All EGFR mutations are (not) created equal: focus on uncommon EGFR mutations.

PURPOSE: Most common EGFR mutations in NSCLC include del19 and exon 21 L858R. Approximately 10% of patients have uncommon EGFR mutations (indels, missense mutations involving G719, L861 and S768 codons, and exon 20 insertions) that do not respond to TKIs. METHODS: Of 490 EGFR mutated NSCLC samples, 60 cases harboring uncommon/compound EGFR mutations were reviewed retrospectively, and 44 were included for survival analysis. RESULTS: Sixty (12.2%) patients with a median age of 63 years (25-84 years) had uncommon/compound EGFR mutations. Majority had no history of smoking (52; 86.7%). Most common major uncommon mutations (G719X in exon 18, L861Q in exon 21 and S768I in exon 20) were identified in 19 (31.7%) patients. 17 (28.3%) cases demonstrated exon 20 insertions. De novo T790M was observed in 7 (11.7%) cases and 9 cases exhibited compound/dual mutations. Among the 12 patients who received first-line EGFR TKI, 7 received afatinib. Median progression-free survival of patients following first-line afatinib was 8.13 months, irrespective of mutation type exhibited. Overall response rate to first-line afatinib therapy was 57.1%. CONCLUSION: The current study highlighted that rare/dual EGFR mutations are heterogeneous with distinct clinical features in a large Indian cohort of EGFR mutated patients with NSCLC.

TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma

SMARCA4/BRG1-deficient lung adenocarcinoma (SD-LUAD) is being recognized as a distinct subtype based on subtle differences in its clinical, morphological, and immunophenotypic attributes compared to other non–small cell lung carcinomas. We present here a case of SD-LUAD with curious thyroid transcription factor 1 (TTF1) expression in a morphologically heterogenous lung adenocarcinoma. The better differentiated area showed preservation of TTF1 expression, and a poorly differentiated tumor had loss of TTF1 expression with universal BRG1 loss.

Founder BRCA1 mutations in Nepalese population

Background@#Founder mutation is a heritable genetic alteration observed with high frequency in a geographically and culturally isolated population where one or more ancestors becomes the forebearer of the altered gene. The current study reports two founder mutations in the BRCA1 gene in the Nepalese people. @*Methods@#Germline BRCA testing in all surface epithelial ovarian cancers and the selected case of breast, prostate, and pancreatic cancers has been the standard practice from 2016 to 2021. One thousand one hundred thirtythree probands were screened for germline BRCA variants by next generation sequencing. The variants were classified as per the American Society of Medical Genetics and Genomics recommendations. Pathogenic (class V) and likely pathogenic (class IV) were considered clinically relevant and utilized for cascade screening. @*Results@#Nepalese population made up a subcohort of 5.12% (58/1,133) of probands tested for germline BRCA1/2 variants. Twenty-seven of these 58 tested harbored pathogenic genetic alterations in BRCA1/2 genes, with 23 being BRCA1 mutant. Sixteen of 23 BRCA1 mutant cases shared one common pathogenic mutation c.2214_2215insT (p.Lys739Ter) (NM_007294.4). Additionally, a second highly recurrent mutation in BRCA1 gene c.5068A>T (p.Lys1690Ter) (NM_007294.4) was noted in six patients from this population. @*Conclusions@#The overwhelming abundance of the above two variants in a geographically confined population confers these two genetic alterations a status of founder mutations amongst the people of Nepal. A more extensive population-based study to reaffirm these findings will help establish a dual site-specific germline testing similar to the “Multisite-3-assay” in Ashkenazi Jews as the primary screening tool, especially in a resource-constrained environment.

Ecological Analysis of the Temporal Trends in the Association of Social Vulnerability and Race/Ethnicity with County-Level COVID-19 Incidence and Outcomes in the United States

BackgroundThe COVID-19 pandemic adversely affected the socially vulnerable and minority communities in the U.S. initially, but the temporal trends during the year-long pandemic remain unknown. ObjectiveWe examined the temporal association between the county-level Social Vulnerability Index (SVI), a percentile-based measure of social vulnerability to disasters, its subcomponents and race/ethnic composition with COVID-19 incidence and mortality in the U.S. in the year starting in March 2020. MethodsCounties (n=3091) with [≥] 50 COVID-19 cases by March 6th, 2021 were included in the study. Associations between SVI (and its subcomponents) and county level racial composition with the incidence and death per capita were assessed by fitting a negative-binomial mixed-effects model. This model was also used to examine potential time varying associations between weekly number of cases/deaths and SVI or racial composition. Data was adjusted for percentage of population aged [≥]65 years, state level testing rate, comorbidities using the average Hierarchical Condition Category (HCC) score, and environmental factors including average fine particulate matter (PM2.5), temperature and precipitation. ResultsHigher SVI, indicative of greater social vulnerability, was independently associated with higher COVID-19 incidence (adjusted incidence rate ratio [IRR] per-10 percentile increase:1.02, (95% CI 1.02, 1.03, p<0.001), and death per capita (1.04, (95% CI 1.04, 1.05, p<0.001). SVI became an independent predictor of incidence starting from March 2020, but this association became weak or insignificant by the winter, a period that coincided with a sharp increase in infection rates and mortality, and when counties with higher proportion of White residents were disproportionately represented ("third wave"). By Spring of 2021, SVI was again a predictor of COVID-19 outcomes. Counties with greater proportion of Black residents also observed similar temporal trends COVID-19-related adverse outcomes. Counties with greater proportion of Hispanic residents had worse outcomes throughout the duration of the analysis. ConclusionExcept for the winter "third wave" when majority White communities had the highest incidence of cases, counties with greater social vulnerability and proportionately higher minority populations, experienced worse COVID-19 outcomes. Article Summary/Strengths & LimitationsO_LIExamined full 12 months of county-level data in the US delineating the temporal trends in the association between social vulnerability index and COVID-19 outcomes C_LIO_LIInvestigated COVID-19 outcomes in predominantly Black and Hispanic communities in comparison to White communities in the US C_LIO_LIAnalysis is ecological, descriptive, and on the county-level rather than on an individual level C_LIO_LIAnalysis adjusted for confounders including county level age [≥] 65, comorbidities, and environmental factors C_LIO_LIAnalysis limited to the US C_LI

Impact of COVID-19 on healthcare workers at a cancer care centre

BackgroundThe services of front-line health care workers (HCWs) have been paramount in the management of novel coronavirus disease 2019 (COVID-19). Health care professionals have been at high occupational risk of getting disease and even dying of the disease, however; they have been the subject of very limited studies in terms of COVID-19. The objectives of this study are to examine the incidence and the impact of COVID-19 infection among HCWs in terms of recovery, productivity, quality of life (QOL) and post-COVID complications. Materials and MethodsThis was a retrospective, questionnaire based study including demographic details, workplace characteristics, symptoms, source/ spread of infection, details of recovery and the consequences of COVID-19 comprising impaired productivity/ QOL, post-COVID-19 complications and others. The data were analyzed by using IBM SPSS software (Version 23, SPSS Inc., Chicago, IL, USA). Results and ConclusionsOut of a total of 1482 employees, 18.3% (271) were laboratory confirmed to have contracted novel contagion during the study period of 5 months. The median age at diagnosis was 29 (range, 21-62) years. Front-line workers and female workers were the most infected personnel with COVID-19. Flu-like symptoms were the most frequently experienced symptoms. The median time for recovery was 20 (range, 2-150) days. The relationship between pre-existing comorbidities and age was highly significant. The QOL and productivity were associated with pre-existing comorbidities, severity of the disease, time for recovery and post-COVID syndrome. More than a half (51.8%) of all HCWs had suffered from post-COVID complications. There was no fatality reported due to COVID-19. The post-COVID complications were related to pre-existing comorbidities, severity of disease, time for recovery and status of recovery. Further research to explore the consequences of COVID-19 is warranted. The general public needs to be aware of symptoms and management of the post-COVID syndrome.

SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non–small cell lung cancer

Background@#SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway. @*Methods@#All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases. @*Results@#Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified. @*Conclusions@#It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Robust home brew fragment sizing assay for detection of MET exon 14 skipping mutation in non–small cell lung cancer patients in resource constrained community hospitals

Background@#A mutation/deletion involving donor or acceptor sites for exon 14 results in splicing out of exon 14 of the mesenchymal epithelial transition (MET) gene and is known as “MET exon 14 skipping” (ΔMET14). The two recent approvals with substantial objective responses and improved progression-free survival to MET inhibitors namely capmatinib and tepotinib necessitate the identification of this alteration upfront. We herein describe our experience of ΔMET14 detection by an mRNA-based assay using polymerase chain reaction followed by fragment sizing. @*Methods@#This is a home brew assay which was developed with the concept that the transcripts from true ΔMET14 will be shorter by ~140 bases than their wild type counterparts. The cases which were called MET exon 14 skipping positive on next-generation sequencing (NGS) were subjected to this assay, along with 13 healthy controls in order to establish the validity for true negatives. @*Results@#Thirteen cases of ΔMET14 mutation were detected on NGS using RNA-based sequencing. Considering NGS as a gold standard, the sizing assay using both gel and capillary electrophoresis that showed 100% specificity for both with concordance rates of 84.6% and 88.2% with NGS, respectively, were obtained. @*Conclusions@#Owing to the cost-effective nature and easy to use procedures, this assay will prove beneficial for small- and medium-sized laboratories where skilled technical personnel and NGS platforms are unavailable.

SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non–small cell lung cancer

Background@#SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway. @*Methods@#All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases. @*Results@#Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified. @*Conclusions@#It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Robust home brew fragment sizing assay for detection of MET exon 14 skipping mutation in non–small cell lung cancer patients in resource constrained community hospitals

Background@#A mutation/deletion involving donor or acceptor sites for exon 14 results in splicing out of exon 14 of the mesenchymal epithelial transition (MET) gene and is known as “MET exon 14 skipping” (ΔMET14). The two recent approvals with substantial objective responses and improved progression-free survival to MET inhibitors namely capmatinib and tepotinib necessitate the identification of this alteration upfront. We herein describe our experience of ΔMET14 detection by an mRNA-based assay using polymerase chain reaction followed by fragment sizing. @*Methods@#This is a home brew assay which was developed with the concept that the transcripts from true ΔMET14 will be shorter by ~140 bases than their wild type counterparts. The cases which were called MET exon 14 skipping positive on next-generation sequencing (NGS) were subjected to this assay, along with 13 healthy controls in order to establish the validity for true negatives. @*Results@#Thirteen cases of ΔMET14 mutation were detected on NGS using RNA-based sequencing. Considering NGS as a gold standard, the sizing assay using both gel and capillary electrophoresis that showed 100% specificity for both with concordance rates of 84.6% and 88.2% with NGS, respectively, were obtained. @*Conclusions@#Owing to the cost-effective nature and easy to use procedures, this assay will prove beneficial for small- and medium-sized laboratories where skilled technical personnel and NGS platforms are unavailable.

Title: Immunity status of Health Care Workers post recovery from COVID-19: An online longitudinal panel survey

BackgroundCorona virus has literally travelled "around the world in 80 days" akin to Fogg and Passepartoute of Jules Verne fame. Manning of corona virus disease 2019 (COVID-19) wards and ICUs, also surgery on COVID-positive patients is increasingly being relegated to that subset of health care workers (HCW) who themselves have resumed duties after surviving COVID-19 infection. Convalescent plasma therapy has been widely endorsed. Several vaccines are in the pipeline as potential preventive measures against the virus keeping HCW on the priority-list of recipients. Immunity passports are being validated for foreign travel. These events share a common presumption that exposure to COVID-19 virus (natural infection/inoculation) produces protective adaptive immunity. It is unknown whether all (COVID-19) infected patients mount a protective immune response and for how long any protective effect will last. MethodsThis single institutional prospective longitudinal panel survey questions were deployed to the respondents online via email/WhatsApp groups to ascertain the symptomology and immunity status of HCW in the months following COVID-19 infection. The survey was administered to the same set/cohort of health care workers over 6 months. Results165 responses from 151 respondents (70 at 1-2months; 95 at 3-4 months including 14 at both time points) were analysed. 7.14% of infected HCW failed to develop IgG antibodies at 4-6 weeks. 91.7% HCW with IgG titres in the highest bracket had experienced anosmia. Mean antibody titres were 12.08 {+/-} 9.56 and 9.72 {+/-} 9.34 at 1-2 months and 3-4 months post-development of first symptom, respectively. ConclusionUnderstanding of COVID-19 patterns of variation in HCW may guide their deployment in the COVID ward and COVID-OTs. Revelation of this enigma (by quantification of serial IgG antibody levels) is critical for predicting response to vaccines under trial, fostering effective stratagems and tactics for pandemic control, ascertaining validity of immunity passports and understanding longevity/durability of protection by forecasting immunological memory against SARS-CoV-2.

COVID-19 Mortality in Cancer Patients: A Report from a Tertiary Cancer Centre in India

BackgroundCancer patients, especially those receiving cytotoxic therapy are assumed to have a higher probability of death from COVID-19. We have conducted this study to identify the Case Fatality Rate (CFR) in cancer patients with COVID-19 and have explored the relationship of various clinical factors to mortality in our patient cohort. MethodsAll active cancer cases presented to the hospital from 8th June to 24 August 2020, and developed symptoms/ radiological features suspicious of COVID-19 were tested by Real-time polymerase chain reaction assay and/or cartridge-based nucleic acid amplification test from a combination of naso-oropharyngeal swab for SARS-CoV-2. Clinical data, treatment details, and outcomes were assessed from the medical records. ResultsOf the total 3101 cancer patients admitted to the hospital, 1088 patients were tested and 186 patients were positive for SARS-CoV-2. The CFR in the cohort was 27/186 (14.5%). Univariate analysis showed that the risk of death was significantly associated with the presence of comorbidities [OR: 2.68; (95%CI: 1.13-6.32); P = 0.02], multiple comorbidities [OR: 3.01; (95%CI: 1.02-9.07); P = 0.046 for multiple vs. single], and the severity of COVID-19 presentation [OR: 27.48; (95%CI: 5.34-141.49); P = 0.0001 for severe vs. not severe]. Among all comorbidities, diabetes [OR: 3.3; (95%CI: 1.35-8.09); P = 0.008] and cardiovascular diseases [OR: 3.77; (95%CI: 1.02-13.91); P = 0.045] were significant risk factors for death. The receipt of anticancer treatments including chemotherapy, surgery, radiotherapy, targeted therapy, and immunotherapy within a month before the onset of COVID-19 symptoms had no significant effect on the mortality of cancer patients. ConclusionTo the best of our knowledge, this is the first study from India reporting the CFR, clinical associations, and risk factors for mortality in SARS-CoV-2 infected cancer patients. Our study shows that the frequency of COVID-19 in cancer patients is high, and the CFR is 7.6 times more than the national average. Anticancer therapies did not increase the risk of death. Pre-existing comorbidities specially diabetes, multiple comorbidities, and severity of COVID-19 presenting symptoms are significantly linked with COVID-19 related death in the cohort.

Impact of Social Vulnerability on COVID-19 Incidence and Outcomes in the United States

ImportancePrior pandemics have disparately affected socially vulnerable communities. Whether regional variations in social vulnerability to disasters influence COVID-19 outcomes and incidence in the U.S. is unknown. ObjectiveTo examine the association of Social Vulnerability Index (SVI), a percentile-based measure of county-level social vulnerability to disasters, and its sub-components (socioeconomic status, household composition, minority status, and housing type/transportation accessibility) with the case fatality rate (CFR) and incidence of COVID-19. DesignEcological study of counties with at least 50 confirmed COVID-19 cases as of April 4th, 2020. Generalized linear mixed-effects models with state-level clustering were applied to estimate county-level associations of overall SVI and its sub-component scores with COVID-19 CFR (deaths/100 cases) and incidence (cases/1000 population), adjusting for population percentage aged [≥]65 years, and for comorbidities using the average Hierarchical Condition Category (HCC) score. Counties with high SVI ([≥]median) and high CFR ([≥]median) were identified. SettingPopulation-based study of U.S. county-level data. ParticipantsU.S. counties with at least 50 confirmed COVID-19 cases. Main outcomes and measuresCOVID-19 CFR and incidence. ResultsData from 433 counties including 283,256 cases and 6,644 deaths were analyzed. Median SVI was 0.46 [Range: 0.01-1.00], and median CFR and incidence were 1.9% [Range: 0-13.3] and 1.2 per 1000 people [Range: 0.6-38.8], respectively. Higher SVI, indicative of greater social vulnerability, was associated with higher CFR (RR: 1.19 [1.05, 1.34], p=0.005, per-1 unit increase), an association that strengthened after adjustment for age[≥]65 years and comorbidities (RR: 1.63 [1.38, 1.91], p<0.001), and was further confirmed in a sensitivity analysis limited to six states with the highest testing levels. Although the association between overall SVI and COVID-19 incidence was not significant, the SVI sub-components of socioeconomic status and minority status were both predictors of higher incidence and CFR. A combination of high SVI ([≥]0.46) and high adjusted CFR ([≥]2.3%) was observed in 28.9% of counties. Conclusions and RelevanceSocial vulnerability is associated with higher COVID-19 case fatality. High social vulnerability and CFR coexist in more than 1 in 4 U.S. counties. These counties should be targeted by public policy interventions to help alleviate the pandemic burden on the most vulnerable population. KEY POINTSO_ST_ABSQuestionC_ST_ABSIs county-level social vulnerability to disasters associated with the case fatality rate (CFR) and incidence of SARS-CoV-2 infection during the COVID-19 pandemic in the U.S.? FindingsEach unit increase in county-level social vulnerability, measured using the Social Vulnerability Index (SVI), was associated with a 63% higher CFR after adjusting for age and comorbidities. Both CFR and incidence of COVID-19 were significantly higher in counties with lower socio-economic status and higher proportion of minority populations. MeaningU.S. counties with higher social vulnerability are experiencing greater mortality rates during the COVID-19 pandemic.

MRI Appearance of Florid Cystic Endosalpingiosis of the Uterus: a Case Report

Endosalpingiosis is a non-neoplastic proliferation of ectopic tubal epithelium. It may be found incidentally or the patients may present with chronic pelvic pain. It may resemble a gynecologic malignancy on imaging findings and clinicians and radiologists should be aware of this benign entity to render a correct diagnosis and to avoid over-treatment. We report here the MR imaging appearance of a case of florid cystic endosalpingiosis.