Significance: Epstein–Barr virus establishes a life-long latent infection (i.e., no virus is produced) in B cells in most people worldwide. A specific group of latency-associated proteins is expressed in B-cell and epithelial malignancies and likely contributes to tumorigenesis, but the role of epithelial cells in the virus life cycle is not well understood. We grew epithelial cells in organotypic cultures, allowing the cells to differentiate and stratify as they do in vivo. Unlike B-cell infection, EBV infection of epithelial cultures resulted in spontaneous production of high levels of virus, likely expanding the virus pool and increasing efficiency of transmission. This model of EBV-infected epithelium will enhance our understanding of the role of epithelial cells in the EBV life cycle.

Immunotherapy targeting program cell death protein 1 (PD-1) in addition to chemotherapy has improved the survival of triple-negative breast cancer (TNBC) patients. However, the development of resistance and toxicity remain significant problems. Using the translationally relevant 4T1 mouse model of TNBC, we report here that dietary administration of the phytochemical quercetin enhanced the antitumor action of Cyclophosphamide, a cytotoxic drug with significant immunogenic effects that is part of the combination chemotherapy used in TNBC. We observed that quercetin favorably modified the host fecal microbiome by enriching species such as Akkermansia muciniphilia, which has been shown to improve response to anti-PD-1 therapy. We also show that quercetin and, to a greater extent, Cyclophosphamide increased the systemic frequency of T cells and NK cells. In addition, Cyclophosphamide alone and in combination with quercetin reduced the frequency of Treg, which is consistent with an antitumor immune response. On the other hand, Cyclophosphamide did not significantly alter the host microbiome, suggesting complementarity between microbiome- and immune-mediated mechanisms in potentiating the antitumor action of Cyclophosphamide by quercetin. Overall, these results support the potential for microbiota-centered dietary intervention to overcome resistance to chemoimmunotherapy in TNBC.

Background: The US FDA announced its commitment to prohibiting menthol as a characterizing flavor in tobacco. The relationship between cigarette menthol and exposure to toxic substances in mainstream tobacco smoke is not well characterized. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 2015 to 2016 special sample were used to study markers of 26 harmful and potentially harmful constituents (HPHC) in tobacco smoke. These include urine metabolites of polycyclic aromatic hydrocarbons (PAH), volatile organic compounds (VOC), and heavy metals in exclusive menthol (n = 162) and nonmenthol (n = 189) cigarette smokers. Urine metabolites of 7 PAHs, 15 VOCs, and 4 heavy metal biomarkers were compared by menthol status. Multivariable analyses were conducted on creatinine-adjusted concentrations. Results: There were no significant differences in cotinine levels or in 22 of 26 HPHCs. Among the urine metabolites of PAHs, the levels of 1-hydroxyphenanthrene were about 16% lower in menthol smokers. Among the urine metabolites of VOCs, menthol cigarette smokers presented significantly lower concentrations of acrylamide, N,N-dimethylformamide, and acrylonitrile. Menthol and nonmenthol smokers presented similar levels of heavy metals. Menthol did not affect the levels of cotinine and the nicotine metabolite ratio in urine. Conclusions: Menthol and nonmenthol cigarettes deliver similar levels of most HPHCs. Impact: Findings on toxicity are similar for menthol and nonmenthol cigarettes.

Background: Low-dose computed tomography (LDCT) increases the early detection of lung cancer. Identifying modifiable behaviors that may affect tumor progression in LDCT-detected patients increases the likelihood of long-term survival and a good quality of life. Methods: We examined cigarette smoking behaviors on lung cancer stage, progression, and survival in 299 ever-smoking patients with low-dose CT-detected tumors from the National Lung Screening Trial. Univariate and multivariate Cox models were used to estimate the hazard ratio (HR) for smoking variables on survival time. Results: Current vs. former smokers and early morning smokers (≤5 min after waking, i.e., time to first cigarette (TTFC) ≤ 5 min) had more advanced-stage lung cancer. The adjusted HR for current vs. former smokers was 1.3 (95% confidence interval [CI] 0.911–1.98, p = 0.136) for overall survival (OS) and 1.3 (0.893–1.87, p = 0.1736) for progression-free survival (PFS). The univariate hazard ratios for TTFC ≤ 5 min vs. >5 min were 1.56 (1.1–2.2, p = 0.013) for OS and 1.53 (1.1–2.12, p = 0.01) for PFS. Among current smokers, the corresponding HRs for early TTFC were 1.78 (1.16–2.74, p = 0.0088) and 1.95 (1.29–2.95, p = 0.0016) for OS and PFS, respectively. In causal mediation analysis, the TTFC effect on survival time was mediated entirely through lung cancer stage. Conclusion: The current findings indicate smoking behaviors at diagnosis may affect lung cancer stage and prognosis.

Background: The role of adjuvant chemotherapy in early-stage small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) remains unclear, particularly for small tumors. This study assesses the survival benefits of adjuvant chemotherapy after surgical resection with a novel focus on tumors less than 1 cm. Materials and methods: Data from the National Cancer Database (NCDB) was extracted for patients with SCLC (n = 11,962) and LCNEC (n = 6821) who underwent surgical resection between 2004 and 2020. Exclusion criteria were limited survival (< 30 days), positive lymph nodes, distant metastases, large tumors (> 5 cm), residual microscopic disease, and neoadjuvant therapy. The primary outcome was overall survival (OS) from diagnosis, which was evaluated using Kaplan–Meier methods and multivariate Cox regression analyses. A propensity score matching (PSM) analysis was performed to compare outcomes in patients with SCLC and tumors ≤ 1 cm who received adjuvant chemotherapy versus surgery alone. Results: The study involved 4114 SCLC and 3954 LCNEC patients. Adjuvant chemotherapy was associated with a significant increase median OS in both SCLC (6.26 vs. 4.18 years; p < 0.001) and LCNEC (7.02 years vs. 4.89 years; p < 0.001), while also being an independent predictor of better OS in SCLC (HR: 0.74) and LCNEC (HR: 0.75) (p < 0.001). The benefit was more noticeable in tumors ≤ 1 cm, showing a significant OS increase after PSM (median OS 7.34 vs. 5.02 years; p = 0.0048). Conclusion: Adjuvant chemotherapy after surgery is associated with improved overall survival in stage I SCLC and LCNEC, particularly in SCLC tumors of 1 cm or less.