Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti-SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20-directed therapies, and anti-CD38/B-cell maturation antigen-directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not. Significance: Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577. This article is highlighted in the In This Issue feature, p. 549.

A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer.

Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hitherto remains an incurable entity and the second leading cause of cancer-related mortality in men in the US. Recent advances have uncovered multiple complex and intermingled mechanisms underlying this transformation. While most of these mechanisms revolve around androgen receptor (AR) signaling, novel pathways which act independently of the androgen axis are also being discovered. The aim of this article is to review the pathophysiological mechanisms that help bypass the apoptotic effects of ADT to create castrate resistance. The article discusses castrate resistance mechanisms under two categories: 1. Direct AR dependent pathways such as amplification or gain of function mutations in AR, development of functional splice variants, posttranslational regulation, and pro-oncogenic modulation in the expression of coactivators vs corepressors of AR. 2. Ancillary pathways involving RAS/MAP kinase, TGF-beta/SMAD pathway, FGF signaling, JAK/STAT pathway, Wnt-Beta catenin and hedgehog signaling as well as the role of cell adhesion molecules and G-protein coupled receptors. miRNAs are also briefly discussed. Understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer is paramount to the development of targeted agents to overcome these mechanisms. A number of targeted agents are currently in development. As we strive for more personalized treatment across oncology care, treatment regimens will need to be tailored based on the type of CRPC and the underlying mechanism of castration resistance.

Mucormycosis Leading to Cerebral Edema and Cerebellar Tonsillar Herniation after Allogeneic Bone Marrow Transplant: A Case Report.

INTRODUCTION: Mucormycosis following hematopoietic stem cell transplant (HSCT) carries a very high mortality rate. Pulmonary mucormycosis often leads to systemic dissemination and eventual death. It is imperative for transplant providers to have a high level of suspicion for mucormycosis and initiate early treatment. Here, we present a 64-year-old woman who died of disseminated mucormycosis 13 days following her allogeneic HSCT. CASE PRESENTATION: A 64-year-old female with a history of acute myeloid leukemia (AML) presented for allogeneic HSCT and passed away from intracerebral hemorrhage secondary to mucormycosis infection 13 days following her transplant. On autopsy, it was found she had angioinvasive mucormycosis in her frontal lobe leading to cerebral edema which eventually led to tonsillar herniation and brainstem infarction. Her lungs were the likely source of infectious dissemination. DISCUSSION: This case represents an unusual course of events following HSCT in that no other published case shows tonsillar herniation resulting from mucormycosis-related intracerebral swelling. We also report this case because it is believed mucormycosis in HSCT patients is underreported. Additionally, our case highlights the importance of increased vigilance for mucormycosis in patients with prolonged neutropenia prior to HSCT and the potential link of voriconazole prophylaxis and increased risk for mucormycosis.