Can cell-free DNA (cfDNA) in pleural lavage serve as a predictive and prognostic biomarker among surgically treated Stage I-III a nonsmall cell lung cancer (NSCLC)? A pilot study.

BACKGROUND AND OBJECTIVES: The role of cell-free DNA (cfDNA) in operable nonsmall cell lung cancer (NSCLC) is unclear. This study was aimed to evaluate the feasibility for identification of cfDNA in pleural lavage fluid and its correlation with plasma in resectable NSCLCs. METHODS: Consecutively resected NSCLCs were evaluated for cfDNA levels in preoperative plasma (PLS1), intraoperative pleural-lavage (PLV) and postoperative (at 1 month) plasma sample (PLS2). CfDNA was isolated and measured quantitatively by qPCR in a TaqMan probe-detection approach using the human ß-actin gene as the amplifying target. RESULTS: All (n = 34) except one were negative for malignant cells in PLV cytology. CfDNA could be isolated from all the three samples (PLS1, PLV, and PLS2) successfully in each patient. The median cfDNA levels in PLS1, PLV and PLS2 were 118 ng/mL (IQR 61-158), 167 ng/mL (IQR 59.9-179.9) and 103 ng/mL (IQR 66.5-125.4) respectively. The median follow-up was 34.1 months (IQR 25.2-41.6). A significant overall-survival (OS) and disease-free survival (DFS) were recorded for patients with cfDNA level cut-offs at 125, 170, and 100 ng/mL, respectively for PLS1, PLV, and PLS2. Patients with raised cfDNA in PLS1 (>125 ng/mL) and PLV (>170 ng/mL) had significantly poorer 2-year OS, p = 0.005 and p = 0.012, respectively. The hazards (OS) were also higher for those with raised cfDNA in PLV (HR = 5.779, 95% CI = 1.162-28.745, p = 0.032). PLV (>170 ng/mL) had increased pleural recurrences (p = 0.021) and correlated significantly with poorer DFS at 2-years (p = 0.001) with increased hazards (HR = 9.767, 95% CI = 2.098-45.451, p = 0.004). Multivariable analysis suggested higher cfDNA in PLV as a poor prognostic factor for both OS and DFS. CONCLUSIONS: Among patients with operable NSCLC, it is feasible to identify cfDNA in pleural lavage and correlate PLV cfDNA with pleural recurrences and outcomes.

Retrospective application of WHO reporting system for lung cytopathology with assessment of risk of malignancy.

INTRODUCTION: The recently introduced World Health Organization (WHO) Reporting System for Lung Cytopathology presents 5 diagnostic categories with corresponding risk of malignancy (ROM) and management protocols. This study uses the system to categorize our institutional respiratory tract cytology specimens, evaluating ROM and diagnostic accuracy for each category. MATERIALS AND METHODS: In a retrospective analysis (May 2020 to August 2021), the following respiratory cytology specimens were classified based on the WHO categories: bronchoalveolar lavage (BAL), bronchial wash/bronchial brushings (BB/BW), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), fine-needle aspiration cytology (FNAC), sputum, biopsy imprint (BI), and endotracheal wash. Exclusions comprised pleural effusions and EBUS-TBNA from mediastinal and hilar lymph nodes. Correlation of cytologic and histopathologic diagnoses was performed to assess ROM collectively and individually. RESULTS: A total of 1518 respiratory samples (BAL [968], BW/BB [380], EBUS-TBNA [42], FNAC [32], sputum [80], BI [11] and endotracheal wash [5]) of 1410 patients were screened, of which 522 cases (34.3%) had histopathologic correlation. One hundred forty-one cases (9.3%) were Insufficient/Inadequate/Non-Diagnostic (ND), 1221 (80.4%) were Benign (B), 3 (0.2%) were Atypical (A), 32 (2.1%) were Suspicious for malignancy (SM) and 121 (8.0%) were Malignant (M). The estimated ROM for each category was 49.2% for ND, 13.3% for B, 66.6% for A, 81.5% for SM and 92.7% for M. FNAC and EBUS-TBNA exhibited the highest sensitivity (100%) compared with BW/BB (66.3%). Specificity ranged from 96.8% to 100% across the samples, while diagnostic accuracy varied from 58.8% to 100%. CONCLUSIONS: Application of the WHO reporting system enhances standardized terminology, aiding clinicians in informed decision-making and improving patient care through accurate risk assessment of malignancy.

Pulmonary Mucoepidermoid Carcinoma Mimicking Carcinoid Lung on 18 F-FDG and 68 Ga-DOTANOC PET/CT.

ABSTRACT: Pulmonary mucoepidermoid carcinoma (PMEC) is a rare pulmonary neoplasm. Although 18 F-FDG PET/CT has been shown to present with increased metabolic activity in PMEC, literature does not report increased somatostatin receptor expression in these tumors. We present the case of a 15-year-old boy where PMEC mimicked a typical carcinoid of the lung on DOTANOC PET/CT by showing significant uptake on 68 Ga-DOTANOC.

Concordance of Immunohistochemistry and Fluorescence In Situ Hybridization in the Detection of Anaplastic Lymphoma Kinase (ALK) and Ros Proto-oncogene 1 (ROS1) Gene Rearrangements in Non-Small Cell Lung Carcinoma: A 4.5-Year Experience Highlighting Challenges and Pitfalls.

CONTEXT.­: ALK and ROS1 rearrangements are essential biomarkers to be tested in advanced lung adenocarcinomas. While D5F3 Ventana assay is a companion diagnostic for anaplastic lymphoma kinase-targeted therapy, immunohistochemistry is only a screening tool for detecting ROS1 rearrangement. Confirmation by cytogenetic or molecular techniques is necessary. OBJECTIVE.­: To evaluate the utility of ALK and ROS1 fluorescence in situ hybridization as a complement to immunohistochemistry in routine predictive biomarker testing algorithms. DESIGN.­: The study was ambispective, spanning 4.5 years during which lung adenocarcinoma samples were subjected to EGFR mutation testing by real-time polymerase chain reaction, and ALK/ROS1 rearrangement testing by immunohistochemistry (Ventana D5F3 assay for anaplastic lymphoma kinase protein; manual assay with D4D6 clone for Ros proto-oncogene 1 protein). Fluorescence in situ hybridization was performed in all anaplastic lymphoma kinase equivocal and Ros proto-oncogene 1 immunopositive cases. RESULTS.­: Of 1874 samples included, EGFR mutations were detected in 27% (481 of 1796). Anaplastic lymphoma kinase immunohistochemistry was positive in 10% (174 of 1719) and equivocal in 3% (58 of 1719) of samples tested. ALK fluorescence in situ hybridization showed 81% (77 of 95) concordance with immunohistochemistry. Ros proto-oncogene 1 immunopositivity was noted in 13% (190 of 1425) of cases, with hybridization-confirmed rearrangements in 19.3% (26 of 135) of samples, all of which showed diffuse, strong- to moderate-intensity, cytoplasmic staining in tumor cells. Ros proto-oncogene 1 protein overexpression without rearrangement was significantly common in EGFR-mutant and ALK-rearranged adenocarcinomas. CONCLUSIONS.­: Immunostaining is a robust method for ALK-rearrangement testing, with fluorescence in situ hybridization adding value in the rare equivocal stained case. ROS1-rearrangement testing is more cost-effective if immunohistochemistry is followed by fluorescence in situ hybridization after excluding EGFR-mutant and ALK-rearranged adenocarcinomas.

Neurosarcoidosis: The Pan-Neurology Disease.

Neurosarcoidosis (NS) is a protean illness with multiple clinical and radiological presentations giving it the moniker of "a chameleon" or the great mimic. NS can present as a wide spectrum of neurological syndromes localizing both to the central and peripheral nervous systems. The absence of a diagnostic serum test makes it difficult to diagnose with certainty and remains largely a histopathological diagnosis and one of exclusion. A high index of suspicion should be there in suspecting NS, and it should always be excluded among patients presenting with acute to subacute neurological deficits.

Dataset for reporting of thymic epithelial tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Thymic epithelial tumours (TET), including thymomas and thymic carcinomas and thymic neuroendocrine neoplasms, are malignant neoplasms that can be associated with morbidity and mortality. Recently, an updated version of the World Health Organization (WHO) Classification of Thoracic Tumours 5th Edition, 2021 has been released, which included various changes to the classification of these neoplasms. In addition, in 2017 the Union for International Cancer Control (UICC) / American Joint Committee on Cancer (AJCC) published the 8th Edition Staging Manual which, for the first time, includes a TNM staging that is applicable to thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. METHODS AND RESULTS: To standardize reporting of resected TET and thymic neuroendocrine neoplasms the accrediting bodies updated their reporting protocols. The International Collaboration on Cancer Reporting (ICCR), which represents a collaboration between various National Associations of Pathology, updated its 2017 histopathology reporting guide on TET and thymic neuroendocrine neoplasms accordingly. This report will highlight important changes in the reporting of TET and thymic neuroendocrine neoplasms based on the 2021 WHO, emphasize the 2017 TNM staging, and also comment on the rigour and various uncertainties for the pathologist when trying to follow that staging. CONCLUSION: The ICCR dataset provides a comprehensive, standardized template for reporting of resected TET and thymic neuroendocrine neoplasms.

Three Dimensional Evaluation of Accuracy of Bracket Positioning.

Introduction: The success of orthodontic treatment depends on accurate bracket placement, so researchers are constantly exploring new direct and indirect bonding methods with the help of cutting-edge imaging technologies like cone beam computed tomography (CBCT), which provides full three-dimensional visualization of tissues down to the root of the tooth. Aim: The primary goals of this analysis are to determine the degree of section angulation and adhesive thickness, as well as the accuracy of the vertical and flat section positions. The correlation between total clinical crown height, minor edge to focus of section, and minimum edge to complete curve crown length is one of several possible goals of this investigation (FACC). Materials and Methods: Currently, 10 patients aged 15-30 who needed fixed appliance treatment were enrolled in an in vivo research conducted by the orthodontics department. Cases with and without extractions of the crooked teeth were counted. Full mouth analysis is being used in this investigation. Ten patients were selected at random and placed in either Group A (the study group) or Group B (the control group) (control group). Group A bonds are more indirect, whereas group B bonds are more like "normal" direct bonds. We used a Canon 700D camera, a biocompatible transparent 3D printing resin, and a 3M Gemini MBT.022 in bracket kit for CT scanning and imaging. Brackets are placed by experienced orthodontists in both treatment groups. Result: There is a statistically significant (P 0.05) difference between the indirect and direct bonding group when all five factors are taken into account, with the indirect bonding group demonstrating superiority in terms of accuracy. Conclusion: The results of the current investigation support the premise that there is a clinically significant difference between direct bonding and 3D indirect bonding in terms of bracket placement accuracy.

Identification of molecular biomarkers associated with non-small-cell lung carcinoma (NSCLC) using whole-exome sequencing.

OBJECTIVES: Significant progress has been made in the treatment of patients with pulmonary adenocarcinoma (ADCA) based on molecular profiling. However, no such molecular target exists for squamous cell carcinoma (SQCC). An exome sequence may provide new markers for personalized medicine for lung cancer patients of all subtypes. The current study aims to discover new genetic markers that can be used as universal biomarkers for non-small cell lung cancer (NSCLC). METHODS: WES of 19 advanced NSCLC patients (10 ADCA and 9 SQCC) was performed using Illumina HiSeq 2000. Variant calling was performed using GATK HaplotypeCaller and then the impacts of variants on protein structure or function were predicted using SnpEff and ANNOVAR. The clinical impact of somatic variants in cancer was assessed using cancer archives. Somatic variants were further prioritized using a knowledge-driven variant interpretation approach. Sanger sequencing was used to validate functionally important variants. RESULTS: We identified 24 rare single-nucleotide variants (SNVs) including 17 non-synonymous SNVs, and 7 INDELs in 18 genes possibly linked to lung carcinoma. Variants were classified as known somatic (n= 10), deleterious (n= 8), and variant of uncertain significance (n= 6). We found TBP and MPRIP genes exclusively associated with ADCA subtypes, FBOX6 with SQCC subtypes and GPRIN2, KCNJ18 and TEKT4 genes mutated in all the patients. The Sanger sequencing of 10 high-confidence somatic SNVs showed 100% concordance in 7 genes, and 80% concordance in the remaining 3 genes. CONCLUSIONS: Our bioinformatics analysis identified KCNJ18, GPRIN2, TEKT4, HRNR, FOLR3, ESSRA, CTBP2, MPRIP, TBP, and FBXO6 may contribute to progression in NSCLC and could be used as new biomarkers for the treatment. The mechanism by which GPRIN2, KCNJ12, and TEKT4 contribute to tumorigenesis is unclear, but our results suggest they may play an important role in NSCLC and it is worth investigating in future.

Guidelines for endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA): Joint Indian Chest Society (ICS)/Indian Association for Bronchology (IAB) recommendations.

Over the past decade, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become an indispensable tool in the diagnostic armamentarium of the pulmonologist. As the expertise with EBUS-TBNA has evolved and several innovations have occurred, the indications for its use have expanded. However, several aspects of EBUS-TBNA are still not standardized. Hence, evidence-based guidelines are needed to optimize the diagnostic yield and safety of EBUS-TBNA. For this purpose, a working group of experts from India was constituted. A detailed and systematic search was performed to extract relevant literature pertaining to various aspects of EBUS-TBNA. The modified GRADE system was used for evaluating the level of evidence and assigning the strength of recommendations. The final recommendations were framed with the consensus of the working group after several rounds of online discussions and a two-day in-person meeting. These guidelines provide evidence-based recommendations encompassing indications of EBUS-TBNA, pre-procedure evaluation, sedation and anesthesia, technical and procedural aspects, sample processing, EBUS-TBNA in special situations, and training for EBUS-TBNA.

Evaluation of high-risk human papillomavirus in sinonasal papillomas and squamous cell carcinomas.

The sinonasal tract is considered a second hotspot for human papillomavirus (HPV)-related tumors in the head and neck, with HPV being identified in up to 62% of squamous cell carcinomas (SCCs) and 38% of papillomas. There is limited data from geographical regions with low prevalence of high-risk (HR)-HPV on the association of HR-HPV in sinonasal neoplasms and on utility of p16 as a surrogate marker. p16 immunohistochemistry, HR-HPV mRNA ISH and quantitative real-time PCR (qPCR) were performed on a retrospective cohort of sinonasal papillomas and SCCs. KRAS mutation analysis was done in oncocytic papillomas. p16 positivity was present in 22/142 cases (15.5%) including eight inverted papillomas, one oncocytic papilloma (OP), and 13 SCC. Among these, mRNA ISH showed HR-HPV in the OP and two SCC, while another SCC was found to harbour HPV18 by qPCR. Two HPV-associated SCCs had foci of OP. mRNA ISH was negative in all p16 negative cases. p16 immunohistochemistry showed 68% concordance with mRNA ISH, and had sensitivity and negative predictive value of 100%; specificity was 67%, and positive predictive value was 14.3%. Association with HR-HPV in sinonasal papillomas and SCC is rare, and may be seen in cases demonstrating oncocytic morphology. p16 immunohistochemistry has low specificity and positive predictive value in low-prevalence populations; thus, reflex direct HR-HPV testing should be performed in p16 immunopositive cases. This two-step approach is viable in resource-limited settings, as the proportion of p16 positive cases is small.

Cytomorphology of paediatric hepatocellular carcinoma: A useful diagnostic adjunct.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC. METHODS: Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping. RESULTS: Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases. CONCLUSIONS: Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.

A brief review of the WHO reporting system for lung cytopathology.

The International Academy of Cytology has joined with the International Agency for Research on Cancer to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians, and improve patient care. The WHO System describes 5 categories for reporting lung cytopathology: 'Insufficient/Inadequate/Nondiagnostic', 'Benign', 'Atypical', 'Suspicious for malignancy', and 'Malignant', each one with a clear descriptive term, a definition, a risk of malignancy, and a suggested management algorithm. The key diagnostic cytopathologic features of each of the lesions within each category have been established by consensus through an Expert Editorial Board, who are also the authors of this review and selected for each reporting system and chosen based on their expertise in the field and/or diversity of geographical representation. Many other co-authors from around the world also contributed. The assignment of writing and editing responsibilities used the same model as that used for the WHO Classification of Tumours (https://whobluebooks.iarc.fr/about/faq/). The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and guides in sampling and processing techniques to optimize the handling and preparation of specimens. The WHO System was created by the authors to be applicable globally and is based on cytomorphology with possibilities for additional diagnostic management of the patient. The authors are aware that local medical and pathology resources would differ, especially in low- and middle-income countries. The WHO Tumour Classification for Thoracic Tumors, Fifth Edition, is directly accessible through the online WHO System.

Immunohistochemical Analysis of the Expression of Cytokeratins in Acquired Cholesteatoma and Its Clinico-Radiological Correlation.

BACKGROUND AND OBJECTIVES: Cholesteatomatous chronic otitis media acquires epithelial proliferation and differentiation characteristics, which render it able to erode the underlying bone and cause complications. We attempt to characterize the cholesteatoma epithelium by observing the expression of cytokeratins (such as 34ße12, CK17, and CK13) and Ki67 among patients with cholesteatoma with different aggressiveness as compared to disease-free controls. Subjects and. METHODS: In this prospective study (2017-2021), we enrolled all consenting consecutive patients with cholesteatomatous chronic otitis media. They were staged in accordance with the staging guidelines of the European Academy of Otology and Neurotology and the Japanese Otological Society. Bony external auditory canal (EAC) skin specimens of the patients undergoing tympanoplasty were chosen as controls. We did an immunohistochemical analysis of the cholesteatoma specimens and normal bony EAC controls by observing the expression of 34ße12, CK17, CK13, and Ki67 across the layers of the epithelium. Fisher's exact test and chi-square test were used to evaluate any statistical significance between the cases and the controls, and the subgroups were made based on the clinical stage. RESULTS: An increased expression of CK17 (p<0.001), CK13 (p<0.03), and Ki67 (p<0.001) was observed in cholesteatoma specimens when compared to normal bony EAC controls. Also, there was a loss of expression of 34ße12 in a subset of cholesteatoma specimens, all of which showed full-thickness expression of CK13. There was no difference in the expression of cytokeratin among specimens from patients belonging to different subgroups based on clinical stage, age, sex, duration of ear symptoms, or type of hearing loss (conductive vs. sensorineural). CONCLUSIONS: The majority of cholesteatoma specimens significantly overexpressed CK17, CK13, and Ki67 when compared to normal bony EAC skin controls, while a subset showed loss of expression of 34ße12, which provides some insight into its pathogenesis.

Mapping the immune landscape in small cell lung cancer by analysing expression of immuno-modulators in tissue biopsies and paired blood samples.

Small cell lung carcinomas (SCLC) are aggressive tumors with high propensity to metastasize. Recent NCCN guidelines have incorporated immunotherapy in extensive stage SCLC. Limited benefit in few patients compounded by side effects of unwonted immune-checkpoint-inhibitor (ICPI) usage necessitates identification of potential biomarkers predicting response to ICPIs. Attempting this, we analysed expression of various immunoregulatory molecules in tissue biopsies and paired blood samples of SCLC patients. In 40 cases, immunohistochemistry for expression of immune inhibitory receptors CTLA-4, PD-L1 and IDO1 was performed. Matched blood samples were quantified for IFN-γ, IL-2, TNF-α and sCTLA-4 levels using immunoassay and additionally for IDO1 activity (Kynurenine/Tryptophan ratio) using LC-MS. Immunopositivity for PD-L1, IDO1 and CTLA-4 was identified in 9.3%, 6.2% and 71.8% cases, respectively. Concentration of serum IFN-γ (p-value < 0.001), TNF-α (p-value = 0.025) and s-CTLA4 (p-value = 0.08) were higher in SCLC patients while IL-2 was lower (p-value = 0.003) as compared to healthy controls. IDO1 activity was significantly elevated in SCLC cohort (p-value = 0.007). We proffer that SCLC patients show immune suppressive milieu in their peripheral circulation. Analysis of CTLA4 immunohistochemical expression along with s-CTLA4 levels appears prospective as biomarkers for predicting responsiveness to ICPIs. Additionally, evaluation of IDO1 appears cogent both as prognostic marker and potential therapeutic target as well.

Significance of Clinico-radiological Correlation in a Patient with Pulmonary Intimal Sarcoma Simulating as Pulmonary Thromboembolism.

Pulmonary intimal sarcoma (PAS) is a highly aggressive malignant mesenchymal tumor affecting the central pulmonary arteries. Similar clinical presentation and indeterminate laboratory parameters often result in misdiagnosis of this condition as pulmonary thromboembolism, which is a relatively common disease. Certain imaging features can however allow differentiation between these two diagnoses. We present one such case of PAS that was initially treated as pulmonary embolism; and briefly review the relevant imaging characteristics to avoid overlooking PAS especially in patients with an atypical clinical history for thromboembolism.

Fine needle aspiration cytology of metastatic SMARCA4-deficient sinonasal teratocarcinosarcoma: First report in literature.

Inactivating mutations of SMARCA4 and accompanying loss of BRG1 immunoexpression were recently identified in majority of sinonasal teratocarcinosarcomas (TCS). These rare and aggressive neoplasms have potential for nodal metastasis, presenting opportunities for diagnosis on fine needle aspiration cytology (FNAC). However, their cytological features have not been described till date. A 22-year-old male was diagnosed to have SMARCA4-deficient TCS on a nasal mass biopsy, and was started on neoadjuvant chemotherapy. Four months later, FNAC from cervical lymph nodes showed predominantly discohesive tumor cells with moderate to abundant cytoplasm and enlarged vesicular nuclei with prominent nucleoli. Occasional cohesive fragments showed ovoid to spindled tumor cells attached to fibrovascular cores. Few loosely cohesive cells with scant cytoplasm and nuclei having stippled chromatin, and rhabdoid cells were also seen. Frequent mitoses, apoptosis and nuclear streaking were evident. Overt squamous or glandular differentiation was absent. Tumor cells showed loss of BRG1 immunostaining and ß-catenin immunopositivity on a cell block, consistent with metastatic SMARCA4-deficient TCS. The diversity of cell types in SMARCA4-deficient TCS can result in a broad spectrum of cytological features that overlap with that of other regional metastatic tumors including neuroendocrine carcinoma, olfactory neuroblastoma and melanoma. Further, all components of TCS as seen in the primary tumor may not be present in nodal metastases. Thus, SMARCA4-deficient TCS should be considered in the differential diagnosis of metastatic poorly/undifferentiated malignancies in cervical lymph node aspirates, and appropriate ancillary tests viz. BRG1 immunostaining employed for accurate diagnosis.

Lung cancer in Asian Indian females: Identification of disease-specific characteristics and outcome measures over a 12-year period.

Aim: Globally, the incidence of lung cancer amongst women appears to be increasing. We aimed to compare the socio-epidemiological and clinical characteristics of lung cancer amongst men and women from a large cohort at a tertiary care hospital in Northern India. Methods: Records of patients diagnosed with lung cancer between January 2008 and March 2020 were reviewed. Baseline epidemiological data, clinical characteristics, histologic profiles, treatment administered, and survival were compared between males and females. Results: A total of 2054 male and 438 female patients were included in analysis. Compared to males, female patients were younger [median age, 56 vs. 60 years, P < 0.001)], less likely to be working, less educated beyond secondary level and less likely to be smokers (29.1% vs. 84.9%, P < 0.0001). No difference in baseline performance status was observed. Females were more frequently diagnosed with adenocarcinoma (54.2% vs. 30.2%, P = <0.0001), stage IV disease (70.8% vs. 63%, P = 0.001), and had higher rate of EGFR mutation (37.2% vs. 21.5%, P < 0.0001). There was no difference in the proportion of females receiving cancer-specific therapy. Multivariate Cox proportional hazards model revealed higher progression-free survival [median 9.17 vs. 7.23 months; P = 0.007] and overall survival [median 13.80 vs. 9.10 months respectively, P = 0.001] amongst females compared to males. Conclusion: Amongst a large cohort of lung cancer, females demonstrated several distinct and characteristic demographics as well as disease-related features, especially better survival outcomes.

SMARCA4-deficient Undifferentiated Uterine Sarcoma: Clinicopathological Features of an Emerging Entity.

SMARCA4-deficient undifferentiated uterine sarcoma is a recently described molecularly defined entity among the subset of aggressive undifferentiated uterine tumors. Mutation in the SMARCA4 gene is a key driver alteration, as also seen in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) and thoracic undifferentiated carcinoma. Limited number of cases of SMARCA4-deficient undifferentiated uterine sarcoma has been reported in literature. We hereby describe a case of this distinct entity in a 52-year-old woman. Histomorphological examination showed sheets of monomorphic epithelioid cells with a variable proportion of cells displaying rhabdoid features, brisk mitotic activity, and lymphovascular invasion. A panel of immunohistochemical markers was required to exclude the differential diagnoses. The tumor was microsatellite stable. Loss of SMARCA4 expression and intact expression of INI1 in tumor cells by immunohistochemistry (IHC) confirmed the diagnosis of SMARCA4- deficient undifferentiated uterine sarcoma. The patient had a rapidly progressive clinical course.

Prevalence of highly actionable mutations among Indian patients with advanced non-small cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality in India. To clarify rates of actionable mutations, and thereby identify opportunities to improve the delivery of best available care for a large volume of patients, a comprehensive review of available data is warranted. METHODS: Studies that reported prevalence of any actionable gene variant among adult Indian patients with advanced NSCLC were selected from three databases (PubMed, EMBASE, and Cochrane Library). Ranges in actionable variant prevalence were reported. Meta-analysis of proportions was completed among studies specifically evaluating mutational prevalence within ALK or EGFR. Sensitivity analyses were undertaken among populations sharing high heterogeneity. RESULTS: Twenty-six studies were selected. Ranges in actionable mutational prevalence among NSCLC patients were as follows: ALK: 4.1-21.4%, BRAF: 1.5-3.5%, EGFR: 11.9-51.8%, HER2: 0-1.5%, KRAS: 4.5-6.4%, NTRK: 0-.7%, and ROS-1: 3.5-4.1%. Following sensitivity analysis, pooled ALK mutational prevalence rates were 8.3% (95% CIs: 6.6-10.4%) and 4.01% (95% CIs: 2.3-7.0) for adenocarcinoma and NSCLC patients, respectively. Pooled EGFR mutational prevalence rates were 28.7% (95% CIs: 23.5-34.6%) and 24.2% (95% CIs: 19.9-29.1%) for adenocarcinoma and NSCLC patients, respectively. CONCLUSIONS: Nearly 40% of Indian patients with advanced adenocarcinoma and 30% with NSCLC share an actionable mutation in ALK or EGFR. Approximately one-half of adenocarcinoma patients have an actionable variant. Efforts should be directed toward efficiently identifying candidates for targeted agents and delivering such treatments.

When "No-Smoking" is not enough: Hypoxia and nicotine acetylcholine receptor signaling may drive lung adenocarcinoma progression in never-smokers.

The question of how lung cancer progresses in never-smokers remains largely unanswered. In our analysis of data from 1727 lung cancer patients, we observed a difference of only 47 days in the overall survival between lung adenocarcinoma patients who were smokers vis-a-vis never-smokers - the disease has a poor prognosis irrespective of the smoking status, or gender. We have investigated the possible collaboration between the nAChR and hypoxia signaling pathway to explicate a mechanism of disease progression in never-smokers using patient-derived tumor cells. We found a previously unidentified increase in both acetylcholine and nAChR-α7 levels in non-small cell lung cancer cells in hypoxia. A similar increase in ubiquitously expressed nAChR-α7 transcripts was also observed in other cancer lines and primary tumor tissues. A direct binding of HIF-1α with the hypoxia-response element (HRE) present at -48 position preceding the transcriptional start site in nAChR-α7 promoter region was established. Crucially, the increased acetylcholine levels in hypoxia drove a feedback loop via modulation of PI3K/AKT pathway to stabilize HIF-1α in hypoxia. Further, hypoxia-mediated metastasis and induction of HIF-1α in these cells was significantly reversed by bungarotoxin, an antagonist of nAChR-α7. The nAChR-AKT-HIF network needs to be further investigated to conclusively prove its mechanism and to explore its therapeutic potential. Our study gives a plausible explanation for the equally worse prognosis of lung adenocarcinoma in never-smokers wherein the nAChR signaling is enhanced in hypoxia by acetylcholine in the absence of nicotine.