Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.

Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.

Design, Setting, And Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021.

A Bayesian platform trial design with hybrid control based on multisource exchangeability modelling.

Enrolling patients to the standard of care (SOC) arm in randomized clinical trials, especially for rare diseases, can be very challenging due to the lack of resources, restricted patient population availability, and ethical considerations. As the therapeutic effect for the SOC is often well documented in historical trials, we propose a Bayesian platform trial design with hybrid control based on the multisource exchangeability modelling (MEM) framework to harness historical control data. The MEM approach provides a computationally efficient method to formally evaluate the exchangeability of study outcomes between different data sources and allows us to make better informed data borrowing decisions based on the exchangeability between historical and concurrent data.

Implicit and Explicit Dehumanization of Older Family Members: Novel Determinants of Elder Abuse Proclivity.

Elder abuse affects one in six older persons globally. Three limitations impede progress in prevention: most research is victim- rather than perpetrator-based; the reliance on explicit, self-reported factors; and failure to account for psychological factors, such as dehumanization, that motivate abuse. The current study addressed these gaps by examining whether implicit and explicit dehumanization of t could explain elder abuse proclivity.

AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers.

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2- metastatic breast cancer (MBC) patients. However, 30-40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies.

Bayesian local exchangeability design for phase II basket trials.

We propose an information borrowing strategy for the design and monitoring of phase II basket trials based on the local multisource exchangeability assumption between baskets (disease types). In our proposed local-MEM framework, information borrowing is only allowed to occur locally, that is, among baskets with similar response rate and the amount of information borrowing is determined by the level of similarity in response rate, whereas baskets not considered similar are not allowed to share information. We construct a two-stage design for phase II basket trials using the proposed strategy.

Non-crisis related pain occurs in adult patients with sickle cell disease despite chronic red blood cell exchange transfusion therapy.

Background: Chronic red blood cell transfusions reduce acute care utilization for sickle cell disease (SCD) pain. However, little is known about whether chronic transfusions treat or prevent the development of non-crisis pain. We investigated patient-report of pain in adults with SCD receiving chronic exchange transfusions (CET) compared to adults not on CET with similar disease characteristics.

Unified exact design with early stopping rules for single arm clinical trials with multiple endpoints.

Adaptive designs are gaining popularity in early phase clinical trials because they enable investigators to change the course of a study in response to accumulating data. We propose a novel design to simultaneously monitor several endpoints. These include efficacy, futility, toxicity and other outcomes in early phase, single-arm studies.

A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1.

Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges.

Patients And Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330).

Impact of structural ageism on greater violence against older persons: a cross-national study of 56 countries.

Objective: To determine the association between country-level structural ageism and prevalence of violence against older persons.

Design: Country-level ecological study.

Setting: Structural ageism data were drawn from the nationally representative World Values Survey 2010-2014 (WVS), global databases from the WHO, United Nations and the World Bank.

Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm.

Accounting for Multiple Comparisons in Statistical Analysis of the Extensive Bioassay Data on Glyphosate.

Glyphosate is a widely used herbicide worldwide. In 2015, the International Agency for Research on Cancer (IARC) reviewed glyphosate cancer bioassays and human studies and declared that the evidence for carcinogenicity of glyphosate is sufficient in experimental animals. We analyzed 10 glyphosate rodent bioassays, including those in which IARC found evidence of carcinogenicity, using a multiresponse permutation procedure that adjusts for the large number of tumors eligible for statistical testing and provides valid false-positive probabilities.

A two-stage phase II clinical trial design with nested criteria for early stopping and efficacy.

We propose a two-stage design for a single arm clinical trial with an early stopping rule for futility. This design employs different endpoints to assess early stopping and efficacy. The early stopping rule is based on a criteria determined more quickly than that for efficacy.

Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma.

Background: The cancer-associated fibroblast (CAF) population is implicated in immune dysregulation. Here, we test the hypothesis that CAF profiles in pretreatment tumor specimens are associated with response to immune checkpoint blockade of programmed cell death 1 (PD-1).

Methods: Pretreatment whole tissue sections from 117 melanoma patients treated with anti-PD-1 therapy were assessed by multiplex immunofluorescence to detect CAFs defined by Thy1, smooth muscle actin (SMA), and fibroblast activation protein (FAP).

Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors.

Background: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells.

Methods: Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment.

A parametric meta-analysis.

In a meta-analysis, we assemble a sample of independent, nonidentically distributed p-values. The Fisher's combination procedure provides a chi-squared test of whether the p-values were sampled from the null uniform distribution. After rejecting the null uniform hypothesis, we are faced with the problem of how to combine the assembled p-values.

The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma.

Purpose: exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer-associated mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown. We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.

Clinical Trial Design Using A Stopped Negative Binomial Distribution.

We introduce a discrete distribution suggested by curtailed sampling rules common in early-stage clinical trials. We derive the distribution of the smallest number of independent and identically distributed Bernoulli trials needed to observe either successes or failures. This report provides a closed-form expression for the mass function, moment generating function, and provides connections to other, standard distributions.

Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma.

Purpose: Because durable response to programmed cell death 1 (PD-1) inhibition is limited to a subset of melanoma patients, new predictive biomarkers could have clinical utility. We hypothesize that pretreatment tumor-infiltrating lymphocyte (TIL) profiles could be associated with response.

Experimental Design: Pretreatment whole tissue sections from 94 melanoma patients treated with anti-PD-1 therapy were profiled by multiplex immunofluorescence to perform TIL quantification (CD4, CD8, CD20) and assess TIL activation (CD3, GZMB, Ki67).

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer.

Introduction: With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients.

Methods: Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features.

Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.

Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.

DNA polymerase beta participates in DNA End-joining.

DNA double strand breaks (DSBs) are one of the most deleterious lesions and if left unrepaired, they lead to cell death, genomic instability and carcinogenesis. Cells combat DSBs by two pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ), wherein the two DNA ends are re-joined. Recently a back-up NHEJ pathway has been reported and is referred to as alternative NHEJ (aNHEJ), which joins ends but results in deletions and insertions.

A parametric model to estimate the proportion from true null using a distribution for p-values.

Microarray studies generate a large number of p-values from many gene expression comparisons. The estimate of the proportion of the p-values sampled from the null hypothesis draws broad interest. The two-component mixture model is often used to estimate this proportion.

Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective, Single-arm Trial.

Background: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM.

Patients And Methods: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season.