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Purpose: Standard-dose immune checkpoint inhibitors (SD-ICIs) are the standard of care as initial therapy in microsatellite instable-high (MSI-H) advanced/metastatic colorectal adenocarcinomas (mCRC), but there are preclinical data to suggest that low-dose ICIs (LD-ICI) might also have similar efficacy., Materials and Methods: A retrospective study of patients with MSI-H mCRC receiving ICIs between June 2017 and January 2023 was conducted. The primary end point of the study was 12-month progression-free survival (PFS), which was computed using the Kaplan-Meier method., Results: A total of 65 patients were available for analysis during the study period. Sixty patients (92%) received nivolumab, whereas the remaining received pembrolizumab. First-line ICIs were received by 18 patients (28%), whereas 47 patients (72%) received ICIs during later lines. Thirty patients (47%) received LD-ICIs (all received nivolumab), with the remaining receiving SD-ICIs (53%). At a median follow-up of 16.5 (95% CI, 11.8 to 21.2) months, median PFS was not reached in the entire cohort. The 12-month PFS rate in the LD-ICI cohort was 90%, whereas it was 75.8% in the SD-ICI cohort. There were no statistical differences in patients receiving ICIs as first-line therapy (12 months PFS-94.4%) or during later lines of therapy (12-month PFS-77.9%; P = .56)., Conclusion: ICIs in the current study show survivals which are similar to those seen in seminal trials in patients with MSI-H mCRC. Low-dose ICIs appear to work in MSI-H mCRC and should be explored prospectively in clinical trials. Patients with MSI-H status should be exposed to ICIs, whether initially or later during treatment, whenever feasible.

Lung cancer varies between Caucasians and Asians. There have been differences recorded in the epidemiology, genomics, standard therapies and outcomes, with variations according to the geography and ethnicity which affect the decision for optimal treatment of the patients. To better understand the profile of lung cancer in Southeast Asia, with a focus on India, we have comprehensively reviewed the available data, and discuss the challenges and the way forward. A substantial proportion of patients with lung cancer in Southeast Asia are neversmokers, and adenocarcinoma is the common histopathologic subtype, found in approximately a third of the patients. EGFR mutations are noted in 23-30% of patients, and ALK rearrangements are noted in 5-7%. Therapies are similar to global standards, although access to newer modalities and molecules is a challenge. Collaborative research, political will with various policy changes and patient advocacy are urgently needed., Competing Interests: Dr. Vanita Noronha has received institutional research funding from AstraZeneca Pharma India Ltd, Glenmark, Nanobiotix SA, Novartis, and Roche Products (India) Pvt. Ltd. All research grants have been paid to the institution. Dr. Kumar Prabhash has received institutional research funding from Pfizer, Roche Products (India) Pvt. Ltd., and Alkem. All research grants have been paid to the institution., (© 2024 The Authors.)

Objective: Sporadic optic chiasmatic-hypothalamic gliomas (OCHGs), though histologically low-grade tumors, manifest as aggressive neoplasms radiologically, leading to difficulty in diagnosis. Molecular alterations of the BRAF gene are detectable in a majority of sporadic OCHGs. The purpose of our study was to elucidate the characteristic imaging features of sporadic OCHGs and to investigate whether imaging phenotypes could potentially correlate with specific BRAF gene alterations associated with these tumors., Methods: We retrospectively reviewed baseline magnetic resonance (MR) images and medical records of 26 patients with histopathologically proven sporadic OCHGs. MR imaging (MRI) features were systematically evaluated. Statistical analysis was performed to determine whether there was a significant association between imaging findings and BRAF molecular alterations., Results: Twenty-two cases (84.6%) presented with solid-cystic masses, while four (15.4%) presented with purely solid lesions. In all 26 cases, the solid component revealed central necrosis; there was minimal necrosis in 11 cases (42.3%), moderate in 8 (30.7%), and marked in 7 (26.9%). The presence of multiple cysts (>4) and minimal necrosis showed a significant association with BRAFV600E mutation (P < 0.005). Marked necrosis in the solid component significantly correlated with BRAF wild genotype (P < 0.001). The presence of a single peripheral cyst significantly correlated with BRAF fusion (P = 0.04)., Conclusion: Sporadic OCHGs have a distinctive appearance on imaging. The solid-cystic composition coupled with varying degrees of central necrosis are clues to the radiological diagnosis of this entity and can facilitate early recognition in clinical practice. Imaging could potentially serve as a non-invasive predictor of the BRAF alteration status, thereby serving as a prognostic marker and guiding personalized management., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

Background: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ)., Methods: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue., Results: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations., Conclusion: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944)., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Circulating tumor cells are a promising biomarker in many malignancies. CTC dissemination during the operative procedure can lead to disease recurrence. The effect of preoperative transarterial embolization on the release of CTCs and miRNA panels and oncological outcomes in large hepatocellular carcinomas has been evaluated., Materials and Methods: The study included non-metastatic HCC >5 cm in size, that were completely resected after TAE (n = 10). Blood was collected pre-TAE, post-TAE, postoperative (day 2,30 and 180) and analyzed for the presence of CTC and miRNA (miR-885-5p, miR-22-3p, miR-642b-5p). The samples were subjected to CTC enrichment, isolation and staining using the markers CD45, EpCAM, and cytokeratin (CK). The data was analyzed using Gene Expression Suite software., Results: The CTC enumeration resulted in three groups: Group 1- CTC present at both pre-TAE and postoperative day 30 (n = 4), Group 2- CTC present at pre-TAE and clearing at postoperative day 30 (n = 2), Group 3- No CTC detected at any stages (n = 3). Group 2 patients had better survival compared with the other groups. Downregulation of miRNA 22-3p also had favorable prognostic implications., Conclusion: Although preoperative TAE does not seem to impact CTC shedding, CTC clearance may prove to be a valuable biomarker in prognosticating HCC. A larger study to evaluate the significance of CTCs as a prognostic marker is warranted to further evaluate these findings., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V.)

Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix-related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers., Implications: Surgery deregulates hallmarks of cancer in human tissue., (©2024 The Authors; Published by the American Association for Cancer Research.)

Management of lung cancer today obligates a mutational analysis of the epidermal growth factor receptor (EGFR) gene particularly when Tyrosine Kinase Inhibitor (TKI) therapy is being considered as part of prognostic stratification. This study evaluates the performance of automated microfluidics-based EGFR mutation detection and its significance in clinical diagnostic settings. Formalin-fixed, paraffin-embedded (FFPE) samples from NSCLC patients (n = 174) were included in a two-phase study. Phase I: Validation of the platform by comparing the results with conventional real-time PCR and next-generation sequencing (NGS) platform. Phase II: EGFR mutation detection on microfluidics-based platform as part of routine diagnostics workup. The microfluidics-based platform demonstrates 96.5% and 89.2% concordance with conventional real-time PCR and NGS, respectively. The system efficiently detects mutations across the EGFR gene with 88.23% sensitivity and 100% specificity. Out of 144 samples analysed in phase II, the platform generated valid results in 94% with mutation detected in 41% of samples. This microfluidics-based platform can detect as low as 5% mutant allele fractions from the FFPE samples. Therefore the microfluidics-based platform is a rapid, complete walkaway, with minimum tissue requirement (two sections of 5 μ thickness) and technical skill requirement. The method can detect clinically actionable EGFR mutations efficiently and can be considered a reliable diagnostic platform in resource-limited settings. From receiving samples to reporting the results this platform provides accurate data without much manual intervention. The study helped to devise an algorithm that emphasizes effective screening of the NSCLC cases for EGFR mutations with varying tumour content. Thus it helps in triaging the cases judiciously before proceeding with multigene testing., (© 2024 Company of the International Journal of Experimental Pathology (CIJEP).)

Objective: To investigate the prosthetic parameters, clinical indices, crestal bone levels, and inflammatory biomarkers in peri-implant crevicular fluid as influenced by two different implant restorative materials i.e., metal ceramic and monolithic zirconia at baseline, 1 Year and 2 Years., Materials and Methods: Twenty patients with bilateral implants placed in the same arch were selected. Monolithic zirconia (4Y-PSZ) crown was placed on one side whereas a metal ceramic (M C) crown was inserted on the contralateral side after randomization. Interproximal marginal bone level (MBL), clinical parameters, MMP-8 levels in PICF, and prosthetic characteristics (as determined by modified USPHS criteria) were evaluated at baseline, 1-year, and 2-year follow-ups. Data were descriptively examined. The results were evaluated using the Chi-Square Test, ANOVA, and student t-test. At p < .05., statistical significance was determined., Results: Twenty MC crowns and twenty Mono-ZrO2 crowns were delivered. A 100% survival of the implants and the prosthetic crowns was achieved across all patients with no instances of failure noted throughout the two-year follow-up period. The periodontal changes observed in the participants were analysed and demonstrated statistically insignificant alterations. Prosthetic alterations were assessed according to USPHS criteria, revealing minor ceramic chippings and instances of screw loosening within the MC group during both the 1- and 2-year follow-up periods. These incidents were collectively categorized as technical issues. Regarding anatomical form and color match to the surrounding dentition, the Mono- ZrO2 crowns obtained much lower evaluations when compared to the M-C crowns. However, when evaluating the loss of marginal bone and level of inflammatory markers there were no discernible variations between the groups., Conclusions: The null hypothesis that there is no similarity in the survival rates and interactions at the peri-implant interface between the two types of restorations was rejected. Both monolithic zirconia and metal ceramic crowns demonstrated no statistical differences across all parameters examined in the present prospective investigation.

Abstract: Synovial sarcoma (SS) is rarely documented in the female genital tract, especially confirmed by molecular testing for SYT::SSX translocation and TLE1 immunostaining. A 62-year-old lady presented with a progressively increasing lump and pain over her right groin, for 6-month duration. Radiologically, a well-defined, solid-cystic mass was seen involving the right labia with necrotic areas, sparing the underlying muscles and the overlying skin. She underwent a biopsy followed by a surgical excision. Histopathologic examination revealed a spindle cell sarcoma, including tumor cells exhibiting a prominent hemangiopericytomatous pattern. There were focal areas of epithelial differentiation (pseudoglandular) along with areas of round cell morphology and increased mitoses (poor differentiation) in the resected specimen. Immunohistochemically, the tumor cells were diffusely positive for TLE1, patchily positive for pan keratin (AE1/AE3) and EMA, the latter more in the areas of epithelial differentiation, while negative for CD34, SMA, desmin, S100P, and SOX10. INI1/SMARCB1 showed a characteristic weak to absent (mosaic) staining pattern. Furthermore, the tumor displayed SS18::SSX 1 fusion by RT-PCR. This constitutes one of the few reported cases of vulvar SS, confirmed by molecular testing and the first documented vulvar SS showing a mosaic pattern of INI1/SMARCB1 immunostaining. A review of the literature and diagnostic implications are presented herewith., (Copyright © 2023 Copyright: © 2023 Indian Journal of Pathology and Microbiology.)

Introduction: CDKN2A/B homozygous deletion is one of the defining features of grade 4 in IDH-mutant astrocytic tumours., Aim: To evaluate CDKN2A/B-deletion in IDH-mutant astrocytic tumours and its clinicopathological impact., Materials and Methods: CDKN2A/B-deletion was evaluated by Fluorescence in-situ hybridisation (FISH) and interpreted by two recently accepted methods., Results: Eighty-three out of 94 cases (histologically-grade 2: 3, grade 3: 46, grade 4: 34) were interpretable on FISH. Concordant CDKN2A/B-deletion was observed in 71% (27/38) of lower-grade tumours (n = 49) and 90% (27/30) of histological grade 4 tumours (n = 34). Both the interpretation methods showed good agreement (Kappa = 0.75). CDKN2A/B-deletion showed an inverse correlation for < 10% MIB-1 labeling index (p = 0.01) while that by method-2 showed a significant correlation for grade 4 (p = 0.02). No significant correlation was observed for any other clinicopathological parameters. Twenty-four patients showed progression/recurrence (including deaths), and no significant difference in frequency of CDKN2A/B deletion was observed among cases with disease progression across different histological grades., Conclusions: CDKN2A/B-deletion was observed across all the histological grades of IDH-mutant astrocytic tumours, expectedly more in the higher grade. FISH, as a method, can be used for the detection of CDKN2A/B homozygous deletion, when there is concordant interpretation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Human epidermal growth factor receptor 2 (HER2) overexpression is seen in 4%-16% of biliary tract cancers (BTCs). We aimed to evaluate the clinical activity of gemcitabine-cisplatin (GC) plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTCs., Methods: This study was an investigator-initiated, open-label, single-arm, multi-institutional, phase II trial in adult patients with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+ and fluorescent in situ hybridization-positive), treatment-naïve BTCs. The primary end point of the study was 6-month progression-free survival (PFS). Next-generation sequencing was performed on tissue samples to evaluate mutational status., Results: From March 2020 to August 2022, of the 876 screened patients, 118 (13.4%) were found to have HER2-positive status, of whom 90 were enrolled in the study. Most patients had GBC (n = 96; 96%) with two or more sites of metastatic disease (n = 70; 78%). With a median follow-up of 17.3 (95% CI, 15.22 to 19.32) months, 72 patients had disease progression with a median PFS of 7 (95% CI, 6.2 to 7.8) months. The diagnosis to event 6-month PFS rate was 75.6% (95% CI, 66.6 to 84.6). A complete or partial response was seen in 50 (55.5%) patients and 22 (24.4%) patients had stable disease as the best response to treatment, for an overall disease control rate of 80%. The presence of isolated TP53 mutations was associated with inferior PFS compared with other mutations (TERT promoter, HER2, PIK3CA, etc) or no detected mutations (6.51 v 12.02 v 10.58 months; P < .001)., Conclusion: The combination of GC and trastuzumab achieved its primary end point of improving PFS compared with historical data in the treatment-naïve HER2-positive BTC. Evaluating additional mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 therapy in the future (Clinical Trial Registry India number: CTRI/2019/11/021955).

Objectives: Kirsten rat sarcoma viral oncogene homologue ( KRAS ) mutations in lung cancers, long considered untargetable, have had a recent rise in interest due to promising data of agents targeting KRAS p.G12C. As Indian data are scarce, we sought to identify baseline clinical characteristics, prognostic factors and outcomes of lung cancer patients with KRAS mutations at our hospital., Methods: Patients with KRAS mutant lung cancers treated at our institute from 2016 to 2022 were analysed., Results: 133 patients with KRAS mutant lung cancers were identified. Median age was 57 (interquartile range 28-78) years, and 58 (43.6%) were smokers. 17 (12.7%) had brain metastases. The commonest variant was p.G12C, seen in 53 (39.8%) patients. Six (4.5%) had programmed death ligand 1 (PDL-1) expression >50% by Ventana SP263 PDL-1 assay, and 13 (9.7%) had epidermal growth factor mutation. Of 92 patients with available treatment details, the majority received intravenous chemotherapy, nine (9.8%) received tyrosine kinase inhibitors and four (4.4%) received immunotherapy (pembrolizumab). Median progression-free survival (PFS) with first-line therapy was 6 (95% confidence interval (CI) 2.8-9.2) months and median overall survival (OS) was 12 (CI 9.2-14.8) months. The incidence of brain metastases was higher in patients with G12C mutations ( p = 0.025). Brain metastases (HR: 3.57, p < 0.001), Eastern Cooperative Oncology Group performance status (PS) ≥ 2 (HR: 2.13, p = 0.002) and G12C mutation (HR: 1.84, p = 0.011) were associated with inferior PFS, while brain metastases (HR: 4.6, p < 0.001), PS ≥ 2 (HR: 2.33, p = 0.001) and G12C mutation (HR: 1.93, p = 0.01) were associated with inferior OS., Conclusion: This is the largest dataset of KRAS mutant lung cancers from India. Brain metastases were higher in patients with G12C mutations and associated with poorer PFS and OS. G12C mutation and PS ≥ 2 were also associated with inferior PFS and OS. Experience with targeted therapy for KRAS mutations remains an area of future exploration due to the unavailability of these agents in India., Competing Interests: There is no conflict of interest to disclose., (© the authors; licensee ecancermedicalscience.)

Introduction: ROS1 as a driver mutation is observed in approximately 1%-2% of all non-small cell lung cancer (NSCLC). Given its rarity, we share our experience regarding ROS1 -positive NSCLC including the access to ROS1 tyrosine kinase inhibitors (TKIs) in a low-middle income country like India., Methods: It is a retrospective analysis of ROS1 -positive NSCLC patients registered between January 2015 to December 2021 for demographics, treatment patterns and outcomes i.e., overall survival (OS) and progression free survival (PFS)., Results: Baseline characteristics were available for 70 patients of 78 patients positive for ROS1 by fluorescent in situ hybridisation. Median age at presentation was 52 years, 39 (55.7%) were males, most (51, 72.86%) were non-smokers and ten patients (14.3%) had poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) i.e., PS >2 at presentation. A total of 67 patients receiving cancer directed therapy were analysed for survival. The first line (1L) therapies included - ROS1 TKIs in 38, chemotherapy in 20, epidermal growth factor receptor TKI in eight and chemotherapy-bevacizumab in one only. ROS1 TKI was provided to 20 patients as part of an assistance programme. The median OS for patients who received ROS1 TKI was not attained (95% CI 37.85-NA), while it was 8.11 (95% CI 6.31-NA) months for those who did not (HR-0.1673). The median PFS for the 1L ROS1 TKI compared to the no-TKI group was 27.07 (95% CI 24.28-NA) months versus 5.78 (95% CI 3.42-12) months (HR: 0.2047). Poor ECOG PS at presentation was the only independent prognosticator for survival., Conclusion: Using ROS1 TKI improves clinical outcomes in all-comers though statistically not significant. To further improve outcomes, future trials should pay special attention to patients with poor PS and find a way to increase the current limited access to TKI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© the authors; licensee ecancermedicalscience.)

Cellular heterogeneity and extracellular matrix (ECM) stiffening have been shown to be drivers of breast cancer invasiveness. Here, we examine how stiffness-dependent crosstalk between cancer cells and mesenchymal stem cells (MSCs) within an evolving tumor microenvironment regulates cancer invasion. By analyzing previously published single-cell RNA sequencing datasets, we establish the existence of a subpopulation of cells in primary tumors, secondary sites and circulatory tumor cell clusters of highly aggressive triple-negative breast cancer (TNBC) that co-express MSC and cancer-associated fibroblast (CAF) markers. By using hydrogels with stiffnesses of 0.5, 2 and 5 kPa to mimic different stages of ECM stiffening, we show that conditioned medium from MDA-MB-231 TNBC cells cultured on 2 kPa gels, which mimic the pre-metastatic stroma, drives efficient MSC chemotaxis and induces stable differentiation of MSC-derived CAFs in a TGFβ (TGFB1)- and contractility-dependent manner. In addition to enhancing cancer cell proliferation, MSC-derived CAFs on 2 kPa gels maximally boost local invasion and confer resistance to flow-induced shear stresses. Collectively, our results suggest that homing of MSCs at the pre-metastatic stage and their differentiation into CAFs actively drives breast cancer invasion and metastasis in TNBC., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Introduction BCOR::CCNB3 -positive undifferentiated sarcomas are rare. Herein, we present clinicopathological features including immunohistochemical and molecular data, along with the radiological profile of 12 such tumors. Methods Tumors were tested for BCOR::CCNB3 fusion by reverse transcription polymerase chain reaction (RT-PCR) technique. Eight tumors were tested for EWSR1 and three for SS18 gene rearrangements by fluorescence in situ hybridization, and two for SS18::SSX fusion by fragment analysis. Results Ten of 12 patients were male with ages ranging between 4 and 17 years (median = 13, average = 14.4). Nine tumors occurred in bones and three in soft tissues (median size = 8 cm). Four of five tumors within the appendicular bones were metadiaphyseal and appeared as permeative lesions, invariably associated with cortical thickening. Three tumors displayed mineralization. Histopathologically, the tumors comprised round to epithelioid cells with round to oval to spindle-shaped nuclei, mostly diffusely arranged in a myxoid stroma with intervening thin-walled vessels. Immunohistochemically, tumor cells were positive for BCOR (10/11), SATB2 (8/9), TLE1 (5/6), cyclinD1 (4/4), and EMA (3/8). All tumors revealed BCOR::CCNB3 fusion transcript. Nine patients underwent neoadjuvant chemotherapy, including five who underwent surgical resection, with two patients, who received adjuvant radiation therapy. A single patient, each, underwent palliative chemotherapy and palliative radiotherapy, respectively. Four patients developed pulmonary metastasis and three developed local recurrences. Four patients were alive-with-disease and two were free-of-disease. Conclusions It is crucial to identify BCOR::CCNB3 fusion-positive sarcomas, given significant treatment-associated implications. Certain clinicoradiological, histopathological features, absent EWSR1 rearrangement and BCOR, SATB2, and TLE1 immunoexpression are useful for triaging these tumors for molecular testing. A review of the literature on these ultra-rare tumors, including their diagnostic mimics is presented., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: At present, the evidence regarding digital impressions' accuracy recorded by using digital scanners is lacking. This systematic review aimed to evaluate whether the type of scanning (intraoral/extraoral) affects the Accuracy of Digital Impressions., Method: Two independent reviewers performed a systematic search in the database both electronically and manually (PubMed, Ebsco HOST, the Cochrane Library, and Google Scholar) for articles published from 1 January 2010 to 1 December 2022. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42020188765) and followed the PRISMA statement. The question in focus was as follows: Does the type of scanning (intraoral or extraoral) affect the accuracy of digital impression?, Results: A total of 449 papers were obtained by searching electronically and manually. In total, 15 complete-text papers qualified for assessment based on eligibility criteria. After reading the full-text articles, five studies were excluded. Ten studies were selected for the qualitative analysis. The qualitative data reported that the accuracy of both types of scanners (intraoral and extraoral) lies within the range of clinical acceptability. Nevertheless, the intraoral scanners seem to be more accurate when compared to the extraoral scanners for a partial arch situation., Conclusions: Scanning type affects the accuracy of the digital impression. Various factors influence the scanning ability. Intraoral scanners seem to be more accurate compared to extraoral scanners for a partial arch situation. More studies comparing the accuracy of the intraoral scanner and extraoral scanner for a complete arch scan and in an in vivo study setting are needed.

Melanotic pigment in the thyroid is practically synonymous with chronic minocycline therapy and rare cases of melanotic medullary thyroid carcinoma. However, primary melanoma of the thyroid has not been reported yet. We report a rare case of a 25-year-old male with a locally aggressive thyroid mass and distant metastases at presentation. Radiologically, a 8.3×7.6-cm nodule was identified in the right thyroid lobe. Fine-needle aspiration cytology (FNAC) showed discohesive atypical plasmacytoid cells with prominent nucleoli and no cytoplasmic pigmentation. Serum calcitonin levels were normal. A trucut biopsy showed a malignant tumor with a similar cytomorphology, including marked nuclear pleomorphism. In addition, intracytoplasmic melanin was seen in <1% of cells. Tumor cells were immunonegative for AE1/AE3, TTF1, synaptophysin, and chromogranin while positive for SOX10, S100P, HMB45, and Melan A, confirming the diagnosis of malignant melanoma, without any detectable MTC component in the biopsy. An HRAS G13R mutation was detected on NGS, which, intriguingly, is a known mutation in MTC, and exceedingly rare in melanocytic lesions. No other clinically or radiologically apparent primary lesion was identified elsewhere in the patient. The unusual histology and hitherto unreported molecular findings make this case of primary thyroid melanocytic neoplasm worth reporting. Abstruse origin of melanoma cells in the thyroid gland with molecular signature suggestive of MTC in our case raises a nomenclature and management conundrum, prompting us to revisit the "ontogeny recapitulates phylogeny" theory., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Molecular Profiling of solid tumours is extensively used for prognostic, theranostic, and risk prediction. Next generation sequencing (NGS) has emerged as powerful method for molecular profiling. The present study was performed to identify molecular alterations present in solid tumours in Indian tertiary cancer centre., Methods: Study included 1140 formalin Fixed paraffin embedded samples. NGS was performed using two targeted gene panels viz. Ampliseq Focus panel and Sophia Solid Tumor Plus Solution. Data was analyzed using Illumina's Local Run Manager and SOPHiA DDM software. Variant interpretation and annotations were done as per AMP/ACMG guidelines., Results: Total 896 cases were subjected to NGS after excluding cases with suboptimal nucleic acid quality/quantity. DNA alterations were detected in 64.9% and RNA fusions in 6.9% cases. Among detected variants, 86.7% were clinically relevant aberrations. Mutation frequency among different solid tumours was 70.8%, 67.4%, 64.4% in non-small cell lung (NSCLC), lung squamous cell carcinomas and head neck tumours respectively. EGFR, KRAS, BRAF, ALK and ROS1were commonly altered in NSCLC. Gastrointestinal tumours showed mutations in 63.6% with predominant alterations in pancreatic (88.2%), GIST (87.5%), colorectal (78.7%), cholangiocarcinoma (52.9%), neuroendocrine (45.5%), gall bladder (36.7%) and gastric adenocarcinomas (16.7%). The key genes affected were KRAS, NRAS, BRAF and PIK3CA. NGS evaluation identified co-occurring alterations in 37.7% cases otherwise missed by conventional assays. Resistance mutations were detected in progressive lung tumours (39.5%) against EGFR TKIs and ALK/ROS inhibitors., Conclusion: This is the largest Indian study on molecular profiling of solid tumours providing extensive information about mutational signatures using NGS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

According to the recent World Health Organization (WHO) classification, CIC-rearranged sarcomas, including CIC::DUX4-positive sarcomas constitute an aggressive subtype of undifferentiated round cell sarcomas. There is a single study on these tumors from our subcontinent. We present clinicopathological features of 5 additional cases of this tumor entity, including literature review. Thirty-nine undifferentiated round cell sarcomas, excluding Ewing sarcomas (ES), were tested for CIC::DUX4 fusion, including Type I (165 base pair size) and II (230 bp) by reverse transcription-polymerase chain reaction. Twenty-five of those tumors were tested for EWSR1 gene rearrangement, 5 for SS18 and 4 for SS18::SSX fusion, and were negative for those tests. Five tumors (12.8 %) were positive for CIC::DUX4(Type II) fusion. Five CIC:: DUX4-positive sarcomas occurred in 4 males and one female; of 25-43 years of age, in soft tissues, including thigh (n = 2), chest wall (n = 1), iliac region (n = 1) and foot (n = 1). Tumor size varied from 2.2 to 19 cm. Microscopically, the tumors were predominantly composed of nodules and sheets of malignant round to epithelioid cells, including "rhabdoid-like" (n = 2) and spindle-shaped (n = 2) with eosinophilic to vacuolated cytoplasm (4/5), distinct nucleoli (4/5), brisk mitoses, focal myxoid to hyalinised stroma (4/5) and necrosis (5/5). Immunohistochemically, tumor cells were positive for WT1 (5/5), calretinin (3/4), pan-keratin (1/4), CD99/MIC2 ("dot-like" to cytoplasmic membranous) (4/4), while negative for desmin (0/4), S100P (0/4), and NKX2.2 (0/5). INI1/SMARCB1 was retained (3/3). All patients underwent excision with adjuvant radiotherapy and chemotherapy (Ewing sarcoma regimen). A single patient developed recurrence, and 2 developed pulmonary metastasis, including one with brain metastasis. CIC:: DUX4-positive sarcomas are ultra-rare tumors, that mainly occur in the soft tissues and in young adult patients. Histopathologically, these tumors display a wide spectrum, including round to epithelioid cells, variable amount of cytoplasmic vacuolization and myxoid stroma with necrosis. Immunohistochemically, these tumors express WT1 and calretinin. Despite adjuvant therapies, these tumors have dismal outcomes, especially in large-sized tumors. CIC::DUX4-positive sarcomas need to be differentiated from their histopathological mimics, including ES, in view of significant treatment-related implications., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

While factors influencing outcomes of rhabdomyosarcoma (RMS) in developed countries have evolved from clinical characteristics to molecular profiles, similar data from developing countries are scarce. This is a single-centre analysis of outcomes in treated cases of RMS, with emphasis on prevalence, risk-migration and prognostic impact of Forkhead Box O1 (FOXO1) in non-metastatic RMS. All children with histopathologically proven RMS, treated between January 2013 and December 2018 were included. Intergroup Rhabdomyosarcoma Study-4 risk stratification was used, with treatment based on a multimodality-regimen with chemotherapy (Vincristine/Ifosfamide/Etoposide and Vincristine/Actinomycin-D/Cyclophosphamide) and appropriate local therapy. Formalin-fixed paraffin-embedded tissues were tested using Reverse Transcriptase-Polymerase Chain Reaction for FOXO1-fusions (PAX3(P3F); PAX7(P7F)). A total of 221 children (Cohort-1) were included, of which 182 patients had non-metastatic disease (Cohort-2). Thirty-six (16%), 146 (66%), 39 (18%) patients were low-risk (LR), intermediate-risk (IR) and high-risk, respectively. FOXO1-fusion status was available in 140 patients with localised RMS (Cohort 3). P3F and P7F were detected in 25/49 (51%) and 14/85 (16.5%) of alveolar and embryonal variants, respectively. The 5-year-event-free survival (EFS)/overall survival (OS) of Cohorts 1, 2 and 3 was 48.5%/55.5%, 54.6%/62.6% and 55.1%/63.7%, respectively. Amongst the localised RMS, presence of nodal metastases and primary tumour size > 10 cms were adverse prognostic factorvs ( p < 0.05). On incorporating fusion-status in risk-stratification, 6/29 (21%) patients migrated from LR (A/B) to IR. All patients who re-categorised as LR (FOXO1 negative) had a 5-year EFS/OS of 80.81%/90.91%. FOXO1-negative tumours had a better 5-year relapse-free survival (58.92% versus 44.63%; p = 0.296) with a near-significant correlation in favourable-site tumours (75.10% versus 45.83%; p = 0.063). While FOXO1-fusions have superior prognostic utility compared to histology alone in localised, favourable-site RMS, traditional prognostic factors (tumour size and nodal metastases) impacted outcome the most in this subset. Strengthening of early referral systems in community and timely local intervention can help in improving outcome in resource-constrained countries., Competing Interests: The authors declare no conflicts of interest influencing the contents on this article., (© the authors; licensee ecancermedicalscience.)

Vaibhavi Vengurlekar Objectives  Malignant melanoma demonstrates frequently occurring mutations of genes in the serine/threonine kinase pathway, namely BRAF, NRAS, and neurofibromin 1. There is rare documentation of a detailed analysis of these mutations in cases of melanoma among Indian patients. We present molecular features in cases of malignant melanoma, diagnosed at a tertiary cancer referral center in India, over a period of 8 years (2011-2018). Materials and Methods  This study was performed on formalin fixed paraffin embedded tissues of 88 histologically confirmed cases of malignant melanoma. BRAF gene alterations were studied by both Sanger sequencing and real-time polymerase chain reaction techniques ( n  = 74). Molecular testing for BRAF and NRAS gene alterations was accomplished in 74/88 cases (80%). Molecular test results were correlated with clinicopathological features using IBM SPSS Statistical software 25.0. Results  The age ranged from 13 to 79 years (median = 57), with a M:F ratio of 1.4:1. BRAF mutations were observed in 12/74 (16.21%) patients, including V600E ( n  = 7), A594T ( n  = 1), T599 = ( n  = 2), V600K ( n  = 1), and Q612P ( n  = 1), while NRAS mutations were observed in 6/38 (15.7%) patients. Among various subtypes, nodular melanoma was the most frequent subtype (33%) among cutaneous malignant melanomas. Among non-cutaneous melanomas, mucosal melanomas were observed in 37.5% of cases. Conclusion  This constitutes one of the few reports on comprehensive analysis of molecular alterations underlying melanomas in Indian patients. A larger sample size, with more extensive molecular markers, would yield additional information on the disease manifestation., Competing Interests: Conflict of Interest None declared., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Introduction: ALK inhibitors are one of the success stories in precision medicine for treating patients with advanced ALK-positive NSCLC. Nevertheless, developing countries have substantial constraints in using ALK inhibitors, with limited data from India., Methods: An audit of a prospectively collected database of patients with advanced ALK-positive NSCLC treated from January 2013 to March 2018 was conducted. The SPSS version 20.0 was used for statistical analysis., Results: A total of 441 patients were available for analysis; 62.5% were males, median age was 50 (range: 19-75) years, and 78.3% had Eastern Cooperative Oncology Group performance status of 0 to 1. When all the lines of therapies were included in the analysis, ALK inhibitors could be used in 379 (85.9%) of the total ALK-positive patients and 292 patients (66.2%) received ALK inhibitors in the first line in any strategy. The major reason for not starting ALK inhibitors upfront was financial constraints in 69% of the patients. The median progression-free survival on first-line therapy for the entire cohort was 14.1 months (95% confidence interval [CI]: 12.2-15.9), with a significant difference between patients receiving ALK inhibitor in first line in any strategy versus not in first line (17.2 mo [95% CI: 14.5-19.9] versus 5.9 mo [95% CI: 4.2-7.6], p  < 0.001). The median overall survival was 30.7 months (95% CI: 27.3-34.2), with 37.6 months (95% CI: 28.1-47.1) for ALK inhibitor in the first line versus 20.5 months (95% CI: 15.8-25.1) for subsequent lines of therapy ( p < 0.001)., Conclusions: Most of our patients with ALK-positive NSCLC were exposed to ALK inhibitors through various support mechanisms. Those patients who could receive ALK inhibitors in the first line had a significant survival advantage as compared with others., (© 2022 The Authors.)

Introduction. Adamantinoma is sub-classified into classic/biphasic, osteofibrous dysplasia-like, and de-differentiated type. We present six adamantinomas with a prominent spindle cell component mimicking intraosseous synovial sarcomas. Methods. Six patients were either referred with a diagnosis of intraosseous synovial sarcoma or wherein synovial sarcoma was a differential diagnosis. Three tumors were tested for SS18 gene rearrangement by FISH and two for SS18::SSX fusion by RT-PCR technique. Results. There were three males and three females with an average age of 20.6 years. Radiologically, the lesions were expansile and showed lytic and/or sclerotic components, involving the cortex and/or medulla. Five lesions occurred in the tibia and two in the fibula. Two tumors displayed soft tissue extension and two occurred as multifocal lesions. Two patients were diagnosed with synovial sarcoma and a single patient with sarcomatoid carcinoma, elsewhere. Two "in-house" patients were initially diagnosed with synovial sarcomas. On review, all tumors were cellular comprising monomorphic spindle-shaped cells arranged in sheets and fascicles (n = 6), including a "herringbone-like" pattern (n = 3), focal tubules (n = 1), cohesive nests (n = 5), cords (n = 2), including pseudocystic component (n = 2). Immunohistochemically, tumor cells were positive for p63 (6/6), p40 (4/4), EMA (2/3), AE1/AE3 (5/6), various keratins (2/2), and TLE1 (2/4). Three tumors tested for SS18 rearrangement were negative, while two tumors tested for SS18::SSX fusion were negative. Conclusions. Adamantinomas with spindle cell morphology display overlapping features with synovial sarcoma. A clinico-radiological index of suspicion immunostains (p63 and p40) and molecular test for t(X; 18) translocation are useful in an exact diagnosis, which has treatment-related implications.

Background: Molecular tests in solid tumours for targeted therapies call for the need to ensure precision testing. To accomplish this participation in the External Quality Assessment Program (EQAS) is required. This evaluates the consistency of diagnostic testing procedures and offers guidance for improving quality. Outbreak of COVID-19 pandemic led to worldwide lockdown and disruption of healthcare services including participation in EQAS.The present study describes the extended scope of EQAS offered byMPQAP (Molecular Pathology Quality Assurance Program), the first proficiency test provider for solid tumor diagnostics in India. The study surveys the preparedness of molecular testing laboratories in routine diagnostics and participation for quality assessment scheme., Methods: A documented guideline for measures and precautions to be carried by testing laboratories in performing routine diagnostic tests during the lockdown period were charted and distributed to all MPQAP participant centres. A survey was conducted for MPQAP participants to check whether laboratories were involved in COVID-19 testing and to evaluate the impact of lockdown on the operations of diagnostics procedures. From the acquired response of the survey, 2 cycles out of initially proposed 11 cycles were executed with transformed approach using digital tools and image interpretation modules., Findings: Out of 25 solid tumour testing laboratories registered as participants, 15 consented to participate in survey. The summary of survey conveyed the impact of COVID-19onroutine operations of diagnostics tests such as shortcomings in inventory and human resource management. Thirteen participants showed active willingness and consented to participate in EQAS test scheme., Interpretations: The survey findings and assessment of EQAS cycles endorsed the quality testing procedures carried by participating laboratories throughout the lockdown. It highlighted the utility of EQAS participation during pandemic along with emphasis on safety measures for continual improvement in quality of diagnostic services., Competing Interests: The authors have declared that no competing interests exist.

Adamantinoma-like Ewing sarcoma (ALES) is a rare malignant tumor characterized by EWSR1::FLI1 related fusions and complex epithelial differentiation. ALES poses a tremendous diagnostic challenge owing to its resemblance to a wide variety of common head and neck malignancies. We aimed to study the clinicopathologic spectrum of ALES diagnosed at our institute. A retrospective review of the clinical and pathologic features of all EWSR1-rearranged ALES cases was performed after confirming the diagnosis. The cases lacking EWSR1 rearrangement were excluded. A total of 7 patients were analyzed. The median age was 27 years (range 7-42 years). There were 4 males and 3 female patients. Tumors were distributed as follows: maxilla (n = 2), parotid (n = 2), nasal cavity (n = 1), ethmoid/maxilla (n = 1), and thyroid (n = 1). Tumor size ranged from 2.2 to 5.5 cm. On microscopy, tumors displayed nested-lobular architecture, monomorphic cells, and interlobular fibrotic stroma. Other features included: palisading (n = 5), squamous differentiation (n = 2), keratinization (n = 1), colonisation of salivary ducts (n = 1) and thyroid follicles (n = 1), follicle-like cysts (n = 3), calcification (n = 2), necrosis (n = 3). Mitotic rate was 4-15/2 mm 2 . On immunohistochemistry, cytokeratins (100%), p40 (100%), strong/diffuse membranous CD99 (100%), NKX2.2 (100%), Fli-1 (71%), and synaptophysin (71%) was positive. Patients received chemotherapy (n = 7) and radiotherapy (n = 4). Two patients developed recurrence at 6 and 10 months; 3 developed metastases at 0, 6, and 25 months. ALES is a rare and aggressive malignancy that mimics diverse neoplasms common in the head and neck region. Awareness of the morphologic and immunohistochemistry spectrum of this tumor is essential to avoid diagnostic errors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To address the wide variation in access to cancer care in India requires strengthening of infrastructure, trained oncology workforce, and minimisation of out-of-pocket expenditures. However, even with major investments, it is unlikely to achieve the same level of infrastructure and expertise across the country. Therefore, a resource stratified approach driven by evidence-based and contextualised clinical guidelines is the need of the hour. The National Cancer Grid has been at the forefront of delivery of standardised cancer care through several of its initiatives, including the resource-stratified guidelines. Development of new guidelines is resource and time intensive, which may not be feasible and can delay the implementation. Adaptation of the existing standard guidelines using the transparent and well-documented methodology with involvement of all stakeholders can be one of the most reasonable pathways. However, the adaptation should be done keeping in mind the context, resource availability, budget impact, investment needed for implementation and acceptability by clinicians, patients, policymakers, and other stakeholders. The present paper provides the framework for systematically developing guidelines through adaptation and contextualisation. The process can be used for other health conditions in resource-constraint settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Multidisciplinary molecular tumor boards (MTBs) help in interpreting complex genomic data generated by molecular tumor profiling and improve patients' access to targeted therapies. The purpose of this study was to assess the impact of our institution's MTB on the clinical management of patients with cancer., Methods: This study was conducted at a tertiary cancer center in India. Cases to be discussed in the MTB were identified by molecular pathologists, scientists, or oncologists. On the basis of the clinical data and molecular test reports, a course of clinical management was recommended and made available to the treating oncologist. We determined the proportion of patients who were recommended a change in the clinical management. We also assessed compliance of the treating oncologists with MTB recommendations., Results: There were 339 discussions for 328 unique patients. The median age of the cohort was 54 years (range 17-87), and the majority of the patients were men (65.1%). Of 339 cases, 133 (39.2%) were recommended continuation of ongoing therapy while the remaining 206 (60.7%) were recommended a change in clinical management. Compliance with MTB recommendations for a change in clinical management was 58.5% (79 of 138 evaluable cases). Compliance and implementation for MTB's recommendation to start a new therapy in 104 evaluable cases were 60.5% and 44.2%, respectively. A total of 248 biopsies had at least one actionable mutation. A total of 646 mutations were identified in the cohort, with EGFR being the most frequently altered gene., Conclusion: MTBs help in interpreting results of molecular tests, understanding the significance of molecular abnormalities, and assessing the benefits of available targeted therapies and clinical trials in the management of patients with targetable genetic alterations.

Patients with cancer are at higher risk for adverse coronavirus disease 2019 (COVID-19) outcomes. Here, we studied 1,253 patients with cancer, who were diagnosed with severe acute respiratory syndrome coronavirus 2 at a tertiary referral cancer center in India. Most patients had mild disease; in our settings, recent cancer therapies did not impact COVID-19 outcomes. Advancing age, smoking history, concurrent comorbidities and palliative intent of treatment were independently associated with severe COVID-19 or death. Thus, our study provides useful insights into cancer management during the COVID-19 pandemic., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Omshree ShettyVikas Ostwal Introduction  The present study evaluates the mutation pattern and frequency of BRAF , PIK3CA and RAS in colorectal carcinoma observed in the tertiary cancer center in India. Materials and Methods  Consecutive cases of colorectal adenocarcinoma ( n  = 330) registered from January 2015 to December 2019 (5-year duration) were selected for the study. Molecular analysis for BRAF . PIK3CA (exon 9 and 20) and RAS ( KRAS & NRAS ) was performed on representative formalin-fixed paraffin-embedded tissues by Sanger sequencing. Results were correlated with clinicopathological features. Patient overall survival (OS) was obtained using Kaplan-Meier method. Results  The study cohort was in the age range of 22 to 81 years (median age: 52 years) that included 202 males and 96 females (male: female ratio 2.1:1). BRAF V600E mutation was observed in three cases (1%), while 17 cases (5.7%) had mutations in the PIK3CA gene (exon 9 or exon 20). Mutation analysis for RAS gene ( KRAS & NRAS ) was observed among 42 (15.4%) cases with KRAS mutation and 11 (4%) cases were positive for NRAS mutations. Among RAS, KRAS G12D was the predominant mutation. Median OS with wild-type RAS was 46.6 months (95% confidence interval [CI]: 22.4-70.8), while for RAS mutated patients, it was 25.6 months (95% CI: 16.7-34.5), hazard ratio: 1.7 (95% CI: 1.1-2.7, p  = 0.025). Conclusion  This study evaluated the prevalence of BRAF, PIK3CA and RAS mutations in the Indian cohort and its impact on clinical behavior. There was lower incidence of BRAF mutations in this cohort and PIK3CA mutation (single) did not impact survival of the patients., Competing Interests: Conflicts of Interest Nil., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background and Objectives: The COVID-19 pandemic, with high rate of asymptomatic infections and increased perioperative complications, prompted widespread adoption of screening methods. We analyzed the incidence of asymptomatic infection and perioperative outcomes in patients undergoing cancer surgery. We also studied the impact on subsequent cancer treatment in those with COVID-19., Methods: All patients who underwent elective and emergency cancer surgery from April to September 2020 were included. After screening for symptoms, a preoperative test was performed from nasopharyngeal and oropharyngeal swabs before the procedure. Patients were followed up for 30 days postoperatively and complications were noted., Results: 2108 asymptomatic patients were tested, of which 200 (9.5%) tested positive. Of those who tested positive, 140 (70%) underwent the planned surgery at a median of 30 days from testing positive, and 20 (14.3%) had ≥ Grade III complications. Forty (20%) patients did not receive the intended treatment; 110 patients were retested in the Postoperative period, and 41 (37.3%) tested positive and 9(22%) patients died of COVID-related complications., Conclusion: Routine preoperative testing for COVID-19 helps to segregate patients with asymptomatic infection. Higher complications occur in those who develop COVID-19 in postoperative period. Prolonged delay in surgery after COVID infection may influence planned treatment., (© 2021 Wiley Periodicals LLC.)

Background: Liposarcomas including atypical lipomatous tumors (ALT)/well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPSs) display a histomorphological spectrum with their several diagnostic mimics. Murine double minute 2(MDM2) gene amplification characterizes ALT/WDLPS and DDLPS. Presently, there is no documented study from our subcontinent on the validation of MDM2 gene testing in these tumors., Material and Methods: Twenty-eight cases, diagnosed as ALT/WDLPS (n = 5) and DDLPSs (n = 23), along with 10 other tumors were tested for MDM2 gene amplification, using fluorescence in situ hybridization (FISH) on tissue microarrays (TMAs). Fourteen cases, diagnosed as ALT/WDLPS and DDLPS, along with 49 other tumors were tested for MDM2 immunostaining. Twenty tumors were tested for p16 INK4a immunostaining., Results: FISH was interpretable in 25 (89.2%) cases. Among the 20 cases diagnosed as DDLPSs, 19 displayed MDM2 gene amplification. Among the 5 cases diagnosed as ALT/WDLPS, four showed MDM2 gene amplification. Finally, 19 cases were confirmed as DDLPS and 4 as ALT/WDLPS. Furthermore, 7/19 cases confirmed as DDLPS and all 4 cases as ALT/WDLPS tested for MDM2 immunostaining, displayed its diffuse immunoexpression, while a single case of DDLPS showed its focal immunostaining. None of the 49 control cases displayed diffuse MDM2 immunoexpression. ALL 16 DDLPSs and 4 cases of ALT/WDLPS displayed p16 INK4a immunostaining. The sensitivity for diffuse MDM2 immunostaining was 87.5% in cases of DDLPS, 100% in ALT/WDLPS, and specificity was 100%. The sensitivity for MDM2 gene amplification was 94.7% in cases of DDLPS and 100% in cases of ALT/WDLPS. The sensitivity for p16 INK4a was 100%., Conclusion: This constitutes the first sizable study on MDM2 testing in ALT/WDLPS and DDLPS from our subcontinent using TMAs. MDM2 gene amplification testing continues as the diagnostic gold standard for ALTs/WDLPSs and DDLPSs and is useful in cases of diagnostic dilemmas. Diffuse MDM2 (IF2 clone) and p16 INK4a immunostaining, together seem useful for triaging cases for FISH., Competing Interests: None

Adamantinoma-like Ewing sarcoma is uncommonly reported in the skeletal sites, including small bones of the feet.A 15-year-old girl presented with pain and swelling in her left foot, leading to difficulty in walking for 8 months. Plain radiograph revealed an ill-defined, lytic-sclerotic lesion without significant periosteal reaction in her left calcaneus. Magnetic resonance imaging (MRI) revealed an expansile lesion involving the anterior calcaneus, which was hypointense on T1 and heterogeneously hyperintense on T2-weighted sequences, infiltrating the adjacent bones and soft tissues. On imaging, the differential diagnoses considered were a giant cell tumor and other primary bone tumors.Histopathological examination revealed a tumor composed of small round cells, with interspersed keratin pearls. Immunohistochemically, the tumor cells were positive for CD99/MIC2, pan-cytokeratin (AE1/AE3), p40, p63, NKX2.2, and synaptophysin. Diagnosis of adamantinoma-like Ewing sarcoma was offered on the initial biopsy. Furthermore, the tumor cells revealed EWSR1 gene rearrangement by fluorescence in situ hybridization, confirming this diagnosis. The patient underwent neoadjuvant chemotherapy, had a poor response, and finally underwent below-knee amputation.This constitutes a rare case of adamantinoma-like Ewing sarcoma in the calcaneus. Ewing sarcoma may be considered as a differential diagnosis for intraosseous lytic-sclerotic lesions, even without significant periosteal reaction, at unusual sites, such as the bones of the foot. Awareness of this entity and application of ancillary techniques is recommended for its exact diagnosis and in differentiating this rare variant from its diagnostic mimics. This case also indicates a poor chemotherapy response in this unusual variant of Ewing sarcoma, occurring in the calcaneus., (© 2021. ISS.)

Background: Mutations in ROS1, ALK, and MET genes are targetable alterations in non-small cell lung cancer (NSCLC). They can be evaluated by different techniques, most commonly fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC)., Methods: We explored the prevalence of ROS1, ALK, MET mutations, discuss clinicopathological associations and FISH signal patterns on 413 consecutive cases of EGFR negative lung carcinoma from March 2016 to April 2017 using FISH for ALK, ROS1, and MET along with ALK (D5F3) IHC., Results: ROS1 gene rearrangement, ALK positivity (IHC and/or FISH), and MET amplification were seen in 18/358 (5%) cases, 76/392 cases (19.4%), and 10/370 (2.7%) cases, respectively. ALK FISH and ALK IHC were positive in 51/300 (17%) and 58/330 cases (17.57%), respectively, while 8/330 (2.4%) cases were ALK IHC "equivocal" of which 3/8 (37.5%) were ALK FISH positive. Of ALK FISH and IHC co-tested cases, 43/238 (18.07%) cases were positive by both techniques, while 15/43 (34.88%) of ALK positive cases showed discordant ALK FISH and IHC results. All ROS1 rearranged and MET amplified cases were adenocarcinoma. Signet ring cell histology was associated with 78.57% likelihood of being either ALK or ROS1 positive. Genomic heterogeneity was seen in 30% of MET amplified cases., Conclusions: ALK/ROS1/MET gene alterations were found in 25.18% of NSCLC cases. An ALK IHC "equivocal" interpretation category should be incorporated into practice. Atypical patterns of ROS1 and genomic heterogeneity need to be evaluated further for any clinical relevance., Competing Interests: None

Purpose: To examine the cytotoxicity and genetic expression of SHEDs cultured in eluates of various calcium silicate based pulpotomy materials., Study Design: MTT assay, flow cytometry, alizarin red staining and scratch assay was used to assess the cellular viability, apoptosis, calcium matrix deposits and cell migration respectively. The gene expression of ALP, OCN and BMP -2, were measured with rtPCR. One way ANNOVA and Bonferroni post test was used for statistical analysis., Results: MTT assay analysis reported that all the test specimen had no cytotoxic effects. The highest number of live cells [ % ] was found in RetroMTA. The highest percentage of cell migration was observed in SHEDs cultured in EndoCem Zr. The mean absorbance for calcium matrix deposition was higher or similar in all test specimens, when compared to control groups. The expression of BMP -2 and OCN were significantly higher in cells exposed to RetroMTA and NeoMTA respectively after 24 hrs of incubation. After 72 hrs of incubation the mRNA expression of ALP was significantly higher in MTA., Conclusions: SHEDs cultured in eluates of various calcium silicate based cements exhibited cytocompatibility and maintained odontogenic like phenotype differentiation in SHEDs.

Breast cancer progression features ECM stiffening due to excess deposition and crosslinking of collagen, which dramatically influence tumor behaviour and fate. The mechanisms by which extracellular matrix (ECM) stiffening drives breast cancer invasion is an area of active research. Here we demonstrate the role of exosomes in ECM stiffness triggered breast cancer invasiveness. Using stiffness tuneable hydrogel ECM scaffolds, we show that stiff ECMs promote exosome secretion in a YAP/TAZ pathway-dependent manner. Interestingly, blocking exosome synthesis and secretion by GW4869 abrogated stiffness regulated motility and contractility in breast cancer cells. Reciprocally, exogenous addition of ECM stiffness-tuned exosomes orchestrated a series of changes in cell morphology, adhesion, protrusion dynamics resulting in fostered cell motility and invasion. Proteomic analysis of exosomal lysates followed by overrepresentation analysis and interactome studies revealed enrichment of cell adhesion and cell migration proteins in exosomes from stiff ECM cultures compared to that of soft ones. Quantitative proteomics of exosomes combined with genomic analysis of human breast tumor tissues (TCGA database) identified thrombospondin-1 (THBS1) as a prospective regulator of stiffness-dependent cancer invasion. Knockdown studies confirmed that the pro-invasive effects of stiffness-tuned exosomes are fuelled by exosomal THBS1. We further demonstrated that exosomal THBS1 mediates these stiffness-induced effects by engaging matrix metalloproteinase and focal adhesion kinase. Our studies establish the pivotal role of exosomal communication in ECM stiffness dependent cell migration with exosomal THBS1 as a master regulator of cancer invasion, which can be further exploited as a potential theranostic for improved breast cancer management., (Copyright © 2021 Elsevier Ltd. All rights reserved.)