Citations

Objective: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). Background: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. Methods: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. Results: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil–lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). Conclusions: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

PURPOSEPatients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.METHODSA phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.RESULTSA total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.CONCLUSIONLenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial‐to‐mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer‐compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

Abstract Summary We present MetaMarker, a pipeline for discovering metagenomic biomarkers from whole-metagenome sequencing samples. Different from existing methods, MetaMarker is based on a de novo approach that does not require mapping raw reads to a reference database. We applied MetaMarker on whole-metagenome sequencing of colorectal cancer (CRC) stool samples from France to discover CRC specific metagenomic biomarkers. We showed robustness of the discovered biomarkers by validating in independent samples from Hong Kong, Austria, Germany and Denmark. We further demonstrated these biomarkers could be used to build a machine learning classifier for CRC prediction. Availability and implementation MetaMarker is freely available at https://bitbucket.org/mkoohim/metamarker under GPLv3 license. Supplementary information Supplementary data are available at Bioinformatics online.

Abstract Bacteriolytic strategies offer unique advantages to combat a broad range of cancers often refractive to conventional chemotherapies and/or radiotherapies. C. novyi-NT is an attenuated strain of Clostridium novyi, a spore-forming, gram-positive, obligate anaerobe that lacks a lethal alpha- toxin, expressed by the parental strain. When administered intravenously or intratumorally with percutaneous injection, C. novyi-NT colonizes and replicates within the hypoxic region of the tumors, eliciting robust, tumor-confined cell lysis. In this first-in-man phase 1 study, patients with injectable treatment-refractory solid tumors received a single intratumoral injection of C. novyi-NT spores across 6 dose cohorts (spore concentrations of 104, 3x104, 105, 3x105, 106, 3x106) using a 3+3 trial design. The primary endpoints were to assess the safety profile, the dose limiting toxicity, and the maximum tolerated dose of C. novyi-NT. Key secondary endpoints included assessments of the preliminary antitumor activity of the injected tumor, an overall response evaluated by RECIST v. 1.1, and the host immune and inflammatory response to C. novyi-NT. Twenty-four patients were enrolled between November, 2013 and April, 2017. A single intratumoral injection of C. novyi-NT led to germination and resultant tumor lysis of injected tumor masses in 46% of patients across all dosing cohorts. The cohort 5 dose of 106 spores was defined as the maximum tolerated dose. Dose-limiting toxicities were grade 4 sepsis and grade 4 gas gangrene (n=1), all in patients with germination. In the 22 evaluable patients, 21 (95%) had stable disease (SD) as the best response for the injected lesion (tumor shrinkage of &gt; 10% was observed in 21% of patients) and 19 (86%) had overall SD as the best response per RECIST 1.1. C. novyi-NT injection resulted in transient serum cytokine responses consistent with inflammasome activity, activation of innate immunity, tissue remodeling, and angiogenesis. Tumor antigen specific ELISPOT assays pre- and post- treatment documented enhanced secretion of IFNγ and TNFα by circulating T-cells, indicating improved systemic tumor specific T-cell responses. Multiparametric in situ immunostaining of core biopsies suggested improved immune cell infiltration in metastatic lesions. These early signs of improved antitumor activity in patients with advanced solid tumors have encouraged a new trial of C. novyi-NT in combination with immune checkpoint inhibitors. Citation Format: Filip Janku, Mrinal Gounder, Abdul Mohammad Pezeshki, Ravi Murthy, Andrea Wang-Gillam, Dale Shepard, David S. Hong, Sarina A. Piha-Paul, Anjali Raina, Alexey A. Leontovich, Gary DeCrescenzo, Brent L. Kreider, David Tung, Mary Varterasian, Halle H. Zhang, Khashayarsha Khazaie. First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A011.

Abstract While the accumulation and aggregation of amyloid-β and tau are central events in the pathogenesis of Alzheimer’s disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer’s disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood–brain barrier. Because the blood–brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer’s disease pathogenesis. However, the pathological relationship between blood–brain barrier properties and Alzheimer’s disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer’s disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer’s disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer’s disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer’s disease-related proteins, in particular amyloid-β40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer’s disease is associated with insoluble amyloid-β40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-β40, amyloid-β42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer’s disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer’s disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer’s disease pathogenesis in both synergistic and additive manners to typical amyloid-β and tau pathologies.

Abstract Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.