T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer.

Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor activity, but challenges related to drug delivery, immunogenicity, and treatment-associated adverse effects limited their success. The ongoing development of novel BiTE constructs continues to address these barriers and to yield promising results in terms of efficacy and safety. This review will highlight some of most recent developments of BiTE therapies for patients with advanced prostate cancer and the evolving data surrounding BiTE constructs undergoing clinical evaluation.

Diagnostic Challenges and Treatment Approach to Seronegative Autoimmune Encephalitis.

Seronegative autoimmune encephalitis (AE) is a rare, immune-mediated inflammatory syndrome that presents with a wide spectrum of neuropsychiatric symptoms, such as cognitive impairment, seizures, psychosis, focal neurological defects, and altered consciousness. This disease process presents with no identifiable autoimmune antibodies, which leads to uncertain diagnosis, delayed treatment, and prolonged hospital admissions. Early diagnosis and prompt treatment of AE should not be delayed, as early recognition and treatment leads to improved outcomes and disease reversibility for these patients. In this study, we present a case report of a 77-year-old male who presented with acutely altered mental status. This patient underwent an extensive workup and demonstrated no signs of clinical improvement throughout a prolonged hospital admission. The diagnostic challenges and treatment obstacles encountered during our care of this patient are described in this case report, along with recommendations for early diagnosis and prompt treatment for patients with suspected seronegative AE.

Predictive and Prognostic Biomarkers and Tumor Antigens for Targeted Therapy in Urothelial Carcinoma.

Urothelial carcinoma (UC) is the fourth most prevalent cancer amongst males worldwide. While patients with non-muscle-invasive disease have a favorable prognosis, 25% of UC patients present with locally advanced disease which is associated with a 10-15% 5-year survival rate and poor overall prognosis. Muscle-invasive bladder cancer (MIBC) is associated with about 50% 5 year survival when treated by radical cystectomy or trimodality therapy; stage IV disease is associated with 10-15% 5 year survival. Current therapeutic modalities for MIBC include neoadjuvant chemotherapy, surgery and/or chemoradiation, although patients with relapsed or refractory disease have a poor prognosis. However, the rapid success of immuno-oncology in various hematologic and solid malignancies offers new targets with tremendous therapeutic potential in UC. Historically, there were no predictive biomarkers to guide the clinical management and treatment of UC, and biomarker development was an unmet need. However, recent and ongoing clinical trials have identified several promising tumor biomarkers that have the potential to serve as predictive or prognostic tools in UC. This review provides a comprehensive summary of emerging biomarkers and molecular tumor targets including programmed death ligand 1 (PD-L1), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor (FGFR), DNA damage response and repair (DDR) mutations, poly (ADP-ribose) polymerase (PARP) expression and circulating tumor DNA (ctDNA), as well as their clinical utility in UC. We also evaluate recent advancements in precision oncology in UC, while illustrating limiting factors and challenges related to the clinical application of these biomarkers in clinical practice.

Descriptive analysis of Acute Ischemic stroke in COVID-19 patients through the course of the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) has been associated with Acute Ischemic Stroke (AIS). Here, we characterize our institutional experience with management of COVID-19 and AIS. Baseline demographics, clinical, imaging, and outcomes data were determined in patients with COVID-19 and AIS presenting within March 2020 to October 2020, and November 2020 to August 2021, based on institutional COVID-19 hospitalization volume. Of 2512 COVID-19 patients, 35 (1.39%, mean age 63.3 years, 54% women) had AIS. AIS recognition was frequently delayed after COVID-19 symptoms (median 19.5 days). Four patients (11%) were on therapeutic anticoagulation at AIS recognition. AIS mechanism was undetermined or due to multiple etiologies in most cases (n = 20, 57%). Three patients underwent IV TPA, and three underwent mechanical thrombectomy, of which two suffered re-occlusion. Three patients had incomplete mRNA vaccination course. Fourteen (40%) died, with 26 (74%) having poor outcomes. Critical COVID-19 severity was associated with worsened mortality (p = 0.02). More patients (12/16; 75%) had either worsened or similar 3-month functional outcomes, than those with improvement, indicating the devastating impact of co-existing AIS and COVID-19. Comparative analysis showed that patients in the later cohort had earlier AIS presentation, fewer stroke risk factors, more comprehensive workup, more defined stroke mechanisms, less instance of critical COVID-19 severity, more utilization of IV TPA, and a trend towards worse outcomes for the sub-group of mild-to-moderate COVID-19 severity. AIS incidence, NIHSS, and overall outcomes were similar. Further studies should investigate outcomes beyond 3 months and their predictive factors, impact of completed vaccination course, and access to neurologic care.

Increasing Diversity in Cardiology: A Fellowship Director's Perspective.

Background Underrepresented-minorities (URM) remain few in number amongst practicing cardiologists and across cardiology fellowship training programs in the U.S. Increased diversity is needed across the entire field and is particularly necessary within graduate medical education cardiology fellowship training programs. Objectives This cross-sectional study was performed to identify which strategies were supported and implemented by cardiology fellowship program directors (PDs) to increase URM representation, to determine which entities hold the responsibility to increase diversity according to program directors, and to quantify URM representation in cardiology fellowship programs. Methods A 15-item survey was submitted to all American College of Graduate Medical Education (ACGME) accredited cardiology fellowship programs via electronic mail. Results Of 250 cardiology fellowship programs, 71 responses were received (28.4%). The number of URM faculty varied from 0-1 to more than six, and URM faculty held leadership roles in most programs (62.0%). A total of 16 respondents (22.5%) were URM program directors. Most respondents agreed that diversity was important to their training program (85.9%). The majority endorsed direct recruitment of URM applicants (60.6%), opportunities for applicants to connect with (54.9%) or be recruited by URM fellows (54.9%), holistic application review (67.6%), promoting mentorship by URM faculty (69.0%), URM faculty involvement in applicant interviewing (54.9%), and increased recruitment of URM faculty members (73.2%). Program directors allocated major responsibility to increase diversity to fellowship programs (71.8%), residency programs (63.3%), and medical schools (53.5%). Conclusions This study found that most cardiology programs have URM faculty in leadership roles, and nearly a quarter of the surveyed program directors were URMs. Cardiology program directors endorsed and employed numerous strategies to increase diversity and URM representation in fellowship programs. Additionally, program directors held fellowship training programs most responsible for increasing URM representation in the field of cardiology.