Updates in the Treatment of Non-Metastatic Castrate-Resistant Prostate Cancer: The Benefit of Second-Generation Androgen Receptor Antagonists.

OBJECTIVE: To review pharmacology, efficacy, safety, and considerations for use, of second-generation androgen receptor (AR) antagonists in treatment of nonmetastatic castrate-resistant prostate cancer (M0CRPC). DATA SOURCES: Conducted search in PubMed and Google scholar (January, 1, 2002-December 31, 2022), using relevant terms. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies, conducted in humans evaluating second-generation AR antagonists for M0CRPC, and additional articles and package inserts were considered. DATA SYNTHESIS: Apalutamide, darolutamide, and enzalutamide are effective in delaying the time to development of metastatic prostate cancer in men with M0CRPC with a rapid prostate-specific antigen (PSA) doubling time (<10 months). No head-to-head, randomized, clinical trials have been conducted. The most common adverse effects include fatigue and hypertension, and quality of life is maintained in most patients. Cost is similar among the agents (~$15,000/month). Drug-drug interactions vary among these agents and should be considered, when selecting therapy as well as likely adherence. Darolutamide is administered twice daily with the others once daily. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Second-generation AR antagonists are effective in reducing time to development of metastatic disease and prolonging overall survival in patients with M0CRPC and a PSA doubling time of <10 months. Recent imaging advances may alter how we evaluate outcomes. CONCLUSIONS: Second-generation AR antagonists improve disease control and overall survival. Generally, they are well tolerated and QOL is maintained. Selection of the best agent is based on the adverse effect profile, potential for drug- and disease-interactions, administration, cost, and patient preference.

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review.

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody-drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets.

Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.

Response with pembrolizumab in a patient with EGFR mutated non-small cell lung cancer harbouring insertion mutations in V834L and L858R.

INTRODUCTION: Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC) being the most common of them. About a third of NSCLC cases have an epidermal growth factor (EGFR) mutation, which is usually susceptible to tyrosine kinase inhibitors (TKIs). In rare cases where patients progress through TKI therapy, the use of immune checkpoint inhibitors (ICIs) remains controversial. CASE REPORT: We describe a case of a patient with significant history of smoking and EGFR mutated programmed death ligand-1 (PD-L1) positive NSCLC who was initially treated with TKI therapy. MANAGEMENT/OUTCOME: While patient progressed on TKI therapy, he was able to achieve a durable response with a single PD-L1 agent, pembrolizumab. Contrary to the available evidence, the presented EGFR mutant NSCLC responded to PD-L1 pathway inhibition. DISCUSSION: From our observation Pembrolizumab could be promising in patients with rare EGFR mutations who do not respond to EGFR directed therapy. Our report provides supporting data for the use of immunotherapies in patients with EGFR mutated NSCLC.

Neurologic complications of melanoma.

Neurologic complications are common in patients with melanoma and are often associated with a poor prognosis. In an era with new, effective treatments, patients are living longer, and this has resulted in an increase in complications of both the disease and the therapy. A multidisciplinary approach to neurologic complications in patients with melanoma, with involvement from medical oncology, neuro-oncology, radiation oncology, and often neurosurgery, is necessary. In this review, neurologic complications of melanoma, including clinical implications and treatment strategies, are described.

A fatal case of Immune thrombocytopenia secondary to the immune checkpoint inhibitor ipilimumab in a patient with BRAF wild type metastatic melanoma.

INTRODUCTION: Immune checkpoint inhibitors have revolutionized the field of oncology in recent years. Ipilimumab is a monoclonal antibody that targets the protein cytotoxic T-lymphocyte 4, which is involved in the inhibition of cytotoxic T-lymphocytes. When uninhibited, cytotoxic T-lymphocytes can act to recognize and kill cancer cells. This increased activity of immune cells can inadvertently destroy healthy tissue leading to a class of side effects known as immune-related adverse events. Immune thrombocytopenia purpura secondary to checkpoint inhibitors is an uncommon complication (<1%) and in most instances resolve spontaneously without aggressive treatment. CASE REPORT: We present a case of immune thrombocytopenia purpura developing in a patient recently started on ipilimumab for BRAF wild-type metastatic melanoma. The patient presented to his primary oncologist with confusion and lethargy. Subsequent blood work revealed a platelet count of 16,000 ng/mL. The patient was transferred to the emergency department where a computed tomography scan revealed bilateral frontal lobe hemorrhages. The patient was admitted to the intensive care unit for further management. MANAGEMENT AND OUTCOME: The patient received IV immunoglobulins at 1 g/kg every 24 h in addition to IV Decadron 40 mg daily. In addition, the patient continued to receive significant platelet transfusions. The patient's platelet count recovered to 78,000 ng/mL (baseline for this patient > 130,000 ng/mL.) The patient developed worsening mental status and was found to have significant increase in previously found bilateral frontal hemorrhages. The patient was transitioned to comfort measures only due to very poor prognosis and passed away in hospice care. DISCUSSION: Checkpoint inhibitors have provided durable responses in multiple cancers that previously had a paucity of treatment options. This case demonstrates that immune thrombocytopenia purpura is a possible adverse event of these therapies and thus platelet monitoring should be included in all patients.

Pharmacist intervention in colorectal cancer screening initiative.

OBJECTIVES: To assess the novel approach of using the community pharmacist as the primary health care team member to facilitate colorectal cancer (CRC) risk counseling and screening in socioeconomically disadvantaged populations. SETTING: A collaborative effort between the UConn Health Colon Cancer Prevention Program and UConn School of Pharmacy in conjunction with large independent chain pharmacies (medium to medium-high volume) located in metropolitan areas of Connecticut, including Hartford, Bridgeport, New Haven, and Stamford. Pharmacies located in hospitals, across the street from a large physician practice, or within the community. PRACTICE DESCRIPTION: The study involved 2 phases. The first phase involved education and training for community pharmacists regarding counseling approaches for patients on the topic of CRC. The second phase of the study involved patient recruitment and counseling with subsequent fecal immunohistochemical testing (FIT). PRACTICE INNOVATION: A community pharmacist provided face-to-face counseling on CRC risk factor reduction and provided CRC screening to patients who were without insurance or underinsured. No CRC screening or education program existed beforehand. EVALUATION: A target sample size of 60 participants was needed with a type 1 error rate of 5% and a power of 80%. Exploration of variables using multivariate logistic regression model included any variable with a univariate P < 0.2. Multivariate P values < 0.05 were considered independent predictors. RESULTS: After approaching 312 consumers, 16 of them consented to the study. The majority of participants (88%) were African American or Latino, and 69% were currently unemployed. Eight participants agreed to complete FIT, and 88% of participants completed FIT correctly. Only 1 positive FIT result was observed, but a subsequent colonoscopy was negative. Of the 12 questions that assessed baseline CRC knowledge in the initial survey, 16 participants answered an average of 2.6 (range, 0-6, SD, 1.6) questions incorrectly. Only 4 participants completed the follow-up survey of CRC knowledge and program satisfaction; thus, exploration of variables was not conducted. Patients indicated high satisfaction with the program of education and FIT dispensing. CONCLUSION: This study faced difficulty in recruiting pharmacists to participate, with the main reason being lack of compensation and disruption to workflow. Patient participation in the trial was also low because of a lack of time or interest in participation. Of the patients who did participate, the level of satisfaction in having the pharmacist speak to them about CRC screening was high. This service is an excellent example of how the pharmacist can provide a more accessible, convenient, and responsive approach to patients' needs while improving health equity. Future studies that employ a revenue model to build the infrastructure and capacity necessary to offer this service efficiently and consistently are needed.

What Is the Timing and Role of Targeted Therapy in Metastatic Melanoma?

ABSTRACT: Melanoma is the most lethal cutaneous malignancy worldwide. The last 15 years have ushered in several regulatory approvals that have dramatically altered the landscape of treatment options for patients with melanoma. Many patients with melanoma harbor activating mutations in the BRAF proto-oncogene, a key component of the mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Therapies targeting BRAF have led to remarkable improvements in both response rates and survival in patients with metastatic disease. In parallel with these developments in MAPK-targeted therapy has been the clinical development of immune checkpoint inhibitors, which also have improved response rates and survival in patients with metastatic disease including randomized trials compared with MAPK-targeted therapy in patients with advanced, BRAF-mutant melanoma. Immune checkpoint inhibitors have become the preferred first-line standard-of-care treatment for patients with newly diagnosed metastatic disease in patients irrespective of BRAF mutational status. Given these developments, it is now less clear how to optimize the use of MAPK-targeted therapy regarding treatment setting and in sequence with immune checkpoint inhibitor.

Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer T-cells (iNKT).

Gastric cancer is the 5th most common malignancy worldwide with only 36% of patients with metastatic disease surviving beyond 5 years. Despite therapeutic improvements with the advent of immune checkpoint inhibitors, most patients with gastric cancer develop disease progression related to tumor resistance. Novel immunotherapeutic approaches, including invariant natural killer (iNKT) cells, are in clinical development and represent potential therapeutic options to overcome resistance. AgenT-797 is an allogeneic human unmodified iNKT derived from healthy donors. Activation of iNKT cells by tumor lipid antigens can trigger direct cytotoxicity and promote indirect anti-tumor immune responses such as recruitment and activation of T cells, NK cells, and dendritic cells through secretion of cytokines and IFNγ. We describe immune modulation leading to durable tumor response in a patient with microsatellite instability-high (MSI-H) advanced gastric adenocarcinoma treated with agent-797 after progression on standard chemotherapy and anti-PD-1 therapy.

The evolving posology and administration of immune checkpoint inhibitors: subcutaneous formulations.

Immune checkpoint inhibitors (ICIs) have transformed cancer care. Recently, atezolizumab gained its first global approval in a subcutaneous (SC) formulation by the UK medicines regulator, being notable as the first time an FDA- and/or European Medicines Agency (EMA)-approved ICI has been licensed via this administration route. Here, we discuss this approval, other SC ICIs in development, and the benefits and challenges of this administration route, including potential implications for patient care.

Harnessing artificial intelligence for prostate cancer management.

Prostate cancer (PCa) is a common malignancy in males. The pathology review of PCa is crucial for clinical decision-making, but traditional pathology review is labor intensive and subjective to some extent. Digital pathology and whole-slide imaging enable the application of artificial intelligence (AI) in pathology. This review highlights the success of AI in detecting and grading PCa, predicting patient outcomes, and identifying molecular subtypes. We propose that AI-based methods could collaborate with pathologists to reduce workload and assist clinicians in formulating treatment recommendations. We also introduce the general process and challenges in developing AI pathology models for PCa. Importantly, we summarize publicly available datasets and open-source codes to facilitate the utilization of existing data and the comparison of the performance of different models to improve future studies.

Genomic and Molecular Characteristics of Ovarian Carcinosarcoma.

Ovarian carcinosarcoma (OCS) is a rare malignancy with a poor prognosis. It is a biphasic tumor with malignant epithelial and mesenchymal components. A few mutations commonly seen in cancer have been identified in OCS, including TP53, PIK3CA, c-myc, ZNF217, ARID1A, and CTNNB1. Some OCS tumors have shown vascular endothelial growth factor positivity and limited HER2 expression. There is evidence of homologous recombination deficiency in OCS. This malignancy can be categorized as copy number high but has not been shown to have a high tumor mutational burden. There are mixed findings regarding the presence of biomarkers targeted by immune checkpoint inhibitors in OCS. For treatments other than systemic chemotherapy, the data available are largely based on in vitro and in vivo studies. In addition, there are case reports citing the use of poly-ADP ribose polymerase inhibitors, vascular endothelial growth factor inhibitors, and immunotherapy with varying degrees of success. This review paper will discuss the molecular and genomic characteristics of OCS, which can guide future treatment strategies.

Bursting the bubble: hereditary spherocytosis masking poor glycemic control.

Hemoglobin A1c (HbA1c) is a very common measure utilized to diagnose diabetes and to monitor the level of glycemic control during the course of management. Despite the high utility of HbA1c, it has some limitations. Physiological conditions that affect the lifespan of red blood cells (RBCs) can falsely elevate or lower HbA1c results. In this case report, we present a case of a patient who was found to have hereditary spherocytosis (HS) after developing nephrotic range proteinuria. The patient had diabetes that was previously thought to be well controlled, but his HS was masking his poor glycemic control. This case highlights the importance of understanding the limitations of the HbA1c in managing patients with diabetes.

Desmoplastic melanoma: an updated clinical review and the emerging role of genetic markers and immunotherapies.

Desmoplastic melanoma (DM) is a rare and histopathologically as well as prognostically distinct subset of melanoma that arises in chronically sun-damaged skin. DM is typically and relatively indolent in nature with most cases not progressing to metastatic disease. DM has been managed with both radiation and surgical approaches. Medical options for the treatment of metastatic DM have traditionally been limited. Recent advances in immunotherapies have shown promising responses in DM ushering in a new class of treatment options. Additionally, with the advent of whole exome sequencing, the genetic make-up of DM has been further characterized creating new possibilities for future targeted therapies.

A Rare Case of Clear Cell Adenocarcinoma of the Cervix with No Intrauterine Diethylstilbestrol Exposure.

Cervical cancer is the fourth most common cancer in females. Clear cell adenocarcinoma of the cervix is an uncommon histological variant and is usually seen with intrauterine exposure to diethylstilbestrol. A 28-year-old female with no intrauterine exposure to diethylstilbestrol presented with postcoital bleeding. A pelvic exam revealed a cervical mass. Imaging confirmed the cervical mass and positron emission tomography scan showed an increased uptake in the cervical mass as well as the para-aortic and pelvic lymph nodes. Biopsy showed a clear cell carcinoma of the cervix. She was treated with cisplatin and paclitaxel for eight cycles and concurrent radiation therapy. She had a complete response to therapy and has been in complete remission nine months from the end of therapy. There are no clear guidelines for the treatment of clear cell carcinoma with current therapy based on the treatment of squamous and non-clear cell adenocarcinoma. Cisplatin and paclitaxel could be an option, given the successful treatment of the patient in our case.

Case of Anthracycline-induced Cardiogenic Shock: A Call to Optimize Modifiable Cardiac Risk Factors Prior to Chemotherapy.

Anthracyclines, including doxorubicin, are an important class of chemotherapeutic agents. Their efficacy, however, is limited by cardiotoxicity. Risk factors for anthracycline-associated cardiotoxicity include dose, treatment-specific risk factors including adjunctive radiotherapy, patient-specific modifiable cardiac risk factors including hypertension, hyperlipidemia, diabetes mellitus, tobacco use and obesity, and patient-specific non-modifiable risk factors such as age. The reduction of treatment-specific factors is not always possible, but treatment and reduction of modifiable risk factors should always be an important aspect of the management plan and may reduce the risk of anthracycline-induced cardiotoxicity. We present the case of a 65-year-old male with multiple modifiable cardiovascular risk factors who developed cardiogenic shock shortly after the administration of combination therapy with anthracyclines for the treatment of Hodgkin's lymphoma.

Hyperprogression in PDL1 Expressive, Recurrent Gastroesophageal-junction Adenocarcinoma After Pembrolizumab.

Hyperprogression is a pattern of accelerated tumor growth noted uncommonly after the use of immune checkpoint inhibitors in some patients. We present a 56-year-old female with gastroesophageal junction (GEJ) adenocarcinoma who was initially treated with neoadjuvant radiation and chemotherapy with carboplatin and paclitaxel, followed by esophagogastrectomy and postoperative FOLFOX chemotherapy. After a stable two-year course, she was noted to have recurrence at the GEJ which was biopsy confirmed. She was started on pembrolizumab, after which she developed several new metastases noted on the PET/CT. Lesions were noted in iliac bones, spine, retroperitoneal lymph nodes, hilar nodes, mediastinum, and lungs. Postdiscontinuation of the pembrolizumab, she received six cycles of paclitaxel with ramucirumab and showed remarkable improvement on the next imaging scan with resolution of osseous lesions, lung nodules and significant improvement in hilar, mediastinal, and retroperitoneal lymph nodes. We hope that this case report sheds further light on this uncommon complication of immune checkpoint inhibitors.