Randomized Phase II Trial of Pazopanib Versus Placebo in Patients With Advanced Extrapancreatic Neuroendocrine Tumors (Alliance A021202).

Purpose: Patients with advanced, well-differentiated extrapancreatic neuroendocrine tumors (epNETs) have limited systemic treatment options. Pazopanib, an oral multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, PDGFR-alpha and-beta, and c-Kit, was tested for efficacy in epNET.

Patients And Methods: We conducted a multicenter, randomized, double-blind, phase II study of pazopanib (800 mg once daily) versus placebo in low- to intermediate-grade epNET with radiologic progressive disease (PD) within 12 months of study entry.

Novel treatment-specific causal biomarkers for colorectal cancer by omics integration.

While monoclonal antibody-based targeted therapies have substantially improved progression-free survival in cancer patients, the variability in individual responses poses a significant challenge in patient care. Therefore, identifying cancer subtypes and their associated biomarkers is required for assigning effective treatment. In this study, we integrated genotype and pre-treatment tissue RNA-seq data and identified biomarkers causally associated with the overall survival (OS) of colorectal cancer (CRC) patients treated with either cetuximab or bevacizumab.

A pilot study investigating the effect of pembrolizumab on the tumoral immunoprofile of newly diagnosed mullerian cancers.

Objective: This pilot window of opportunity study was conducted to assess feasibility, toxicity, and changes in immune parameters in response to one dose of the PD-1 inhibitor, pembrolizumab, in patients newly diagnosed with mullerian epithelial cancers.

Methods: Eligible patients received pembrolizumab 200 mg IV once ≥ 7 days prior to further standard therapy, including adjuvant chemotherapy. Tissue and blood were collected before and ≥ 7 days after pembrolizumab administration.

A phase II, multicenter, single-arm study of pemigatinib in patients with metastatic or unresectable colorectal cancer harboring FGFR alterations.

Background: FGFR alterations are known to be driver alterations in several tumor types. We aimed to assess the efficacy of pemigatinib, an oral FGFR1-3 inhibitor, in patients with metastatic or unresectable colorectal cancer whose tumors harbored FGF/FGFR alterations.

Patients And Methods: The ACCRU-GI-1701 is a single-arm phase II trial which enrolled patients with previously treated FGF/FGFR-altered metastatic colorectal cancer to receive oral pemigatinib daily in 21-day cycles.

B-Lightning: using bait genes for marker gene hunting in single-cell data with complex heterogeneity.

In single-cell studies, cells can be characterized with multiple sources of heterogeneity (SOH) such as cell type, developmental stage, cell cycle phase, activation state, and so on. In some studies, many nuisance SOH are of no interest, but may confound the identification of the SOH of interest, and thus affect the accurate annotate the corresponding cell subpopulations. In this paper, we develop B-Lightning, a novel and robust method designed to identify marker genes and cell subpopulations corresponding to an SOH (e.

Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial).

Purpose: Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody-drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev; ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC).

Gene signatures derived from transcriptomic-causal networks stratify colorectal cancer patients for effective targeted therapy.

Background: Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions.

Methods: We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes.

Circulating immune biomarkers correlating with response in patients with metastatic renal cell carcinoma on immunotherapy.

Since multiple front-line immune checkpoint inhibitor-based (ICI-based) combinations are approved for metastatic renal cell carcinoma, biomarkers predicting for ICI responses are needed past clinical prognostication scores and transcriptome gene expression profiling. Circulating markers represent opportunities to assess baseline and dynamic changes in immune cell frequency and cytokine levels while on treatment. We conducted an exploratory prospective correlative study of 33 patients with metastatic clear cell renal cell carcinoma undergoing treatment with ICIs and correlated changes in circulating immune cell subsets and cytokines with clinical responses to treatment.

Ultra-sensitive, tumor-informed ctDNA profiling in pembrolizumab-treated esophagogastric cancer patients predicts clinical responses.

To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables early prediction of treatment response and early detection of disease progression, we applied NeXT Personal, an ultra-sensitive bespoke tumor-informed liquid biopsy platform, to profile tumor samples from the KeyLargo study, a phase II trial in which metastatic esophagogastric cancer (mEGC) patients received capecitabine, oxaliplatin, and pembrolizumab. All 25 patients evaluated were ctDNA-positive at baseline. Minimal residual disease (MRD) events varied from 406,067 down to 1.

Complement factor H targeting antibody GT103 in refractory non-small cell lung cancer: a phase 1b dose escalation trial.

GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a "3 + 3" schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103.

Characterization of the Biological Variability of the Angiome Biomarkers over Time in Healthy Participants.

Background: Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in patients with cancer, little is known regarding the natural variation of biomarkers in healthy populations. Here we conducted a clinical study to evaluate the natural variability of biomarkers over time in healthy participants.

Incorporating Molecular Data Into Treatment Decision Making in Gastroesophageal and Pancreaticobiliary Cancers: Timing and Strategies.

Gastroesophageal (GE) and pancreatobiliary (PB) cancers represent a significant clinical challenge. In this context, it is critical to understand the key molecular targets within these malignancies including how they are assayed for as well as the clinical actionability of these targets. Integrating biomarkers into the standard of care presents a critical avenue for refining treatment paradigms.

Common variation in a long non-coding RNA gene modulates variation of circulating TGF-β2 levels in metastatic colorectal cancer patients (Alliance).

Background: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms.

CALGB 80802 (Alliance): Impact of Sorafenib with and without Doxorubicin on Hepatitis C Infection in Patients with Advanced Hepatocellular Carcinoma.

Unlabelled: Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf-mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS).

Glycosaminoglycan modifications of betaglycan regulate ectodomain shedding to fine-tune TGF-β signaling responses in ovarian cancer.

In pathologies including cancer, aberrant Transforming Growth Factor-β (TGF-β) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-β responses.

Prognostic and predictive analyses of circulating plasma biomarkers in men with metastatic castration resistant prostate cancer treated with docetaxel/prednisone with or without bevacizumab.

Background: CALGB 90401 (Alliance) was a phase III trial of 1050 patients with metastatic castration-resistant prostate cancer (mCRPC) comparing docetaxel, prednisone, bevacizumab (DP+B) versus DP alone. While this trial did not show an improvement in overall survival (OS), there were improved intermediate outcomes suggesting that subsets of men may derive benefit from this combination. The purpose of this analysis was to identify prognostic and predictive biomarkers associated with OS and progression-free survival (PFS) benefit from DP+B.

Heparan sulfate modifications of betaglycan promote TIMP3-dependent ectodomain shedding to fine-tune TGF-β signaling.

In pathologies such as cancer, aberrant Transforming Growth Factor-β (TGF-β) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pivotal pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-β responses.

Endoglin inhibitor TRC105 with or without bevacizumab for bevacizumab-refractory glioblastoma (ENDOT): a multicenter phase II trial.

Background: Glioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM.

Association of Inflammatory Biomarkers With Survival Among Patients With Stage III Colon Cancer.

Importance: The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited.

Objective: To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer.

Design, Setting, And Participants: This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020.

High Yield of Pleural Cell-Free DNA for Diagnosis of Oncogenic Mutations in Lung Adenocarcinoma.

Background: Pleural cytology is currently used to assess targetable mutations in patients with advanced lung adenocarcinoma. However, it is fraught with low diagnostic yield.

Research Question: Can pleural cell-free DNA (cfDNA) be used to assess targetable mutations in lung adenocarcinoma patients with malignant pleural effusions (MPE)?

Study Design And Methods: Patients with lung adenocarcinoma MPE were recruited prospectively between January 2017 and September 2021.

Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure.

Background: We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF).

Methods: We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF).