Highlights • Flavoring enhances the rewarding and reinforcing value of e-cigarettes with nicotine. • Flavoring may increase the abuse liability of e-cigarettes with nicotine in smokers. • The absence ...of flavoring in e-cigarettes with nicotine may result in decreased use.
The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. ...Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth
in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.
These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers.
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Impulsivity is a core deficit in attention deficit hyperactivity disorder (ADHD). Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to ...modulate cognitive control circuits and could enhance DLPFC activity, leading to improved impulse control in ADHD.
Hypothesis: We predicted 2.0 mA anodal stimulation (tDCS) versus sham stimulation applied over the left DLPFC would improve Conners Continuous Performance Task (CPT) scores. Our secondary hypothesis predicted that stop signal task (SST) reaction time (SSRT) would decrease with tDCS (versus sham).
Thirty-seven participants completed two periods of three tDCS (or sham) sessions two weeks apart in a within-subject, double-blind, counterbalanced order. Participants performed a fractal N-back training task concurrent with tDCS (or sham) stimulation. Participants completed the CPT and SST at the beginning of treatment (baseline), at the end of the treatment, and at a 3-day post-stimulation follow-up.
There was a significant stimulation condition by session interaction for CPT false positive scores (χ2 = 15.44, p < 0.001) driven by a decrease in false positive errors from baseline to end of treatment in the tDCS group (β = −0.36, 95% Confidence Interval (CI) −0.54 to −0.18, p < 0.001). This effect did not persist at follow-up (β = −0.13, p > 0.05). There was no significant stimulation condition by session interaction effect on CPT true positive errors or response time (ps > 0.05). No significant change in SSRT performance was observed (p > 0.05).
These findings suggest that stimulation of the left DLPFC with tDCS can improve impulsivity symptoms in ADHD, supporting the therapeutic potential for tDCS in adult ADHD patients.
•We examined the treatment potential of anodal tDCS stimulation for adult ADHD.•Three TDCS sessions reduced false positives on a continuous performance task.•Repeated tDCS over the left DLPFC may treat impulsivity in adult ADHD.
Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide ...polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BPND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two ¹¹Ccarfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BPND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BPND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.
Abstract
Background
The COVID-19 pandemic has led to delays in patients seeking care for life-threatening conditions; however, its impact on treatment patterns for patients with metastatic cancer is ...unknown. We assessed the COVID-19 pandemic’s impact on time to treatment initiation (TTI) and treatment selection for patients newly diagnosed with metastatic solid cancer.
Methods
We used an electronic health record–derived longitudinal database curated via technology-enabled abstraction to identify 14 136 US patients newly diagnosed with de novo or recurrent metastatic solid cancer between January 1 and July 31 in 2019 or 2020. Patients received care at approximately 280 predominantly community-based oncology practices. Controlled interrupted time series analyses assessed the impact of the COVID-19 pandemic period (April-July 2020) on TTI, defined as the number of days from metastatic diagnosis to receipt of first-line systemic therapy, and use of myelosuppressive therapy.
Results
The adjusted probability of treatment within 30 days of diagnosis was similar across periods (January-March 2019 = 41.7%, 95% confidence interval CI = 32.2% to 51.1%; April-July 2019 = 42.6%, 95% CI = 32.4% to 52.7%; January-March 2020 = 44.5%, 95% CI = 30.4% to 58.6%; April-July 2020 = 46.8%, 95% CI= 34.6% to 59.0%; adjusted percentage-point difference-in-differences = 1.4%, 95% CI = −2.7% to 5.5%). Among 5962 patients who received first-line systemic therapy, there was no association between the pandemic period and use of myelosuppressive therapy (adjusted percentage-point difference-in-differences = 1.6%, 95% CI = −2.6% to 5.8%). There was no meaningful effect modification by cancer type, race, or age.
Conclusions
Despite known pandemic-related delays in surveillance and diagnosis, the COVID-19 pandemic did not affect TTI or treatment selection for patients with metastatic solid cancers.
Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib ...starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio HR
, 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.
We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients ...revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFRA289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFRA289V mutation in glioblastoma, postulating EGFRA289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.
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•EGFRA289D/T/V-mutated GBM tumors have distinct in vivo imaging characteristics•EGFRA289D/T/V-associated decrease in OS is driven by tumor proliferation and invasion•EGFRA289V leads to phosphorylation of Erk followed by increased MMP1 secretion•Targeting of EGFRA289V via mAb806 can reduce tumor growth and increase survival
Binder et al. show that glioblastoma (GBM) expressing EGFR A289 mutants exhibit invasive features and are associated with shorter survival in patients and mice. GBM cells expressing EGFRA289V increase ERK-dependent MMP1 expression but are sensitive to an EGFR monoclonal antibody being clinically developed.
Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell ...carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial-mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.
Objective
Continuing to smoke after a cancer diagnosis undermines prognosis. Yet few trials have tested Food and Drug Administration (FDA)‐approved tobacco use medications in this population. ...Extended use varenicline may represent an effective treatment for cancer patients who smoke given barriers to cessation including a prolonged time line for relapse.
Methods
A placebo‐controlled randomized trial tested 12 weeks of varenicline plus 12 weeks of placebo (standard ST) vs 24 weeks of varenicline (extended ET) with seven counseling sessions for treatment‐seeking cancer patients who smoke (N = 207). Primary outcomes were 7‐day biochemically confirmed abstinence at weeks 24 and 52. Treatment adherence and side effects, adverse and serious adverse events, and blood pressure were assessed.
Results
Point prevalence and continuous abstinence quit rates at weeks 24 and 52 were not significantly different across treatment arms (P's > 0.05). Adherence (43% of sample) significantly interacted with treatment arm for week 24 point prevalence (odds ratio OR = 2.31; 95% confidence interval CI, 1.15‐4.63; P = 0.02) and continuous (OR = 5.82; 95% CI, 2.66‐12.71; P < 0.001) abstinence. For both outcomes, adherent participants who received ET reported higher abstinence (60.5% and 44.2%) vs ST (44.7% and 27.7%), but differences in quit rates between arms were not significant for nonadherent participants (ET: 9.7% and 4.8%; ST: 12.7% and 10.9%). There were no significant differences between treatment arms on side effects, adverse and serious adverse events, and rates of high blood pressure (P's > 0.05).
Conclusions
Compared with ST, ET varenicline does not increase patient risk and increases smoking cessation rates among patients who adhere to treatment. Studies are needed to identify effective methods to increase medication adherence to treat patient tobacco use effectively.
Blood tests to detect circulating tumor cells (CTC) offer great potential to monitor disease status, gauge prognosis, and guide treatment decisions for patients with cancer. For patients with brain ...tumors, such as aggressive glioblastoma multiforme, CTC assays are needed that do not rely on expression of cancer cell surface biomarkers like epithelial cell adhesion molecules that brain tumors tend to lack. Here, we describe a strategy to detect CTC based on telomerase activity, which is elevated in nearly all tumor cells but not normal cells. This strategy uses an adenoviral detection system that is shown to successfully detect CTC in patients with brain tumors. Clinical data suggest that this assay might assist interpretation of treatment response in patients receiving radiotherapy, for example, to differentiate pseudoprogression from true tumor progression. These results support further development of this assay as a generalized method to detect CTC in patients with cancer.
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