Search

Fionnuala Crowley,1 Michelle Sterpi,1 Conor Buckley,1 Lauren Margetich,1 Shivani Handa,1 Zach Dovey2 1Department of Internal Medicine, Icahn School of Medicine, Mount Sinai Morningside and West, New York, NY, USA; 2Department of Urology, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USACorrespondence: Shivani HandaDepartment of Internal Medicine, Mount Sinai Morningside and West, 1000 Tenth Avenue, New York, NY, 10019, USATel +1-917-520-3693Email Shivani.Handa@mountsinai.orgAbstract: 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.Keywords: castration resistance, prostate cancer, androgen-deprivation therapy, androgen insensitivity, androgen receptor

Claudins, a family of tetraspan transmembrane proteins, are critical to the integrity of tight junctions in epithelia and endothelia, influencing cellular processes such as development, differentiation, and apoptosis. Abnormal claudin expression is associated with various malignancies, particularly affecting tissue architecture and potentially facilitating tumor invasion and metastasis. In this comprehensive review, we explore the multifaceted functions of claudins: their expression, specific roles in cancer with a focus on hepato-pancreato-biliary malignancies and highlight their potential as therapeutic targets. We discuss current claudin-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engager and chimeric antigen receptor T-cell therapies. These approaches show promise in pre-clinical and clinical studies, particularly in hepato-pancreato-biliary cancers with large unmet needs. Despite these early signs of efficacy, challenges remain in effectively targeting these proteins due to their structural resemblance and overlapping functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jeon, Sterpi, Mo and Bteich.)

Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.

Factor XI (FXI) deficiency is an autosomal inherited, milder bleeding disorder that may predispose to a potential risk of life-threatening bleeding during childbirth or surgery. Unfortunately, data regarding obstetric and perioperative management of this condition are scarce, with limited cases reviewed in the last decade. Therefore, the present study aimed to expand this database and identify factors associated with increased bleeding risk. We performed a retrospective chart review of patients with FXI deficiency who underwent childbirth or other surgical procedures between August 2011 and April 2021 within a single academic health system and identified 198 patients who underwent 252 procedures, including 143 vaginal deliveries, 63 cesarean deliveries, and 46 other surgical procedures. Thirty-three of the 252 procedures resulted in bleeding complications. On multivariable logistic regression analysis, personal history of bleeding was the strongest predictor of perioperative or obstetric bleeding (odds ratio [OR], 5.92; P = .001). Higher FXI levels were correlated with lower odds of bleeding (OR, 0.72 with every 10 U/dL increase in FXI level; P = .05). On receiver operative characteristic analysis, FXI level of >40 U/dL predicted a lower bleeding risk with reasonable specificity (75%) but lacked sensitivity (47%). A family history of bleeding, ethnicity, genotype, preprocedural partial thromboplastin time, and platelet levels were not associated with bleeding risk. There were no cases of epidural or spinal hematoma associated with neuraxial anesthesia. FXI levels remain stable during pregnancy and repeated measurements may not be necessary., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Venous thromboembolism (VTE) is a common and impactful complication of cancer. Several clinical prediction rules have been devised to estimate the risk of a thrombotic event in this patient population, however they are associated with limitations. We aimed to develop a predictive model of cancer-associated VTE using machine learning as a means to better integrate all available data, improve prediction accuracy and allow applicability regardless of timing for systemic therapy administration. A retrospective cohort was used to fit and validate the models, consisting of adult patients who had next generation sequencing performed on their solid tumor for the years 2014 to 2019. A deep learning survival model limited to demographic, cancer-specific, laboratory and pharmacological predictors was selected based on results from training data for 23,800 individuals and was evaluated on an internal validation set including 5,951 individuals, yielding a time-dependent concordance index of 0.72 (95% CI = 0.70-0.74) for the first 6 months of observation. Adapted models also performed well overall compared to the Khorana Score (KS) in two external cohorts of individuals starting systemic therapy; in an external validation set of 1,250 patients, the C-index was 0.71 (95% CI = 0.65-0.77) for the deep learning model vs 0.66 (95% CI = 0.59-0.72) for the KS and in a smaller external cohort of 358 patients the C-index was 0.59 (95% CI = 0.50-0.69) for the deep learning model vs 0.56 (95% CI = 0.48-0.64) for the KS. The proportions of patients accurately reclassified by the deep learning model were 25% and 26% respectively. In this large cohort of patients with a broad range of solid malignancies and at different phases of systemic therapy, the use of deep learning resulted in improved accuracy for VTE incidence predictions. Additional studies are needed to further assess the validity of this model., Competing Interests: Conflict of Interest Disclosures Simon Mantha, Subrata Chatterjee, Rohan Singh and John Cadley have filed a U.S. patent application related to this work. Simon Mantha is principal owner for Daboia Consulting LLC. Andrés Muñoz Martín has the following disclosures to report: consultant or advisory role for Pfizer-BMS, Sanofi, Celgene, Leo Pharma, Incyte, Astra-Zeneca, MSD, Lilly, Servier, Bayer and Roche; research funding from Leo Pharma, Sanofi and Celgene; paid speaker for Rovi, Bayer, Menarini, Stada and Daichii Sankyo; intellectual property rights for a risk assessment model of venous thromboembolism in cancer patients (work distinct from what is reported herein). Magdalena Ruiz is a medical advisor at IQVIA (CRO company). Gerald A. Soff has received research support or consulted for Johnson and Johnson/Janssen Scientific Affairs, Sobi/Dova Pharmaceuticals, Anthos Therapeutics, Luzsana (HengruiUSA), and Sanofi. The other authors have no potential conflicts of interest to report.

Metastasis is an intricate process whereby tumor cells migrate from the primary tumor, survive in the circulation, seed distal organs, and proliferate to create metastatic foci. CD8 + T cells can detect and eliminate tumor cells. Research on CD8 + T cell-dependent antitumor immunity has classically focused on its role in the primary tumor. There is increasing evidence, however, that CD8 + T cells have unique antimetastatic functions in various steps of the metastatic cascade. Here, we review the mechanisms whereby CD8 + T cells control metastatic lesions. We discuss their role in each step of metastasis, metastatic dormancy, and metastatic clonal evolution as well as the consequent clinical repercussions., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Gastrointestinal cancers have a strong association with splanchnic vein thrombosis (SVT), yet the hospitalization data is unknown., Objective and Methods: We analyzed around 78 million discharges from the 2007-2017 Nationwide Inpatient Sample with an inclusion criterion of adult patients admitted for portal or hepatic vein thrombosis as a primary diagnosis with a gastrointestinal or hepatobiliary malignancy as a secondary diagnosis. The outcomes were in-hospital mortality, complication rates, and resource utilization. Odds ratios (OR) and means were adjusted for confounders using multivariate regression analysis models., Results: Out of the total 32,324 hospitalizations for SVT, 3,220 (10%) were associated with a GI malignancy, of which hepatocellular carcinoma (HCC) and pancreatic cancer were the most common. Portal vein thrombosis accounted for 95% of these hospitalizations. Admissions for pancreatic cancer-associated SVT have increased by 7.2 times from 2007 to 2017. Patients with SVT and concomitant GI malignancies were significantly older and had a higher comorbidity score than those with SVT without GI malignancy. Risk of inpatient mortality for SVT patients were significantly higher for patients with gastric cancer (rate: 12.1%, OR 8.6, 95% CI: 1.8-39.7) and HCC (rate: 7.6%, OR 2.77, 95% CI 1.5-4.8) as compared to non-GI malignancy-related SVT. Odds of variceal bleeding were significantly higher for patients with HCC (OR 1.67, 95% CI: 1.2-2.34) than patients without GI malignancy., Conclusions: Digestive cancer-associated SVTs constitute 10% of all SVT related hospitalizations and are significantly increasing in the past decade. We report the baseline characteristics and predictors of inpatient mortality in this study., Competing Interests: All the listed authors declare that they have no conflict of interest., (Copyright © 2021 by S. Karger AG, Basel.)

Background: The ideal management of ureteropelvic junction obstruction (UPJO) remains debatable. This prospective case-control study aimed to investigate if urinary levels of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and serum levels of cystatin C could distinguish surgical from non-surgical cases of UPJO and if they could detect earlier impairment of renal function., Methods: Biomarkers were measured in the following age-matched groups: (a) 22 infants with surgical UPJO, at initial diagnosis and 12 months postoperatively (groups A1 and A2, respectively); (b) 19 infants with non-surgical UPJO (group B); and (c) 17 controls (group C). Based on serum cystatin C levels, estimated glomerular filtration rate (eGFR) was calculated., Results: Urinary NGAL (uNGAL) was significantly higher in group A1 vs. group A2 (p = 0.02) and in group A1 vs. group C (p = 0.03), whereas there was no statistically significant difference between groups A2 and C (p = 0.77). Likewise, cystatin C levels were significantly higher in group A1 vs. group A2 and in group A1 vs. group C (p = 0.004 and p = 0.02, respectively), but no statistically significant difference between groups A2 and C (p = 0.82). uNGAL and serum cystatin C did not differ between groups B and A, nor did they differ between groups B and C. Cystatin C levels and eGFR of group A1 were significantly higher than those of group A2 and group C (p = 0.0001 and p = 0.02, respectively)., Conclusion: It seems that NGAL and cystatin C are able to distinguish patients who were treated surgically from healthy controls, and their levels appear to improve significantly following surgery.

This report describes the successful management of a case of central neurogenic hyperventilation (CNH) refractory to high dose sedation by increasing the mechanical dead space. A 46-year-old male presented with a history of multiple neurological symptoms. Following an extensive evaluation, he was diagnosed with primary diffuse CNS lymphoma and started on high dose steroids. After initial symptomatic improvement, the patient developed increasing respiratory distress and tachypnea. He was intubated and transferred to the neurointensive care unit (neuro ICU). While in the ICU the patient remained ventilator dependent with significant tachypnea and respiratory alkalosis resistant to fentanyl and propofol. This prompted an attempt to normalize the PaCO 2 via an increase of the mechanical dead space. This approach successfully increased PaCO 2 and bridged the patient until ongoing therapy for the underlying disease resolved the pervasive breathing pattern typical of CNH. Further investigation is warranted to evaluate this strategy, which upon review of the literature appears underused.

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.