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Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.

High-grade endometrial stromal sarcoma (HGESS) may harbor YWHAE-NUTM2A/B fusion, ZC3H7B-BCOR fusion, and BCOR internal tandem duplication (ITD). NTRK3 upregulation and pan-Trk expression were reported in soft tissue lesions that share similar morphology and genetic abnormalities. To confirm these findings in HGESS, differential expression analysis was performed at gene level comparing 11 HGESS with 48 other uterine sarcomas, including 9 low-grade endometrial stromal sarcomas, 23 undifferentiated uterine sarcomas, and 16 leiomyosarcomas, using targeted RNA sequencing data. Pan-Trk immunohistochemistry was performed on 35 HGESS, including 10 tumors with RNA expression data, with genotypes previously confirmed by targeted RNA sequencing, fluorescence in situ hybridization, and/or genomic PCR. Unsupervised hierarchical clustering of the top 25% of differentially expressed probes identified three molecular groups: (1) high NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1 and low ESR1 expression; (2) low NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1 and high ESR1 expression; and (3) low NTRK3, FGFR3, RET, BCOR, GLI1, PTCH1, and ESR1 expression. Among HGESS, 64% of tumors clustered in group 1, while 27% clustered in group 2. Cytoplasmic and/or nuclear pan-Trk staining of variable extent and intensity was seen in 91% of HGESS regardless of cyclin D1 and/or BCOR positivity. ER and PR expression was seen in 44% of HGESS despite ESR1 downregulation. Two patients with ER and PR positive but ESR1 downregulated stage I HGESS were treated with endocrine therapy, and both recurred at 12 and 36 months after primary resection. By RNA expression, HGESS appear homogenous and distinct from other uterine sarcomas by activation of kinases, including NTRK3, and sonic hedgehog pathway genes along with downregulation of ESR1. Most HGESS demonstrate pan-Trk staining which may serve as a diagnostic biomarker. ESR1 downregulation is seen in some HGESS that express ER and PR which raises implications in the utility of endocrine therapy in these patients.

Mutations in the epidermal growth factor receptor (EGFR) are the most common targetable alterations in lung adenocarcinoma. To facilitate rapid testing, the Idylla EGFR assay was incorporated as a screening method before next-generation sequencing (NGS). Validation and experience using an in-house developed analysis pipeline, enhanced with a manual review algorithm is described. Results are compared with corresponding NGS results. In all, 1249 samples were studied. Validation demonstrated 98.57% (69/70) concordance with the reference methods. The limit of detection varied from 2% to 5% variant allele frequency for total EGFR quantitation cycle between 20 and 23. Of the 1179 clinical cases, 23.41% were EGFR-positive by Idylla. Concurrent NGS was successfully performed on 94.9% (799/842) requests. Concordance of Idylla with NGS was 98.62% (788/799) and 98.50% (787/799) using our in-house and Idylla analysis pipelines, respectively. Discordances involved missed mutations by both assays associated with low tumor/low input. Incorporating a manual review algorithm to supplement automated calls improved accuracy from 98.62% to 99.37% and sensitivity from 94.68% to 97.58%. Overall reporting time, from receipt of material to official clinical report, ranged from 1 to 3 days. Therefore, Idylla EGFR testing enables rapid and sensitive screening without compromising subsequent comprehensive NGS, when required. Automated calling, enhanced with a manual review algorithm, reduces false-negative calls associated with low tumor/low input samples.

Purpose: Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types. Experimental Design: TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution). Results: TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%–18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. Conclusions: TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naïve TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had “LGSC-like” morphology (i.e. Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these “usual HGSC-like” tumors often showed evidence of p53 dysfunction, including downregulation of expression (‘null’ or equivocal immunohistochemical p53 staining in 9/14, 64%) and/or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.

Squamous cell carcinomas of the lower female genital tract may be human papillomavirus-associated or independent. We studied the HPV status, mutational repertoire, histology, and clinical data of 28 samples from 26 patients, 65% with a vulvar primary and 35% with a vaginal primary. These represented invasive vulvovaginal squamous cell carcinomas that underwent clinical tumor-normal targeted massively parallel sequencing analysis. HPV status was determined using the HPV high-risk RNA ISH assay and/or by MSK-IMPACT. Eleven patients had HPV-associated squamous cell carcinoma (four vulvar and seven vaginal) and 15 patients had HPV-independent SqCC (13 vulvar and 2 vaginal). Well-differentiated squamous cell carcinomas were always HPV-independent. HPV-independent moderately and poorly differentiated carcinomas frequently had alterations in the NOTCH signaling pathway (6/7), which were also associated with increased tumor budding (P: 0.002). HPV-associated vulvovaginal squamous cell carcinoma had PIK3CA activating mutations (7/11, 64%) as the most common genomic event, while TERT gene alterations, mainly TERT promoter mutations (14/15 cases, 93%) featured significantly in HPV-independent carcinomas. Other common abnormalities in HPV-independent tumors were TP53 mutations (13/15, 87%), CDKN2A alterations (10/15, 67%), and NOTCH1 and FAT1 mutations (7/15, 47% each). A subset of both HPV-associated and -independent tumors had NOTCH pathway alterations (6/11, 55% and 10/15, 67% respectively), but different genes in this pathway were altered in these tumors. In summary, TERT, TP53, CDKN2A, and NOTCH1 gene alterations strongly point away from an HPV-driven process (odds ratios: 0.01, 0.07, 0, and 0, respectively with p values

Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy harboring IDH2 R172 mutations in >80% cases. We explored the potential of genome-wide DNA methylation profiling to elucidate tumor biology and improve the diagnosis of sinonasal undifferentiated carcinoma and its histologic mimics. Forty-two cases, including sinonasal undifferentiated, large cell neuroendocrine, small cell neuroendocrine, and SMARCB1-deficient carcinomas and olfactory neuroblastoma, were profiled by Illumina Infinium Methylation EPIC array interrogating >850,000 CpG sites. The data were analyzed using a custom bioinformatics pipeline. IDH2 mutation status was determined by the targeted exome sequencing (MSK- IMPACTTM) in most cases. H3K27 methylation level was assessed by the immunohistochemistry-based H-score. DNA methylation-based semi-supervised hierarchical clustering analysis segregated IDH2 mutants, mostly sinonasal undifferentiated (n = 10) and large cell neuroendocrine carcinomas (n = 4), from other sinonasal tumors, and formed a single cluster irrespective of the histologic type. t-distributed stochastic neighbor embedding dimensionality reduction analysis showed no overlap between IDH2 mutants, SMARCB1-deficient carcinoma and olfactory neuroblastoma. IDH2 mutants demonstrated a global methylation phenotype and an increase in repressive trimethylation of H3K27 in comparison to IDH2 wild-type tumors (p < 0.001). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed no difference in pathway activation between IDH2-mutated sinonasal undifferentiated and large cell neuroendocrine carcinomas. In comparison to SMARCB1-deficient, IDH2-mutated carcinomas were associated with better disease-free survival (p = 0.034) and lower propensity for lung metastasis (p = 0.002). ARID1A mutations were common in small cell neuroendocrine carcinoma but not among IDH2 mutants (3/3 versus 0/18 and p < 0.001). IDH2 mutations in sinonasal carcinomas induce a hypermethylator phenotype and define a molecular subgroup of tumors arising in this location. IDH2- mutated sinonasal undifferentiated carcinoma and large cell neuroendocrine carcinoma likely represent a phenotypic spectrum of the same entity, which is distinct from small cell neuroendocrine and SMARCB1-deficient sinonasal carcinomas. DNA methylation-based analysis of the sinonasal tumors has potential to improve the diagnostic accuracy and classification of tumors arising in this location.

As Coronavirus Disease 2019 (COVID-19) hospitalization rates remain high, there is an urgent need to identify prognostic factors to improve patient outcomes. Existing prognostic models mostly consider the impact of biomarkers at presentation on the risk of a single patient outcome at a single follow up time. We collected data for 553 Polymerase Chain Reaction (PCR)-positive COVID-19 patients admitted to hospital whose eventual outcomes were known. The data collected for the patients included demographics, comorbidities and laboratory values taken at admission and throughout the course of hospitalization. We trained multivariate Markov prognostic models to identify high-risk patients at admission along with a dynamic measure of risk incorporating time-dependent changes in patients’ laboratory values. From the set of factors available upon admission, the Markov model determined that age &gt, 80 years, history of coronary artery disease and chronic obstructive pulmonary disease increased mortality risk. The lab values upon admission most associated with mortality included neutrophil percentage, red blood cells (RBC), red cell distribution width (RDW), protein levels, platelets count, albumin levels and mean corpuscular hemoglobin concentration (MCHC). Incorporating dynamic changes in lab values throughout hospitalization lead to dramatic gains in the predictive accuracy of the model and indicated a catalogue of variables for determining high-risk patients including eosinophil percentage, white blood cells (WBC), platelets, pCO2, RDW, large unstained cells (LUC) count, alkaline phosphatase and albumin. Our prognostic model highlights the nuance of determining risk for COVID-19 patients and indicates that, rather than a single variable, a range of factors (at different points in hospitalization) are needed for effective risk stratification.

SMARCB1-deficient sinonasal carcinoma (SNC) is an aggressive malignancy characterized by INI1 loss mostly owing to homozygous SMARCB1 deletion. With the exception of a few reported cases, these tumors have not been thoroughly studied by massive parallel sequencing (MPS). A retrospective cohort of 22 SMARCB1-deficient SNCs were studied by light microscopy, immunohistochemistry, fluorescence in situ hybridization (n = 9), targeted exome MPS (n = 12), and Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) (n = 10), a bioinformatics pipeline for copy number/zygosity assessment. SMARCB1-deficient SNC was found in 13 (59%) men and 9 (41%) women. Most common growth patterns were the basaloid pattern (59%), occurring mostly in men (77%), and plasmacytoid/eosinophilic/rhabdoid pattern (23%), arising mostly in women (80%). The former group was significantly younger (median age = 46 years, range = 24-54, vs 79 years, range = 66-95, p 0.0001). Clear cell, pseudoglandular, glandular, spindle cell, and sarcomatoid features were variably present. SMARCB1-deficient SNC expressed cytokeratin (100%), p63 (72%), neuroendocrine markers (52%), CDX-2 (44%), S-100 (25%), CEA (4/4 cases), Hepatocyte (2/2 cases), and aberrant nuclear β-catenin (1/1 case). SMARCB1 showed homozygous deletion (68%), hemizygous deletion (16%), or truncating mutations associated with copy neutral loss of heterozygosity (11%). Coexisting genetic alterations were 22q loss including loss of NF2 and CHEK2 (50%), chromosome 7 gain (25%), and TP53 V157F, CDKN2A W110∗, and CTNNB1 S45F mutations. At 2 years and 5 years, the disease-specific survival and disease-free survival were 70% and 35% and 13% and 0%, respectively. SMARCB1-deficient SNCs are phenotypically and genetically diverse, and these distinctions warrant further investigation for their biological and clinical significance.

Objectives Long-term hospitalized patients have a higher risk of adverse outcomes and mortality rate. These patients often rapidly deteriorate, leading to death. We aim to evaluate end-of-life laboratory values time trends among deceased long-term inpatients. Methods Time-stamped laboratory data for adult inpatients who had died in the hospital were extracted. The data were normalized and time-series analysis was performed. The patients were also clustered based on the laboratory result trends. Results Laboratory results from 257 patients were evaluated. Significant time trends were observed: serum urea nitrogen, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and potassium increased while platelets and albumin decreased. Most patients showed significant shifts in at least four major laboratory indices within the last week of life. Conclusions In the last week of life in chronically hospitalized patients, an alteration of the physiologic state of the patient occurs that manifests as subtle changes in metabolite levels compared with the patient's baseline.

Highlights • Cervical rhabdomyosarcoma does not always present as a cervical mass with vesicles. • Treatment regimens studied in the pediatric population can be used in adults with rhabdomyosarcoma. • More data is needed on outcomes of adult patients treated for rhabdomyosarcoma.

BACKGROUND Fine-needle aspiration (FNA) biopsy is an accurate method for the diagnosis of solid pancreatic masses. However, a significant number of cases still pose a diagnostic challenge. The authors have attempted to design a computer model to aid in the diagnosis of these biopsies. METHODS Images were captured of cell clusters on ThinPrep slides from 75 pancreatic FNA cases (20 malignant, 24 benign, and 31 atypical). A K-means clustering algorithm was used to segment the cell clusters into separable regions of interest before extracting features similar to those used for cytomorphologic assessment. A multilayer perceptron neural network (MNN) was trained and then tested for its ability to distinguish benign from malignant cases. RESULTS A total of 277 images of cell clusters were obtained. K-means clustering identified 68,301 possible regions of interest overall. Features such as contour, perimeter, and area were found to be significantly different between malignant and benign images (P

Almost all uterine mesenchymal tumours have been historically classified as either smooth muscle or endometrial stromal neoplasms. Recent application of molecular techniques has identified numerous lesions with distinctive genetic abnormalities and clinicopathological characteristics. Newly discovered uterine sarcoma subtypes include high-grade endometrial stromal sarcomas with BCOR genetic abnormalities, fibrosarcoma-like uterine sarcomas with NTRK rearrangements and COL1A-PDGFRB fusions, as well as undifferentiated uterine sarcomas with SMARCA4 mutations. Novel PLAG1 and PGR fusions have been identified in subsets of myxoid and epithelioid leiomyosarcomas. Some uterine tumours resembling ovarian sex-cord tumour harbour GREB1 and ESR1 rearrangements. Histological and immunophenotypical features as well as underlying genetic abnormalities defining these lesions are discussed.

Objective The leishmanin skin test (LST) has been used for clinical diagnosis of leishmaniasis and epidemiological studies of the disease. Thus far, evidence has suggested that LST conversion indicates a degree of protection against leishmaniasis. In this study, we have put this assumption to test. Methods and materials A total of 273 participants with positive LST living in a hyperendemic area for leishmaniasis were followed for three years for any occurrence of cutaneous leishmaniasis. Results Twenty-two of the 273 participants contracted leishmaniasis during the 3-year follow-up. These new cases included participants who had a previous history of active disease, those who had a history of leishmanization, or those who were suspected of having a history of subclinical infection. Discussion In this study, the incidence of leishmaniasis in individuals with positive LST was close to the general incidence of the disease in the same hyperendemic area. These results suggest that although LST conversion may be a marker for partial immunity towards leishmaniasis, it may not, however, indicate complete protection against the disease, and consequently there is a need for revision of current vaccine development approaches which are based on rendering vaccinated individuals LST positive.

Chorangiomatosis is a unique placental vascular abnormality that can cause growth retardation and even fetal demise in severe cases. In this study we aim to better understand this lesion and the possible clinical implications.In this study 170 placentas were evaluated, both grossly and microscopically. The patients' charts were reviewed and relevant clinical data were extracted. In the histological examination, presence of placental lesions including chorangiomatosis (focal, multifocal and diffuse) and chorangiosis was determined and possible correlation between placental findings and clinical outcomes investigated.Among the 170 placentas examined, 42 cases of multifocal chorangiomatosis (25.6%), 7 cases with diffuse chorangiomatosis (4.26%), and 56 cases of focal chorangiomatosis (34.1%) were identified. We found that there is a significant correlation between multifocal/diffuse chorangiomatosis and adverse clinical outcomes including lower birth weight and NICU admission.Chorangiomatosis can significantly affect the outcomes of pregnancy and more research is needed to better understand this lesion.

Background: In this prospective case series we have assessed the clinical effects of 8 weeks military training on the lower extremity of the recruits. Materials and Methods: Military recruits who met the eligibility criteria and gave informed consent were entered into the study. They were asked to fill out a self-reporting pain and functionality questionnaire before and after their training. They were also examined by a physician before and after their military training. The questionnaire and examination were concentrated on three blocs: lower back, knee, and foot. Results: Three-hundred and seventy-three study subjects were evaluated. The study showed that there is a significant difference in reporting lower back pain after the training compared to the rate of complaints prior to the training (P < 0.001), knee pain, and foot pain also increased significantly (P < 0.1 and P < 0.0001, respectively) The difference was most prominent in foot complaints. Physical examination also showed significant increase in lower extremity findings following the training (P < 0.05). Conclusion: Our study shows that there is a need for a new approach to military training of male recruits in Iran in order to minimize the adverse health effects.

Over the years, there has been a steady increase in the number of patients requiring dialysis. However, no consensus exists between choosing either hemodialysis (HD) or peritoneal dialysis (PD) as the preferred method of dialysis for patients. In this study, we have compared the quality of life of the patients undergoing either HD or PD. This cross-sectional study was performed in the dialysis center of the Noor and Saint Ali Asghar University Hospital in Isfahan, Iran in 2012. Forty-six patients who underwent PD (28 males and 18 females) and 46 similar patients undergoing HD (26 males and 20 females) were compared. A standardized Persian version of the short form-36 (SF-36) tool was used to assess the quality of life and to assess the quality of dialysis weekly Kt/V in patients undergoing PD and single random Kt/V sampling in HD patients were assessed. Patients undergoing PD reported higher scores in physical functioning. The lowest scores in both groups were reported in mental health section. In physical functioning section, physical role functioning section and overall score of the SF-36 tool, PD patients reported significantly higher scores compared to the HD patients (P

We hypothesize that inclusion of pretest modifiers as an index in the reporting of troponin results can improve the diagnostic accuracy of troponin in identifying acute coronary events. The medical records of patients presenting to the emergency department with a clinical suspicion of acute coronary event were reviewed. All patients who had had troponin levels checked were included in …

Neoadjuvant chemoradiation is one of the cornerstones of colorectal adenocarcinoma management. This approach can lead to tumor regression in some patients and has shown to be prognostically beneficial. We report a case of rectal neuroendocrine tumor occurring following chemoradiation of a rectal adenocarcinoma. The patient is a 45-year-old …

Proliferative myositis is a rapidly growing benign intramuscular proliferative lesion that is believed to be incited by muscle trauma; these lesions are managed by either surgical excision or watchful waiting, as they have shown a tendency for spontaneous regression. The patient is a …