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Background Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored. Methods RNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue. Results Responder patients have both a different microbial community structure than non-responders ( P = 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the genera Ruminococcus , Akkermansia , and Faecalibacterium . Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI ( P = 0.023, P = 0.019, P = 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the genera Bacteroides , Blautia , Akkermansia , and Faecalibacterium . Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the genera Colidextribacter , Frisingicoccus , Marvinbryantia , and Blautia which have not yet been reported. Conclusions The role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.

Background Treatment outcomes of advanced non-small cell lung cancer (NSCLC) have substantially improved with immune checkpoint inhibitors (ICI), although only approximately 19% of patients respond to immunotherapy alone, increasing to 58% with the addition of chemotherapy. The gut microbiome has been recognized as a modulator of ICI response via its priming effect on the host immune response. Antibiotics as well as chemotherapy reduce gut microbial diversity, hence altering composition and function of the gut microbiome. Since the gut microbiome may modify ICI efficacy, we conducted a retrospective study evaluating the effects of prior antibiotic or chemotherapy use on NSCLC patient response to ICI. Methods We retrospectively evaluated 256 NSCLC patients treated between 2011–2017 at Moffitt Cancer Center with ICI ± chemotherapy, examining the associations between prior antibiotic or chemotherapy use, overall response rate and survival. Relative risk regression using a log-link with combinatorial expectation maximization algorithm was performed to analyze differences in response between patients treated with antibiotics or chemotherapy versus patients who didn’t receive antibiotics or chemotherapy. Cox proportional hazards models were constructed to evaluate associations between risk factors and overall survival. Results Only 46 (18% of 256) patients used antibiotics prior to and/or during ICI treatment, and 146 (57%) had prior chemotherapy. Antibiotic users were 8% more likely to have worse overall response rate (RR:1.08; CI:0.93–1.26; p  = 0.321), as well as a 35% worse overall survival (HR:1.35; CI:0.91–2.02; p  = 0.145), although results were not statistically significant. However, prior use of chemotherapy was significantly associated with poor ICI response (RR:1.24; CI:1.05–1.47; p  = 0.013) and worse overall survival (HR:1.47; CI:1.07–2.03; p  = 0.018). Conclusions Patients receiving antibiotics prior to and/or during ICI therapy might experience worse treatment outcomes and survival than unexposed patients, although these associations were not statistically significant and hence warrant further prospective study. Prior chemotherapy significantly reduced ICI response and overall survival. Antibiotic or chemotherapy exposure may negatively impact ICI response, perhaps through disruption of the eubiotic gut microbiome.

Background: Although ∼20% of human cancers are caused by microorganisms, only suspicion exists for a microbial cause of lung cancer. Potential infectious agents were investigated in non-small cell lung cancer (NSCLC) and non-neoplastic lung. Methods: Seventy NSCLC tumours (33 squamous cell carcinomas, 17 adenocarcinomas, 10 adenocarcinomas with lepidic spread, and 10 oligometastases) and 10 non-neoplastic lung specimens were evaluated for molecular evidence of microorganisms. Tissues were subjected to the Lawrence Livermore Microbial Detection Array, an oncovirus panel of the International Agency for Research on Cancer, and human papillomavirus (HPV) genotyping. Associations were examined between microbial prevalence, clinical characteristics, and p16 and EGFR expression. Results: Retroviral DNA was observed in 85% squamous cell carcinomas, 47% adenocarcinomas, and 10% adenocarcinomas with lepidic spread. Human papillomavirus DNA was found in 69% of squamous cell carcinomas with 30% containing high-risk HPV types. No significant viral DNA was detected in non-neoplastic lung. Patients with tumours containing viral DNA experienced improved long-term survival compared with patients with viral DNA-negative tumours. Conclusions: Most squamous cell carcinomas and adenocarcinomas contained retroviral DNA and one-third of squamous cell carcinomas contained high-risk HPV DNA. Viral DNA was absent in non-neoplastic lung. Trial results encourage further study of the viral contribution to lung carcinogenesis.

Background In our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. However, their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors. Methods Gene expression microarrays of 30 primary and 9 metastatic NSCLC patients were preprocessed through a series of quality control analyses. Linear Models for Microarray Analysis and Gene Set Enrichment Analysis were used to assess differential expression. Results Various genes and gene sets had significantly altered expressions between virus-infected and uninfected NSCLC tumors. Notably, 22 genes on the viral carcinogenesis pathway were significantly overexpressed in virus-infected primary tumors, along with three oncogenic gene sets. A total of 12 genes, as well as seven oncogenic and 133 immunologic gene sets, were differentially altered in squamous cell carcinomas, depending on the virus. In adenocarcinoma, 14 differentially expressed genes (DEGs) were identified, but no oncogenic and immunogenic gene sets were significantly altered. In bronchioloalveolar carcinoma, several genes were highly overexpressed in virus-infected specimens, but not statistically significant. Only five of 69 DEGs (7.2%) from metastatic tumor analysis overlapped with 1527 DEGs from the primary tumor analysis, indicating differences in host cellular targets and the viral impact between primary and metastatic NSCLC. Conclusions The differentially expressed genes and gene sets were distinctive among infected viral types, histological subtypes, and metastatic disease status of NSCLC. These results support the hypothesis that tumor viruses play a role in NSCLC by regulating host genes in tumor cells during NSCLC differentiation and progression.

Cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma, is thought to arise from mature tissue-resident memory T cells. The most common subtypes include Mycosis Fungoides and Sezary Syndrome. The role of skin microbiota remains unclear in the symptom manifestation of MF. Among 39 patients with MF, we analyzed bacteria colonizing MF lesions and non-lesional skin in the contralateral side and characterized regional changes in the skin microbiota related to MF involvement using the difference in relative abundance of each genus between lesional and contralateral non-lesional skin. We investigated the relationship between these skin microbiota alterations and symptom severity. No statistically significant difference was found in bacterial diversity and richness between lesional and non-lesional skin. Different skin microbiota signatures were associated with different symptoms. More pronounced erythema in the lesions was associated with an increase in Staphylococcus . Pain and thick skin in the lesions were associated with a decrease in Propionibacterium . The results of this pilot study suggest that the skin microbiota plays an important role in changing skin phenotypes among patients with MF. Larger skin microbiota studies are needed to confirm these findings and support the use of antibiotic treatment to mitigate CTCL symptoms.

Stage IIIA non-small cell lung cancer represents a relatively heterogeneous group of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Presentations of disease range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. Controversy abounds as to the optimal treatment of the various stage IIIA subsets, which is fueled by a lack of meaningful, large randomized trials. Multimodality therapy of some type appears to be preferable in stage IIIA patients.

Background: Sex difference in the immune response may influence patients’ response to immune checkpoint inhibitors (ICIs). We conducted a prospective observation study to determine the correlation between pretreatment sex hormone levels and response to ICIs in metastatic non-small cell lung cancer (NSCLC). Method: Pretreatment plasma samples from 61 patients with newly diagnosed NSCLC prior to ICI therapy were collected. Six sex hormone levels [pyrazole triol, 17 β-estradiol, 5-androstenediol, 3β-androstenediol, dehydroepiandrosterone (DHEA), and S-equol] were measured using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Overall survival (OS) and progression-free survival (PFS) were compared between the high- and low-level groups in the whole cohort. Result: Among the six sex hormones measured, DHEA levels were significantly higher among patients without clinical benefits in the discovery cohort; the remaining sex hormones did not differ significantly. In the whole cohort, median PFS was 22 months for patients with low DHEA levels vs. 3.8 months for those with high DHEA [hazard ratio, 14.23 (95% CI, 4.7–43); p < 0.001]. A significant association was also observed for OS [hazard ratio, 8.2 (95% CI, 2.89–23.35); p < 0.0001]. Conclusions: High pretreatment plasma DHEA levels were associated with poor clinical outcomes for patients with metastatic NSCLC treated with ICIs.

Lobectomy is standard treatment for early-stage lung cancer, but sublobar resection remains debated. We compared outcomes after robotic-assisted video-assisted thoracoscopic (R-VATS) segmentectomy vs lobectomy. We retrospectively analyzed data from 251 consecutive patients who underwent R-VATS lobectomy (n = 208) or segmentectomy (n = 43) by a single surgeon over 36 months. Pulmonary function tests and perioperative outcomes were compared using Chi-squared test, unpaired Student t test, or Kruskal–Wallis test, with significance at P ≤ .05. Intraoperative complications were not significantly different, but median operative times were longer for R-VATS segmentectomies (P < .01). Postoperative complications were not significantly different, except for increased rates of pneumothorax after chest tube removal (P = .032) and of effusions or empyema (P = .011) after R-VATS segmentectomies. Predicted changes for forced expiratory volume in 1 second and diffusion constant of the lung for carbon monoxide are significantly less after R-VATS segmentectomy (P < .001). R-VATS segmentectomy should be considered as an alternative to lobectomy for conserving lung function in respiratory-compromised lung cancer patients, although oncologic efficacy remains undetermined. •R-VATS segmentectomy significantly preserves more pulmonary function than lobectomy.•R-VATS segmentectomy has a higher rate of pulmonary complications than lobectomy.•R-VATS segmentectomy is a viable and safe option for lung cancer patients.

Abstract Background We use real-world data to develop a lung cancer screening (LCS) eligibility mechanism that is both accurate and free from racial bias. Methods Our data came from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. We built a systematic fairness-aware machine learning framework by integrating a Group and Intersectional Fairness and Threshold (GIFT) strategy with an easy ensemble classifier—(EEC-) or logistic regression—(LR-) based model. The best LCS eligibility mechanism EEC-GIFT* and LR-GIFT* were applied to the testing dataset and their performances were compared to the 2021 US Preventive Services Task Force (USPSTF) criteria and PLCOM2012 model. The equal opportunity difference (EOD) of developing lung cancer between Black and White smokers was used to evaluate mechanism fairness. Results The fairness of LR-GIFT* or EEC-GIFT* during training was notably greater than that of the LR or EEC models without greatly reducing their accuracy. During testing, the EEC-GIFT* (85.16% vs 78.08%, P < .001) and LR-GIFT* (85.98% vs 78.08%, P < .001) models significantly improved sensitivity without sacrificing specificity compared to the 2021 USPSTF criteria. The EEC-GIFT* (0.785 vs 0.788, P = .28) and LR-GIFT* (0.785 vs 0.788, P = .30) showed similar area under receiver operating characteristic curve values compared to the PLCOM2012 model. While the average EODs between Blacks and Whites were significant for the 2021 USPSTF criteria (0.0673, P < .001), PLCOM2012 (0.0566, P < .001), and LR-GIFT* (0.0081, P < .001), the EEC-GIFT* model was unbiased (0.0034, P = .07). Conclusion Our EEC-GIFT* LCS eligibility mechanism can significantly mitigate racial biases in eligibility determination without compromising its predictive performance.