundaries With Our Patients and Ourselves.

Cancer is an inherently complex and intense medical condition that often requires prolonged treatment and surveillance over years. Treatments can lead to frequent side effects and anxiety, requiring constant communication and follow-up with patients. Oncologists have the unique privilege of developing close relationships with their patients that evolve through the course of their disease. The advent of newer technology and the changing landscape of medicine have drastically altered how oncologists now manage patient needs. These changes have allowed for much quicker and closer communication but are not without personal and professional challenges. Some may wonder how accessible they can and should be to their patients-essentially, the boundaries they may place to protect their own identities and well-being. An oncologist might wonder how much of their personal contact information they should provide to patients and how often they should be available for questions and discussions when away from the clinic without impairing their relationship. Here, we define and explore the role of boundaries in medicine, and review common ethical dilemmas that oncologists face daily when trying to balance patient care and lives outside of medicine. Although we recognize there is no clear single solution, we will propose possible approaches to setting boundaries and potential pitfalls.

Colonic Adenocarcinoma with Plasmacytoid Feature: Histopathology and Molecular Characteristics of a Rare Neoplasm with an Unusual Presentation.

Colorectal carcinoma with noncohesive tumor cells has been described in tumors with signet ring cells (mucinous adenocarcinoma and signet ring cell adenocarcinoma) and rhabdoid feature (carcinoma with sarcomatoid component). Cases of carcinoma with plasmacytoid morphology are rare in the gastrointestinal tract, and a single case of plasmacytoid colorectal carcinoma has been reported. We report the case of a 37-year-old woman who presented with urinary symptoms, hematuria, and abdominal pain. Imaging studies showed segmental sigmoid wall thickening with pericolic infiltration and focal bladder wall thickening. The cystoscopy with transurethral resection of bladder tumor revealed muscle invasion, dis-cohesive carcinoma with plasmacytoid morphology, which was initially misdiagnosed as the plasmacytoid urothelial carcinoma. Immunohistochemical stains showed the tumor cells to be positive for CDX2, CK20, and SATB2 and negative for p63, GATA3, CK7, and Uroplakin II, indicating the colorectal origin of the tumor. The subsequent colonic wall biopsy showed the same tumor. Molecular studies identified BRAF V600E, SMAD4, and p53 mutations associated with aggressive colorectal adenocarcinoma with mucinous/signet ring cell features. Further whole-exome sequencing and whole transcriptome analysis confirmed the colorectal origin of the tumor. This rare colorectal adenocarcinoma with the plasmacytoid feature may represent the signet ring cell adenocarcinoma lacking extracellular mucin or intracellular vacuole. Diagnosis of this rare histological subtype of colorectal carcinoma is important, particularly in the unusual presentation of this aggressive tumor.

A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer.

Background: We hypothesize that cancer survival can be improved through adapting treatment strategies to cancer evolutionary dynamics and conducted a phase 1b study in metastatic castration sensitive prostate cancer (mCSPC). Methods: Men with asymptomatic mCSPC were enrolled and proceeded with a treatment break after achieving > 75% PSA decline with LHRH analog plus an NHA. ADT was restarted at the time of PSA or radiographic progression and held again after achieving >50% PSA decline. This on-off cycling of ADT continued until on treatment imaging progression. Results: At data cut off in August 2022, only 2 of the 16 evaluable patients were off study due to imaging progression at 28 months from first dose of LHRH analog for mCSPC. Two additional patients showed PSA progression at 12.4 and 20.5 months and remain on trial. Since none of the 16 patients developed imaging progression at 12 months, the study succeeded in its primary objective of feasibility. The secondary endpoints of median time to PSA progression and median time to radiographic progression have not been reached at a median follow up of 26 months. Conclusions: It is feasible to use an individual's PSA response and testosterone levels to guide intermittent ADT in mCSPC.

Forming the Hematology-Oncology Collaborative Videoconferencing (CO-VID) Learning Initiative: Experiential Lessons Learned From a Novel Trainee-Led Multidisciplinary Virtual Learning Platform.

PURPOSE: COVID-19 challenged medical practice and graduate medical education. Building on previous initiatives, we describe and reflect on the formative process and goals of the Hematology-Oncology Collaborative Videoconferencing Learning Initiative, a trainee-led multi-institutional virtual COVID-19 learning model. METHODS: Clinical fellows and faculty from 13 US training institutions developed consensus needs, goals, and objectives, recruited presenters, and generated a multidisciplinary COVID-19 curriculum. Weekly Zoom conferences consisted of two trainee-led instructional segments and a trainee-moderated faculty Q&A panel. Hematology-oncology training program faculty and trainees were the targeted audience. Leadership evaluations consisted of anonymized baseline and concluding mixed methods surveys. Presenter evaluations consisted of session debriefs and two structured focus groups. Conference evaluations consisted of attendance, demographics, and pre- or postmultiple-choice questions on topic learning objectives. RESULTS: In 6 weeks, the initiative produced five conferences: antivirals, anticoagulation, pulmonology, provider resilience, and resource scarcity ethics. The average attendance was 100 (range 57-185). Among attendees providing both pre- and postconference data, group-level knowledge appeared to increase: antiviral (n = 46) pre-/postcorrect 82.6%/97.8% and incorrect 10.9%/2.2%, anticoagulation (n = 60) pre-/postcorrect 75%/93.3% and incorrect 15%/6.7%, and pulmonary (n = 21) pre-/postcorrect 66.7%/95.2% and incorrect 33.3%/4.8%. Although pulmonary management comfort appeared to increase, comfort managing of antivirals and anticoagulation was unchanged. At the conclusion of the pilot, leadership trainees reported improved self-confidence organizing multi-institutional collaborations, median (interquartile range) 58.5 (50-64) compared with baseline 34 (26-39), but did not report improved confidence in other educational or leadership skills. CONCLUSION: During crisis, trainees built a multi-institutional virtual education platform for the purposes of sharing pandemic experiences and knowledge. Accomplishment of initiative goals was mixed. Lessons learned from the process and goals may improve future disaster educational initiatives.

Pathology of Seminoma Coinciding With Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia.

We present the case of a 71-year-old male with an incidental diagnosis of seminoma coinciding with small lymphocytic lymphoma/chronic lymphocytic leukemia in the retroperitoneum. This case report illustrates the cytology, histology, immunohistochemistry, flow cytometry, and fluorescence in situ hybridization features of this exceptional case and sheds light on the importance of a collaborative multidisciplinary team in delivering quality patient care.

Creating a Blueprint of Well-Being in Oncology: An Approach for Addressing Burnout From ASCO's Clinician Well-Being Taskforce.

Optimizing the well-being of the oncology clinician has never been more important. Well-being is a critical priority for the cancer organization because burnout adversely impacts the quality of care, patient satisfaction, the workforce, and overall practice success. To date, 45% of U.S. ASCO member medical oncologists report experiencing burnout symptoms of emotional exhaustion and depersonalization. As the COVID-19 pandemic remains widespread with periods of outbreaks, recovery, and response with substantial personal and professional consequences for the clinician, it is imperative that the oncologist, team, and organization gain direct access to resources addressing burnout. In response, the Clinician Well-Being Task Force was created to improve the quality, safety, and value of cancer care by enhancing oncology clinician well-being and practice sustainability. Well-being is an integrative concept that characterizes quality of life and encompasses an individual's work- and personal health-related environmental, organizational, and psychosocial factors. These resources can be useful for the cancer organization to develop a well-being blueprint: a detailed start plan with recognized strategies and interventions targeting all oncology stakeholders to support a culture of community in oncology.

A Call to Action: Ethics Committee Roundtable Recommendations for Addressing Burnout and Moral Distress in Oncology.

Oncologist well-being is critical to initiating and maintaining the physician-patient relationship, yet many oncologists suffer from symptoms of burnout. Burnout has been linked to poor physical and mental health, as well as increased medical errors, patient dissatisfaction, and workforce attrition. In this Call to Action article, we discuss causes of and interventions for burnout and moral distress in oncology, highlight existing interventions, and provide recommendations for addressing burnout and improving well-being at the individual and organizational levels to deliver ethical, quality cancer care.

Malignant mesothelioma clinical trial combines immunotherapy drugs.

Immunotherapy by checkpoint inhibitor is effective for a number of solid tumors including malignant mesothelioma. Studies utilizing single-agent PD-1 or PD-L1 inhibitor for mesothelioma have reported tumor response rates in approximately 10-20% of patients treated. Given the success of combining these agents with CTLA-4 inhibitor in melanoma, there is a strong rationale to study it in mesothelioma. Recently results from clinical trials investigating this approach have been released. Though limited by small sample size, the studies conclusively demonstrated feasibility and suggested a modestly higher tumor response rate than one would expect from treatment with single-agent PD-1 or PD-L1 inhibitor. Nevertheless, toxicity was also increased. Immunotherapy-related deaths due to encephalitis, renal failure and hepatitis were observed. Further studies are warranted.

Anti PD-L1 combined with other agents in non-small cell lung cancer: combinations with non-immuno-oncology agents.

INTRODUCTION: Lung cancer is the most common cause of cancer-related deaths in the world. Despite recent advances, the estimated 5-year overall survival is only around 17%. There is an urgent need for development of new effective drug strategies for the treatment of advanced-stage lung cancer. Areas covered: This review focuses on ongoing research in immune and non-immune oncology combinations for the treatment of non-small cell lung cancer (NSCLC). Here, we will focus on the combination of PD-L1 inhibitors (immunotherapy) with chemotherapy, vascular endothelial growth factor inhibitors, targeted therapies, and radiation. Expert commentary: Immunotherapy is a major advancement in the treatment of NSCLC due to its durable responses and overall favorable toxicity profile. However, these responses are seen in only a subset of patients. Mechanisms of resistance to this therapy continue to emerge. Studies on combination therapies are underway as the therapeutic mechanisms of these established agents are not only distinctly different but also synergistic with immunotherapy. Overall, some benefits have been noted, although associated toxicities have also been shown, and the long-term benefits including overall survival have yet to be determined.