Low-grade mucoepidermoid carcinoma mimicking benign cystic lesions in the salivary gland: A diagnostic dilemma.

Mucoepidermoid carcinoma (MEC) is a common malignancy arising in the parotid gland. The diagnosis of MEC is typically based on its morphological features alone, characteristically containing mucocytes, intermediate cells and epidermoid cells. However, when cystic degeneration is diffuse, it is challenging to distinguish MEC from other benign cystic tumors. This is a case report of a 58-year-old Caucasian man who presented with a parotid mass. H&E sections of the mass reveal multiloculated cysts lined by bland-looking epithelium with only rare papillary architectures. The papillary proliferation contains mucocytes, and epidermoid cells highlighted by the p63 immunohistochemistry study. The diagnosis was confirmed by FISH result of positive MAML2 (11q21) rearrangement. Patient underwent parotidectomy and is disease-free 6 months post-surgery. MEC with cystic degeneration is a common diagnostic pitfall which can mimic many benign lesions in the salivary gland. We present a rare case with MEC with extensive cystic change, its molecular and pathologic findings and review the diagnostic features of MEC, its benign mimickers and useful tools for distinguishing these entities.

Identification of gene variation feature for targeted therapy of non-small cell lung cancer through combined method of DNA and RNA sequencing.

Next generation sequencing (NGS) is typically used to reveal tumor gene variation feature for targeted therapy of various types of human cancers, including non-small cell lung cancer (NSCLC). Here, we report the role and potential applicable value of combining DNA and RNA sequencing in gene variation detection in NSCLC. 386 NSCLC patients with stage II-IV were enrolled and detected using NGS sequencing of DNA and RNA panels that covered all well-documented target driver genes from the Chinese Society of Clinical Oncology (CSCO). The rate of epidermal growth factor receptor (EGFR) single nucleotide variation (SNV)/indel, mesenchymal-epithelial transition factor (MET) copy number variation (CNV) and anaplastic lymphoma kinase (ALK) fusion were 52.1%, 4.1% and 6.0% in the NSCLC cohort. The landscapes of SNV/indel, CNV and gene fusion in the cohort were depicted as well. Meanwhile, we assessed detection efficacy of DNA and RNA sequencing in gene fusion. Detected number and types of gene fusion using the RNA sequencing were better than those using the DNA sequencing. Gene fusion with intergenic region was only detected by DNA sequencing and MET exon 14 skipping (METΔex14) was more easily identified by RNA sequencing. Finally, we investigated clinical correlations of SNV/indel/CNV/fusion with clinicopathologic features in the NSCLC cohort. Taken together, RNA sequencing significantly complements deficiency of DNA sequencing for gene fusion, which cooperatively presents comprehensive and reliable gene variation features and facilitate the identification of potential drug targets for NSCLC patients.

Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.

Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core "FH-associated" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08 cm, P = 0.01) and associated with younger patients (42.05 vs 47.97, P = 0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5 ± 0.53 vs 3.5 ± 1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P = 0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.

Progression of diabetic nephropathy and vitamin D serum levels: A pooled analysis of 7722 patients.

BACKGROUND AND AIM: Low serum Vitamin D levels have been associated with diabetic nephropathy (DN). Our study aimed to analyse the serum levels of vitamin D in patients suffering from DN and the subsequent changes in serum vitamin D levels as the disease progresses. METHODS: PubMed, Embase, SCOPUS and Web of Science were searched using keywords such as '25 hydroxyvitamin D' and 'diabetic nephropathy'. We included observational studies that reported the association between the serum 25 hydroxy vitamin D levels and diabetic nephropathy without restriction to age, gender, and location. R Version 4.1.2 was used to perform the meta-analysis. The continuous outcomes were represented as mean difference (MD) and standard deviation (SD) and dichotomous outcomes as risk ratios (RR) with their 95% confidence interval (CI). RESULTS: Twenty-three studies were included in our analysis with 7722 patients. Our analysis revealed that vitamin D was significantly lower in diabetic patients with nephropathy than those without nephropathy (MD: -4.32, 95% CI: 7.91-0.74, p-value = .0228). On comparing diabetic patients suffering from normoalbuminuria, microalbuminuria, or macroalbuminuria, we found a significant difference in serum vitamin D levels across different groups. Normoalbuminuria versus microalbuminuria showed a MD of -1.69 (95% CI: -2.28 to -1.10, p-value = .0002), while microalbuminuria versus macroalbuminuria showed a MD of (3.75, 95% CI: 1.43-6.06, p-value = .0058), proving that serum vitamin D levels keep declining as the disease progresses. Notwithstanding, we detected an insignificant association between Grade 4 and Grade 5 DN (MD: 2.29, 95% CI: -2.69-7.28, p-value = .1862). CONCLUSION: Serum Vitamin D levels are lower among DN patients and keep declining as the disease progresses, suggesting its potential benefit as a prognostic marker. However, on reaching the macroalbuminuria stage (Grades 4 and 5), vitamin D is no longer a discriminating factor.

Tuberculostearic acid incorporated predictive model contributes to the clinical diagnosis of tuberculous meningitis.

The conventional confirmation tests of tuberculous meningitis (TBM) are usually low in sensitivity, leading to high TBM mortality. Hence, sensitive methods for indicating the presence of bacilli are required. Tuberculostearic acid (TBSA), a constituent from Mycobacterium tuberculosis had been evaluated as a promising marker, but fails to demonstrate consistent results for definite TBM. This study retrospectively reviewed medical records of 113 TBM suspects, constructing a TBSA-combined scoring system based on multiple factors, which show sensitivity and specificity of 0.8148 and 0.8814, respectively, and the area under the receiver operating characteristic curve of 0.9010. Multivariate analyses revealed four co-predictive factors strongly associated with TBSA: extra-neural tuberculosis, basal meningeal enhancement, CSF glucose/Serum glucose <0.595, and coinfection in CNS (Total). The subsequent machine learning-based validation showed correspondent importance to factors in the TBSA model. This study demonstrates a simple scoring system to facilitate TBM prediction, yield reliable diagnoses and allow timely treatment initiation.

Tuberculostearic acid, a potential parameter for scoring system construction for tuberculous meningitis diagnosis.

Background: This study aimed to validate the value of tuberculostearic acid (TBSA) whether it could implicate the existence of Mycobacterium tuberculosis (Mtb) and assist for the clinical diagnosis of tuberculous meningitis (TBM). Methods: The patient's cerebrospinal fluid (CSF) specimen was collected through the lumbar puncture and detected for TBSA with gas chromatography/mass spectrometry. At the same time, gold standard tests, i.e., CSF direct culture, CSF smear microscopy, or nucleic acid amplification tests, for Mtb were routinely performed. Furthermore, we evaluated all patients by the Lancet consensus scoring system, which classifies suspected patients to "Definite (depend on gold standard results only)," "Probable (>10 pts without imaging or >12 pts with imaging information)," "Possible (6-9 pts without imaging or 6-11 pts with imaging)," and "Not (<6 pts or with alternative diagnoses)" TBM. Results: In total, 140 patients were admitted for our study included 27 confirmed TBM patients and 50 TBSA-positive patients. Sensitivity (0.7407, confidence interval [CI] 95%: 0.5372-0.8889) and specificity (0.7345, CI 95%: 0.6432-0.8132) were calculated. The Lancet consensus scoring system was also applied to evaluate the possibility of TBM in suspected patients, finding that TBSA-positive patients showed a similar grouping distribution as the definite TBM patients. Conclusions: Our study implicates that the prospective utilization of TBSA is worth combining into a scoring system for characterizing the features of Mtb, showing a great potential of TBM diagnosis by TBSA in future.

Impact of Change in Lifestyle and Exercise on Cognitive Function in Patients With Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is a chronic destructive type of arthritis. It has a high prevalence in females as compared to the male population globally. It mainly affects the synovium of peripheral joints and leads to the destruction of joints with time. Patients with RA usually have a high burden of inflammation which may lead to certain physical disabilities and debilitating effects on mental health and cognitive ability. The question we investigated here in this systematic review is how changing lifestyles and increasing exercise or physical activities affects one's cognitive abilities. This article adheres to preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines. We used different databases such as PubMed, MEDLINE, and ScienceDirect to find relevant articles. To ensure the quality of the finally selected 12 studies, we followed different quality appraisal tools.  Based on our review, we found out that increasing physical activities and aerobic exercises positively increase overall well-being and decrease the inflammatory load, which will ultimately positively impact cognitive function in this subgroup of patients. We also discover certain key players affecting motivation, perception, and adherence to physical activities. We encourage future studies to be done on this topic to help in increasing quality of life and increasing independence in this group of patients. Counseling and addressing patient concerns are very important and keep disease activity well controlled so that physical activities become feasible.

The Effect of Statin Therapy on Inflammatory Biomarkers: A Systematic Review.

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors are commonly used drugs in the management of elevated lipid levels and cardiovascular disease. In cardiovascular diseases, among other common chronic conditions, inflammatory biomarkers are used to monitor disease progression and the risk of recurrent adverse events. We explored whether or not there was a positive effect on these biomarkers using HMG-CoA reductase inhibitors. The systematic review was conducted by gathering relevant papers mainly from three databases, identified through a generated Medical Subject Headings (MeSH) strategy. Identification of papers was subsequently followed by applying a selected inclusion and exclusion criteria to narrow the papers chosen for review. Post the application of stipulated criteria, 12 papers remained. They were subsequently assessed for risk of bias using a Cochrane risk analysis tool, identifying most as having some concerns of bias or low risk of bias. We found that HMG-CoA reductase inhibitors exhibit both a lipid-lowering effect addition to an anti-inflammatory effect.

Cardiovascular Benefit of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Type 2 Diabetes: A Systematic Review.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide yet, despite advances in treatment, CVD remains an underestimated and undermanaged condition, with an even greater risk in Type 2 Diabetes Mellitus (T2DM). Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are a promising novel drug class reported to improve Cardiovascular (CV) and renal outcomes in T2DM. Recent large-scale trials have assessed their CV safety with unexpected findings of multiple systemic benefits that could potentially reverse CVD. In this systematic review, we examined ten Randomized Controlled Trials (RCTs) that looked at cardiovascular outcomes in Type 2 diabetics and SGLT-2i. The RCTs were appropriately screened, looking for clear primary or secondary outcomes on CV events, and compared with placebo or other antidiabetic drugs. The RCTs had an average sample population studied of 5,549 participants with a mean follow-up time of 2.66 years. Three of the studies focused on CV parameters and risk factors. The remaining had defined CV composite events, and all consistently observed at least one CV benefit when using SGLT-2i. Our review of SGLT-2i in Type 2 diabetics showed the greatest benefit in reducing Heart Failure (HF) exacerbation and modest lowering of CV complications in high CV risk participants. Overall, there is still uncertainty about the exact mechanisms of SGLT-2i in their CV benefit, and whether they would favor pre-diabetic populations and those at earlier stages of CVD.

Understanding the Genetic and Molecular Basis of Familial Hypertrophic Cardiomyopathy and the Current Trends in Gene Therapy for Its Management.

Hypertrophic cardiomyopathy (HCM) is a genetically acquired disease of cardiac myocytes. Studies show that 70% of this disease is a result of different mutations in various sarcomere genes. This review aims to discuss several genetic mutations, epigenetic factors, and signal transduction pathways leading to the development of HCM. In addition, this article elaborates on recent advances in gene therapies and their implications for managing this condition. We start by discussing the founding mutations in HCM and their effect on power stroke generation. The less explored field of epigenetics including methylation, acetylation, and the role of different micro RNAs in the development of cardiac muscle hypertrophy has been highlighted in this article. The signal transduction pathways that lead to gene transcription, which in turn lead to increased protein synthesis of cardiac muscle fibers are elaborated. Finally, the microscopic events leading to the pathophysiologic macro events of cardiac failure, and the current experimental trials of gene therapy models, and the clustered regularly interspaced short palindromic repeats (CRISPR) type 2 system proteins, are discussed. We have concluded our discussion by emphasizing the need for more studies on epigenomics and experimental designs for gene therapy in HCM patients. This review focuses on the process of HCM from initial mutation to the development of phenotypic expression and various points of intervention in cardiac myocardial hypertrophy development.

Diagnostic Pitfalls of Digital Microscopy Versus Light Microscopy in Gastrointestinal Pathology: A Systematic Review.

Digital microscopy (DM) is one of the cutting-edge advances in pathology, which entails improved efficiency, diagnostic advantages, and potential application in virtual diagnosis, particularly in the current era of the coronavirus disease (COVID-19) pandemic. However, the diagnostic challenges are the remaining concerns for its wider adoption by pathologists, and these concerns should be addressed in a specific subspecialty. We aim to identify the common diagnostic pitfalls of whole slide imaging (WSI), one modality of DM, in gastrointestinal (GI) pathology. From validating studies of primary diagnosis performance, we included 16 records with features on GI cases involved, at least two weeks wash-out periods, and more than 60 case study designs. A tailored quality appraisal assessment was utilized to evaluate the risks of bias for these diagnostic accuracy studies. Furthermore, due to the highly heterogeneous studies and unstandardized definition of discordance, we extract the discordant cases in GI pathology and calculate the discrepant rate, resulting from 0.5% to 64.28%. Targeting discrepancy cases between digital microscopy and light microscopy, we demonstrate five main diagnostic pitfalls regarding WSI as follows: additional time to review slides in WSI, hard to identify dysplasia nucleus, missed organisms like Helicobacter pylori (H. pylori), specific cell recognitions, and technical issues. After detailed reviews and analysis, we generate two essential suggestions for further GI cases signing out by DM. One is to use systematized 20x scans for diagnostic workouts and requesting 40x or even 60x scans for challenging cases; another is that a high-volume slides training should be set before the real clinical application of WSI for primary diagnosis, particularly in GI pathology.