Drinking pattern and time lag of alcohol consumption with colorectal cancer risk in US men and women.

Background: Association between light to moderate alcohol consumption and colorectal cancer (CRC) incidence remains understudied, especially regarding drinking pattern, beverage type and temporal aspects.

Methods: Hazard ratios (HRs) and 95% confidence intervals (CIs) for time to CRC diagnosis were estimated among 137,710 participants. Estimates based on remote (eg, >10 years before follow-up) and recent (eg, the preceding 10 years before follow-up) alcohol intake, using different cutoffs (eg, 8, 10, 12 years, etc) and mutual adjustment, enabled separating independent effects and investigating time lag of alcohol-CRC association.

Cost-Effectiveness of a Biomarker-Based Screening Strategy for Hepatocellular Carcinoma in Patients with Cirrhosis.

Introduction: Given suboptimal performance of ultrasound-based surveillance for early hepatocellular carcinoma (HCC) detection in patients with cirrhosis, there is interest in alternative surveillance strategies, including blood-based biomarkers. We aimed to evaluate the cost-effectiveness of biomarker-based surveillance in patients with cirrhosis.

Methods: We constructed a decision-analytic model to compare ultrasound/alpha-fetoprotein (AFP) and biomarker-based surveillance strategies in 1,000,000 simulated patients with compensated cirrhosis.

ctDNA/MRD Testing for Colon Cancer: A Work in Progress or Ready for Prime-Time Standard of Care?

In patients with surgically resectable colon cancer (CC), clinicopathologic characteristics translate into cancer staging and predict recurrence risk. Adjuvant chemotherapy reduces the risk of recurrence and is offered to high-risk patients. However, some patients are inevitably overtreated or undertreated; better risk stratification is necessary to improve outcomes after surgery.

DLBclass: A Probabilistic Molecular Classifier to Guide Clinical Investigation and Practice in DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease. The increasing recognition and targeting of genetically defined DLBCLs highlights the need for robust classification algorithms. We previously characterized recurrent genetic alterations in DLBCL and identified five discrete subtypes, Clusters 1-5 (C1-C5), with unique mechanisms of transformation, immune evasion, candidate treatment targets and different outcomes following standard first-line therapy.

A TROP2/Claudin Program Mediates Immune Exclusion to Impede Checkpoint Blockade in Breast Cancer.

Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. Here, we demonstrate that Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of emerging anti-cancer Antibody Drug Conjugates (ADCs), controls barrier-mediated immune exclusion in Triple-Negative Breast Cancer (TNBC) through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and strongly associated with outcomes in TNBC.

Leucine zipper-based SAIM imaging identifies therapeutic agents to disrupt the cancer cell glycocalyx for enhanced immunotherapy.

The abnormally thick glycocalyx of cancer cells can provide a physical barrier to immune cell recognition and effective immunotherapy. Here, we demonstrate an optical method based on Scanning Angle Interference Microscopy (SAIM) for the screening of therapeutic agents that can disrupt the glycocalyx layer as a strategy to improve anti-cancer immune responses. We developed a new membrane labeling strategy utilizing leucine zipper pairs to fluorescently mark the glycocalyx layer boundary for precise and robust measurement of glycocalyx thickness with SAIM.

Peritraumatic C-reactive protein levels predict pain outcomes following traumatic stress exposure in a sex-dependent manner.

Background: Chronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner.

Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips.

Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms.

Modulation of antigen delivery and lymph node activation in nonhuman primates by saponin adjuvant saponin/monophosphoryl lipid A nanoparticle.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B-cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells.

The impact of tobacco smoking and smoking cessation on lung cancer and stroke incidence among people with HIV on antiretroviral therapy in South Africa: a simulation modeling study.

Introduction: With declining HIV-related mortality, over 20% of people with HIV (PWH) in South Africa are now over age 50 years, and tobacco-related non-communicable disease burden is increasing. We quantified the impact of smoking and smoking cessation on lung cancer and stroke incidence among PWH in South Africa.

Methods: Using a microsimulation model, we simulated 18 cohorts of initially virologically suppressed PWH over their lifetime, categorised by sex, initial age (35 years/45 years/55 years) and smoking status (current/former/never).

Redirecting E3 ubiquitin ligases for targeted protein degradation with heterologous recognition domains.

Targeted protein degradation (TPD) mediated by proteolysis targeting chimeras or molecular glues is an emerging therapeutic strategy. Despite greater than 600 E3 ligases and their associated components, a limited number have been deployed in TPD. Those commonly used include cereblon and von Hippel-Lindau tumor suppressor (VHL), which is expressed widely and for which high affinity ligands are available.

Systematic Review of the Comparative Studies of Image-guided Thermal Ablation, Stereotactic Radiosurgery, and Sublobar Resection for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

The Clinical Practice Standards Committee of the American Association for Thoracic Surgery assembled an expert panel and conducted a systematic review of the literature detailing studies directly comparing treatment options for high-risk patients with stage I non-small cell lung cancer (NSCLC). A systematic search was performed to identify publications comparing outcomes following image-guided thermal ablation (IGTA), stereotactic ablative radiotherapy (SABR), and sublobar resection-the main treatment options applicable to high-risk patients with stage I NSCLC. There were no publications detailing completed randomized controlled trials comparing these treatment options.

Characterizing Nodal Gamma-Delta T-Cell Lymphoma: Clinicopathological and Molecular Insights.

Peripheral T-cell lymphomas with gamma-delta phenotype (GDTCL) are rare lymphoid malignancies. Beyond the well-recognized entities of extranodal lymphomas with gamma-delta phenotype as defined by the 5th edition of the WHO Classification of Hematolymphoid Tumors and 2022 International Consensus Classification, there is a group of poorly-defined gamma-delta T-cell lymphomas with predominantly nodal presentation, termed as nodal GDTCL (nGDTCL). In this study, we present a series of 12 cases of EBV-negative nGDTCL, highlighting the clinical, histopathological and molecular features of this rare entity.

Non-Generative Artificial Intelligence (AI) in Medicine: Advancements and Applications in Supervised and Unsupervised Machine Learning.

The use of Artificial Intelligence (AI) within pathology and healthcare has advanced extensively. We have accordingly witnessed increased adoption of various AI tools which are transforming our approach to clinical decision support, personalized medicine, predictive analytics, automation, and discovery. The familiar and more reliable AI tools that have been incorporated within healthcare thus far fall mostly under the non-generative AI domain, which includes supervised and unsupervised machine learning (ML) techniques.

Systematic Review of Stereotactic Ablative Radiotherapy (SABR)/ Stereotactic Body Radiation Therapy (SBRT) for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

Stereotactic ablative radiotherapy (SABR) has emerged as an alternative, non-surgical treatment for high-risk patients with stage I non-small cell lung cancer (NSCLC) with increased use over time. The American Association for Thoracic Surgery (AATS) Clinical Practice Standards Committee (CPSC) assembled an expert panel and conducted a systematic review of the literature evaluating the results of SABR, which is also referred to as stereotactic body radiation therapy (SBRT) or stereotactic radiosurgery (SRS), prior to developing treatment recommendations for high-risk patients with stage I NSCLC based on expert consensus. Publications detailing the findings of 16 prospective studies of SABR and 14 retrospective studies of SABR for the management of early-stage lung cancer in 54 697 patients were identified by systematic review of the literature with further review by members of our expert panel.

Systematic Review of Sublobar Resection for Treatment of High-Risk Patients with Stage I Non-Small Cell Lung Cancer.

Sublobar resection offers a parenchymal-sparing surgical alternative to lobectomy and includes wedge resection and segmentectomy. Sublobar resection has been historically utilized in high-risk patients with compromised lung function; however, the technique is becoming more prevalent for normal-risk patients with peripheral lung tumors < 2 cm. In this article, we summarize the technique of sublobar resection, the importance of surgical margins and lymph node sampling, patient selection, perioperative complications, outcomes, and the impact of sublobar resection on the quality of life.

Intratumoral immune cell manipulations as a strategy to enhance cancer vaccine efficiency.

Shortcomings in cancer vaccine development are attributable to weak and transient anti-tumor cellular responses in the tumor microenvironment. This restriction of efficacy may be due to an intratumoral immunosuppressive milieu, consisting of regulatory T cells, M2 macrophages, and myeloid derived suppressor cells. Here, we analyze recent advances and propose future directions in the modulation of cellular state propensities combined with cancer vaccines.

Enhancing representativeness of patient-reported outcomes in routine radiation oncology care: a quality improvement protocol to address non-response.

Introduction: Non-response significantly undermines the representativeness of patient-reported outcome (PRO) data, thereby compromising its utility for facilitating high-value, equitable, patient-centred care in cancer clinics. Quality improvement studies are needed to assess the representativeness of PRO data collected in routine care, identify the underlying causes of non-response and develop novel methods to ensure data representativeness. Using a multilevel framework and a mixed-methods approach, we have three aims: (1) characterise the non-response of the Global-10 across clinic, provider and patient levels; (2) identify multilevel causes of non-response and potential strategies to improve representativeness in PRO collection; and (3) develop effective modifications to missing-data methods to enhance the representativeness of pre-existing PRO data.

Genomic correlates of response and resistance to the irreversible FGFR1-4 inhibitor futibatinib based on biopsy and circulating tumor DNA profiling.

Background: Futibatinib is the only covalent inhibitor of FGFR1-4 to gain regulatory approval in oncology. Here, we present genomic analyses of tissue biopsies and circulating tumor DNA (ctDNA) from patients with one of nearly 20 tumor types treated with futibatinib in the phase I/II FOENIX study.

Patients And Methods: Eligible patients included those with ctDNA samples collected per protocol at baseline and/or progression on futibatinib in the phase Ib portion of the study for FGF/FGFR-altered advanced solid tumors or the phase II portion of the study for FGFR2 fusion/rearrangement-positive cholangiocarcinoma.

Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin.

Immunosuppression commonly disrupts the homeostasis of mutated normal skin, leading to widespread skin dysplasia and field cancerization. However, the immune system's role in maintaining the normal state of mutated tissues remains uncertain. Herein, we demonstrate that T cell immunity to cutaneotropic papillomaviruses promotes the homeostasis of ultraviolet radiation-damaged skin.

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.

Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for β-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here, we compare combined CRISPR-Cas9 editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. Dual targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two single guide RNAs (sgRNAs) resulted in superior HbF induction, including in sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers.

Immune checkpoint inhibitors in the post-transplant landscape of hepatocellular carcinoma: A systematic literature review.

Background: Immune checkpoint inhibitors (ICIs) have shown promise in the treatment of hepatocellular carcinoma (HCC). However, their safety and efficacy in liver transplant recipients with recurrent HCC remain unclear. This systematic review aims to evaluate the use of ICIs for recurrent HCC after liver transplantation and to identify potential predictive factors associated with graft rejection and treatment response.

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing datasets.

Purpose: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome or panel sequencing datasets aligned to a GRCh37, GRCh38, or T2T reference genome.

Methods: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs.