Application of Machine Learning to the Prediction of Cancer-Associated Venous Thromboembolism.

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.

Obstetric and perioperative management of patients with factor XI deficiency: a retrospective observational study.

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.

Antimetastatic defense by CD8+ T cells.

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.

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.

Trends and In-Hospital Outcomes of Splanchnic Vein Thrombosis Associated with Gastrointestinal Malignancies: A Nationwide Analysis.

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.

Refractory Central Neurogenic Hyperventilation: A Novel Approach Utilizing Mechanical Dead Space.

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 PaCO2 via an increase of the mechanical dead space. This approach successfully increased PaCO2 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.

Outcome of oligoprogressing metastatic renal cell carcinoma patients treated with locoregional therapy: a multicenter retrospective analysis.

Locoregional treatment with radical intent should be considered during therapy with targeted agents in patients with metastatic renal cell carcinoma (mRCC) in order to achieve a complete response, especially in the setting of an oligo-progression in one or more metastatic sites. We retrospectively enrolled 55 patients who experienced a disease oligo-progression after at least 6 months from the beginning of first-line therapy in one or more metastatic sites radically treated with locoregional treatments. Post-first-oligo-progression overall survival (PFOPOS) and post-first-oligo-progression free survival (PFOPFS) were evaluated. The global median PFOPOS and PFOPFS were 37 months and 14 months respectively. Patients who continued the same therapy after a locoregional treatment on a site of progression had a significantly longer mPFOPOS compared to patients who changed therapy (39 vs 11 months, p=0.014). An advantage in mPFOPOS was also observed in patients with a Memorial Sloan-Kettering Cancer Center (MSKCC) good risk score compared to patients of the intermediate risk group (39 vs 29 months, p=0.036); patients with bone metastases had a longer mPFOPOS compared to those with visceral metastases (not reached vs 31 months, p=0.045). The only independent predictor of poor prognosis, in terms of PFOPOS at multivariate analysis (p=0.007), proved out to be change of treatment after first progression. In this paper we aim to illustrate that continuing the same systemic therapy, after a radical locoregional treatment on a site of progression, seems to be associated with a prolongation of mPFOPOS.