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Abstract Background Quantification of microRNAs in specific cell populations microdissected from tissues can be used to define their biological roles, and to develop and deploy biomarker assays. In this study, a number of variables were examined for their effect on the yield of microRNAs in samples obtained from formalin-fixed paraffin-embedded tissues by laser microdissection. Results MicroRNA yield was improved by using cresyl violet instead of hematoxylin-eosin to stain tissue sections in preparation for microdissection, silicon carbide instead of glass fiber as matrix in RNA-binding columns, and overnight digestion of dissected samples with proteinase K. Storage of slides carrying stained tissue sections at room temperature for up to a week before microdissection, and storage of the microdissectates at room temperature for up to a day before RNA extraction did not adversely affect microRNA yield. Conclusions These observations should be of value for the efficient isolation of microRNAs from microdissected formalin-fixed tissues with a flexible workflow.

Abstract Background Laboratory assays are needed for early stage non-small lung cancer (NSCLC) that can link molecular and clinical heterogeneity to predict relapse after surgical resection. We technically validated two miRNA assays for prediction of relapse in NSCLC. Total RNA from seventy-five formalin-fixed and paraffin-embedded (FFPE) specimens was extracted, labeled and hybridized to Affymetrix miRNA arrays using different RNA input amounts, ATP-mix dilutions, array lots and RNA extraction- and labeling methods in a total of 166 hybridizations. Two combinations of RNA extraction- and labeling methods (assays I and II) were applied to a cohort of 68 early stage NSCLC patients. Results RNA input amount and RNA extraction- and labeling methods affected signal intensity and the number of detected probes and probe sets, and caused large variation, whereas different ATP-mix dilutions and array lots did not. Leave-one-out accuracies for prediction of relapse were 63% and 73% for the two assays. Prognosticator calls ("no recurrence" or "recurrence") were consistent, independent on RNA amount, ATP-mix dilution, array lots and RNA extraction method. The calls were not robust to changes in labeling method. Conclusions In this study, we demonstrate that some analytical conditions such as RNA extraction- and labeling methods are important for the variation in assay performance whereas others are not. Thus, careful optimization that address all analytical steps and variables can improve the accuracy of prediction and facilitate the introduction of microRNA arrays in the clinic for prediction of relapse in stage I non-small cell lung cancer (NSCLC).

Objective: Presentation with multiple ground glass opacities (GGOs) is an increasingly common occurrence, and the optimal management of these lesions is unclear. Active surveillance has been increasingly adopted as a management strategy for other low-grade malignancies. We hypothesized that active surveillance could be a feasible and safe option for patients with multiple GGOs., Methods: Patients with ≥2 GGOs (ground glass predominant, <50% solid, ≤3 cm) were enrolled in a multi-institutional registry and prospectively followed up on active surveillance with computed tomography scans every 6 to 12 months. Each GGO was catalogued and measured individually at each follow-up visit., Results: Target accrual was met, with 337 patients from 23 institutions. The mean age was 70 years (interquartile range, 65-77 years), and 74% were women. Most were former (70%) or current (9%) smokers, with a mean exposure of 30 pack-years (interquartile range [IQR], 15-44 pack-years). Half of the patients (51%) had a previous lung cancer, and the majority (86%) were already under surveillance at the time of study entry. The median number of GGOs per patient was 3 (IQR, 2-5), with a total of 1467 GGOs under surveillance. The median GGO size was 0.9 cm (IQR, 0.7-1.3 cm). Most GGOs were 0.5 to 1 cm in size., Conclusions: Active surveillance, rather than immediate intervention, was an acceptable option to patients, and accrual to this registry trial was feasible. Safety endpoints and long-term outcomes will be assessed in the planned 5-year follow-up in accordance with the protocol., (Copyright © 2024. Published by Elsevier Inc.)

In this secondary analysis of specimens from the CANTOS trial, the investigators find that patients with clonal hematopoiesis mutations, particularly in the TET2 gene, predict a benefit of decreased cancer risk with the administration of the anti-IL1β agent canakinumab. Despite small numbers and the need for prospective validation, the findings are exciting as they demonstrate the potential for personalized chemoprevention approaches. Such personalized approaches can potentially enhance the feasibility of cancer prevention trials. See related article by Woo et al., p. 429., (©2024 American Association for Cancer Research.)

Objective: Lung cancer remains a major cause of mortality worldwide, necessitating further understanding of carcinogenesis and its driving factors, including those influenced by sex-dependent variables. We hypothesized that sex-specific lung immune composition may contribute to a greater risk of lung cancer in women., Methods: Data from 1056 lung cancer screenings were examined for an association between sex and lung cancer risk using time-to-event analyses. Immune profiling by flow cytometry was performed on male and female lungs of 3 independent mouse models: nontumor bearing, KRAS mutated, and urethane-exposed carcinogenic. A comparable analysis was performed on human bronchoalveolar lavage samples (n = 81) from patients with lung cancer., Results: Of the high-risk screening cohort examined, 60 patients (5.7%) developed lung cancer during median follow-up of 43.4 months. Multivariable stepwise modeling retained female sex (hazard ratio, 1.56; P < .01) and age (P < .01) as prognostic indicators for lung cancer development. Female lung immune profiles in patients included T-cell phenotypes consistent with exhaustion (eg, higher proportions of PD-1+ Ki67-; P = .02), an expanded pool of regulatory T-cells (P = .03), reduced effector T-cell frequencies (P = .008), and enhancements in suppressive myeloid populations (P = .02) versus male patients, and this is recapitulated in mouse studies., Conclusions: Female smokers display higher risk for lung cancer. In murine models and humans, female sex is associated with robust immunosuppression within the lung. Further examination of this link will be important in developing immune-based approaches to lung cancer interception and their optimal application across the sexes., Competing Interests: Conflict of Interest Statement Dr Yendamuri serves as a scientific advisory board member for Karkinos Healthcare and reports grant funding from Lumeda Inc. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of malignant central airway obstruction at diagnosis and its 5-year incidence are largely unknown, as are basic epidemiological data pertaining to this serious condition. To address these data limitations, we retrospectively collected data from the cohort of patients diagnosed with lung cancer at our institution in 2015 and followed cohort patients 5 years forward, until 2020., Methods: We reviewed index PET/CT or CT scans at the time of lung cancer diagnosis to identify the presence, subtype, and severity of malignant central airway obstruction as well as progression/development over the next 5 years., Results: The prevalence of malignant central airway obstruction affecting the airway lumen by 25% or greater was 17%, and its 5-year incidence of development was 8.2%. Notable associations from the multivariate analysis included a younger age and a stepwise increase in obstruction with increasing stage of disease. Squamous cell carcinoma and small-cell lung cancer were the 2 histologic subtypes with the strongest association with obstruction. The presence of malignant central airway obstruction either at time of diagnosis or on follow-up imaging was associated with significantly shortened survival (multivariate Cox proportional HR for MCAO=1.702, P<0.001)., Conclusion: This study provides the first systematic characterization of fundamental epidemiological data on malignant central airway obstructions at a tertiary cancer center in the United States. This data is important to inform research directions and funding efforts of this serious complication. It also serves as a baseline value against which to compare for future studies., Competing Interests: Disclosure: (within the past 36 mo): N.M.I. acknowledges serving as the principal investigator of the Phase II follow-up clinical study in a NIH/NCI award R44CA265656 made to Simphotek Inc. Payments were made to Roswell Park Comprehensive Cancer Center. N.M.I. also acknowledges receiving grant funding from the Johnson & Johnson Lung Cancer Initiative. G.S. acknowledges receiving research grant support, including free Photofrin and fibers from Pinnacle Biologics Inc. G.S. acknowledges current service on a scientific advisory board with honoraria and stock options from Lumeda Inc. (Rocky Hill, CT, USA). G.S. acknowledges grant support from the Lung Cancer Initiative at Johnson & Johnson, and grant support from POP Biotechnologies, LLC, and R44CA265656 to Simphotek Inc. through NCI/NIH awards. The remaining authors declare there is no conflict of interest or other disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Recent disease resurgence in China indicates that corona virus infectious disease is still a pertinent public health problem. We stand at a juncture where we are still unsure about the initial dilemmas regarding its birth, therapies, and the emerging novel strains. Medical literature has focused on the clinical, laboratory, radiological, and therapeutic aspects of disease management. There is paucity of literature on the association between socio-demographic variables on disease severity and clinical outcome., Materials and Methods: This retrospective observational study analyzing the socio-demographic variables was performed at a dedicated COVID care center in western Maharashtra, India. Electronic records of all individuals who were admitted to this hospital from July 29 2020, to June 14, 2021, and diagnosed COVID-19 positive by reverse transcriptase polymerase chain reaction (RT-PCR) were identified after due institutional ethical clearance. Patients admitted from July 29, 2020, to February 27, 2021, were categorized as patients presenting during the 'first wave of viral pandemic'. Those admitted from March 01, 2021, to June 14, 2021, have been included as patients admitted during 'second wave of viral pandemic'. The following outcome parameters were collected (presenting symptoms, duration of symptoms before the individual presented for diagnostic RT-PCR, total duration of symptoms, severity of disease at onset, duration of hospital stay, the final outcome (discharge/death) and Charlson's comorbidity index). The linear regression model was used to establish association between socio-demographic factors and disease severity at onset (mild/moderate/severe/critical)., Results: A total of 37033 patients were screened, and the positivity rate with RT-PCR was 16.99% ( n = 6275) during the study period. Out of which 45% ( n = 2824) of the patients had mild disease requiring home isolation and the remaining 55% of patients required admission. 1590 patients from the first wave and 910 from the second wave of COVID-19 were hospitalized and included in the study after exclusion. The mean age of patients in first wave was 49 years and that in second wave was 54 years with 77.6% and 70.6% males in two waves, respectively. The burden of critical cases was higher in second wave as computed to first wave (10% vs 8%). The second wave had more outreach in the rural population as compared to second one (17.8% vs 12.2%). The mean duration from the onset of symptoms to hospitalization was 03 and 04 days, respectively, in two waves. Mortality associated in two waves was 11.9% and 24%, respectively ( P < 0.05). Higher Charlson's comorbidity index was associated with higher mortality, and the cumulative survival from urban area was more as compared to the rural population (log rank - 9.148, P = 0.0002)., Conclusion: The second COVID-19 wave had significantly higher case mortality. It affected elderly patients and those with rural background. The factors associated with higher mortality during COVID-19 pandemic were rural background, higher Charlson's comorbidity index and late presentation to the hospital. Ongoing vaccine campaigns, thus, should focus on rural areas and individuals with comorbidities especially in developing and least developed countries., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Introduction: The microbiome is known to play a significant role in cancer biology; however, few studies have elucidated its relationship with Nonsmall Cell Lung Cancer (NSCLC) patient outcomes. We hypothesized that there are specific microorganisms that are closely related with NSCLC patient survival., Methods: Total of 647 NSCLC (Adenocarcinoma and Squamous Cell Carcinoma combined) patients in The Cancer Genome Atlas (TCGA) were analyzed using the R software., Results: A Volcano Plot was analyzed with the patients divided into Short and Long Survivors by overall survival of 0.9 years, and we found that a bacterium Rothia was significantly abundant in Short Survivors, and Blastococcus, Leptospira, and Haematobacter in Long Survivors, but presence of Rothia alone was associated with overall survival. The age, race, subtype, and sex were not significantly different by the presence of Rothia in NSCLC. Unexpectedly, Rothia-positive NSCLC was associated with less cell proliferation by gene set enrichment analysis, Mki67 expression, proliferation score, with less fraction altered and homologous recombination deficiency, and with high infiltration of stromal cells, indicating favorable oncological characteristics. Further, Rothia-positive tumors were associated with significantly higher infiltration of CD8 T cells, CD4 T cells, Monocytes, and NK cells, and high interferon-gamma response, T-cell receptor richness, cytolytic activity, indicating favorable tumor immune microenvironment., Conclusions: NSCLC with Rothia was associated with worse survival but also with favorable oncological characteristics such as less cell proliferation and favorable tumor immune microenvironment. We cannot help but speculate that Rothia in NSCLC is associated with mortality unrelated to oncological characteristics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Malignant Central Airway Obstruction (MCAO) presents a significant challenge in lung cancer management, with notable morbidity and mortality implications. While bronchoscopy is the established diagnostic standard for confirming MCAO and assessing obstruction subtype (intrinsic, extrinsic, mixed) and severity, Computed Tomography (CT) serves as an initial screening tool. However, the extent of agreement between CT and bronchoscopy findings for MCAO remains unclear., Methods: To assess the correlation between bronchoscopy and CT, we conducted a retrospective review of 108 patients at Roswell Park Comprehensive Cancer Center, analyzing CT and bronchoscopy results to document MCAO presence, severity, and subtype., Results: CT correctly identified MCAO in 99% of cases (107/108). Agreement regarding obstruction subtype (80.8%, Cohen's κ = 0.683, p < 0.001), and severity (65%, Quadratic κ = 0.657, p < 0.001) was moderate. CT tended to equally overestimate (7/19) and underestimate (7/19) the degree of obstruction. CT was also poor in identifying mucosal involvement in mixed MCAO., Conclusions: CT demonstrates reasonable agreement with bronchoscopy in detecting obstruction. Nevertheless, when CT indicates a positive finding for MCAO, it is advisable to conduct bronchoscopy. This is because CT lacks reliability in determining the severity of obstruction and identifying the mucosal component of mixed disease.

Background and Objective: A versatile biomarker, survivin, is highly expressed in proliferating cells of multiple cancers in humans and animals. It is an apoptosis-regulating protein, engaging in a cascade of reactions that involve several other genes and protein interactions. Currently, researchers are investigating its therapeutic potential due to the evidence linking its overexpression to advanced-stage lung cancer. This review is centered around examining survivin-related molecular mechanisms and its therapeutic role specifically in lung cancer. Our objective is to discuss the role of survivin in prognosis and treatment response, shedding light on immune-targeted therapies, as well as outlining future directions for survivin-based vaccines in lung cancer., Methods: The PubMed database and the United States National Library of Medicine search engine at the National Institutes of Health were searched on 24 August 2023 to identify published research studies. Searching "((((((airway [Title/Abstract]) OR (lung [Title/Abstract])) OR (pulm[Title/Abstract])) OR (bronch[Title/Abstract])) OR (nslc[Title/Abstract])) AND (((cancer[Title/Abstract]) OR (carcino[Title/Abstract])) OR (oncol[Title/Abstract]))) AND (survivin[Title/Abstract])" gave 728 results. After screening the title and abstracts and excluding the review articles 168 titles were shortlisted and full text studied. The discussions are added to relevant sections., Key Content and Findings: Survivin is a cell cycle-dependent, inhibitor of apoptosis protein that contributes to carcinogenesis, tumor vascularization, metastasis, and treatment resistance. Several treatments that impact survivin either directly or indirectly have been reported as effective in treating lung cancer. Immunity-based therapy, a novel approach known for its targeted nature and minimal side effects, is currently under investigation for lung cancer treatment. Emerging survivin-centered vaccines exhibit promising attributes in terms of safety, effectiveness, and ability to stimulate an immune response. These factors point towards a significant potential for advancing the future of lung cancer prevention and enhancing overall survival rates., Conclusions: Nuclear survivin is a potential biomarker for advanced non-small cell lung cancer. It plays a role in determining drug responsiveness and is found to be significantly elevated in cases of resistance to chemotherapy. Multiple compounds and immunization strategies have been identified to impact lung cancer cells; however, they are currently in the early stages of phase I or phase II clinical trials. The substantial promise of survivin-based immunogenicity-focused treatments warrants in-depth investigation and exploration., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-621/coif). S.Y. serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background and Objective: The role of biological sex is seldom considered in characterizing lung cancer, the deadliest cancer in both the United States and the world. Lung cancer has traditionally been regarded as a male disease; as such, research in female-specific phenomena is frequently conflicting or absent. Currently, disparities in lung cancer incidence are primarily driven by females, especially non-smokers and those of younger age. This narrative review provides insight into sex-specific characteristics of lung cancer, highlighting risk factors, diagnosis patterns, carcinogenesis, and treatment outcomes in females., Methods: The PubMed database was searched on July 26, 2023 to identify research published between 2013 and 2023 in English. Sixty-three articles were considered relevant, and their full texts and citations were studied to compile information for this narrative review., Key Content and Findings: Exposure-related risk factors, including personal tobacco use, are thought to impact female lung cancer risk more profoundly. However, studies on occupational exposures are underpowered to conclude risk in females. Data characterizing the effect of endogenous and exogenous hormonal exposures on female lung cancer risk remain two-sided. Screening guidelines are tailored to white males, exacerbating sex and race disparities. The effect of biological sex on carcinogenesis and the immune system response to cancer is not fully understood, though the female immune system clearly reacts more aggressively to lung cancer. In early-stage disease, females have greater survival in the perioperative setting and during follow-up of several years, attributed to favorable histopathology and healthier baseline status. Sex-specific response to systemic treatment continues to be optimized as lack of standardization in randomized trials makes interpreting results difficult when aggregated., Conclusions: Biological sex plays a critical role in non-small cell lung cancer (NSCLC), though further study is needed to depict the complex web of factors that affect lung cancer risk, development, and outcomes. Female underrepresentation in studies has contributed to this lack of understanding. As these disparities are eliminated, we can move towards more effective treatment for both sexes in this pervasive yet deadly disease., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-744/coif). S.Y. is a scientific advisory board member of Karkinos Healthcare, receives grant funding from Lumeda Inc., and serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. The other author has no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Introduction: Survival rates for early-stage non-small cell lung cancer (NSCLC) remain poor despite the decade-long established standard of surgical resection and systemic adjuvant therapy. Realizing this, researchers are exploring novel therapeutic targets and deploying neoadjuvant therapies to predict and improve clinical and pathological outcomes in lung cancer patients. Neoadjuvant therapy is also increasingly being used to downstage disease to allow for resection with a curative intent. In this review, we aim to summarize the current and developing landscape of using neoadjuvant therapy in the management of NSCLC., Methods: The PubMed.gov and the ClinicalTrials.gov databases were searched on 15 January 2023, to identify published research studies and trials relevant to this review. One hundred and seven published articles and seventeen ongoing clinical trials were selected, and relevant findings and information was reviewed., Results & Discussion: Neoadjuvant therapy, proven through clinical trials and meta-analyses, exhibits safety and efficacy comparable to or sometimes surpassing adjuvant therapy. By attacking micro-metastases early and reducing tumor burden, it allows for effective downstaging of disease, allowing for curative surgical resection attempts. Research into neoadjuvant therapy has necessitated the development of surrogate endpoints such as major pathologic response (MPR) and pathologic complete response (pCR) allowing for shorter duration clinical trials. Novel chemotherapy, immunotherapy, and targeted therapy agents are being tested at a furious rate, paving the way for a future of personalized systemic therapy in NSCLC. However, challenges remain that prevent further mainstream adoption of preoperative (Neoadjuvant) therapy. These include the risk of delaying curative surgical resection in scenarios of adverse events or treatment resistance. Also, the predictive value of surrogate markers of disease cure still needs robust verification. Finally, the body of published data is still limited compared to adjuvant therapy. Addressing these concerns with more large scale randomized controlled trials is needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kalvapudi, Vedire, Yendamuri and Barbi.)