Reappraisal of p16 for Determining HPV Status of Head and Neck Carcinomas Arising in HPV Hotspots.

In an era of head and neck oncology where HPV status will soon dictate patient management, reliable HPV detection is critical. P16 immunohistochemistry (IHC) is currently recommended as the test of choice for oropharyngeal squamous cell carcinomas (OPSCCs). The purpose of this study was to determine the performance characteristics of p16 IHC based on a large clinical experience of squamous cell carcinomas (SCC) arising from HPV hot-spot regions of the head and neck. Consecutive OPSCCs, sinonasal SCCs, and metastatic SCCs of unknown primary sites were evaluated for the presence of HPV by p16 IHC and PCR-based HPV DNA testing as part of clinical care. For discrepant cases, high-risk HPV E6/E7 mRNA in situ hybridization (ISH) and, when possible, matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MassArray) genotyping were performed. 746 cancers underwent HPV testing by p16 IHC and DNA PCR genotyping. There was a 95.6% concordance between the 2 assays. Of the 33 discrepant cases, 32 cases (4.3%) were p16 positive but HPV DNA negative. In these cases, 68% were positive for mRNA ISH, invariably related to a non-16 HPV genotype. P16 IHC had an overall accuracy of 98.8%, a sensitivity of 99.8%, and a specificity of 92.1%. P16 IHC is a sensitive and specific assay for determining HPV status. HPV DNA PCR appears vulnerable to HPV genotype diversity and is prone to missing rare non-16 genotypes. HPV mRNA ISH is a practical and reliable direct measure of HPV that may help eliminate the small number of false-positive p16 cases and avoid potential patient harm related to erroneous HPV classification.

Circulating Tumor HPV DNA in Patients With Head and Neck Carcinoma: Correlation With HPV Genotyping.

Circulating tumor human papillomavirus DNA (ctHPVDNA) testing using digital-droplet polymerase chain reaction (PCR) detects fragments of tumor-modified human papillomavirus (HPV) in the plasma of patients with HPV-associated head and neck squamous cell carcinomas (HNSCCs). Its impact on tumor surveillance and primary diagnosis is limited by unresolved issues relating to sensitivity and specificity. The study population consisted of patients with HNSCC who had undergone ctHPVDNA testing. HPV status was determined by p16 immunohistochemistry and PCR-HPV genotyping on the tumor samples. For discrepant cases (HPV-positive/ctHPVDNA-negative), HPV status was confirmed by RNA in situ hybridization and, when possible, targeted single-nucleotide polymorphisms genotyping. A total of 167 patients had ctHPVDNA testing, and 141 tumors were HPV positive by p16 immunohistochemistry and PCR genotyping. Genotypes included types 16 (91.5%), 33 (4.3%), 35 (2.1%), and 18 (2.1%). ctHPVDNA was detected in 133 (94.3%) of HPV-positive HNSCCs but in none of the HPV-negative HNSCCs. Four of the 5 p16-positive cases that were negative by PCR and ctHPVDNA were positive by RNA in situ hybridization, and in 2 of these cases, rare high-risk genotypes were identified. ctHPVDNA had a sensitivity of 91.7%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 63.6%. The likelihood that patients with HPV-positive HNSCC have detectable ctHPVDNA is high. Non-HPV16 genotypes contribute to discrepancies but only in a small subset of cases. This finding validates ongoing efforts to use ctHPVDNA as a surveillance tool, and even as a primary diagnostic assay in patients presenting with masses in the neck and/or oropharynx.

Moderately-differentiated Ovarian Sertoli-Leydig Cell Tumor With a Concurrent Serous Borderline Tumor in a 16-year-old Girl.

Sertoli-Leydig cell tumors (SLCT) are rare tumors of the ovary with a peak incidence in the second to third decade of life. Serous borderline tumors (SBT) are epithelial ovarian neoplasms which occur at a median age of 50 years. A co-occurrence of SLCT and SBT has not yet been reported. Here, we describe a case of a 16-year-old girl who presented with irregular menses, virilization, and an abdominopelvic mass. The mass was surgically removed and an intraoperative consultation revealed an 18.5 cm solid and cystic ovarian mass with the presence of co-existing SLCT and SBT. The diagnosis was confirmed on permanent sections after extensive sampling and immunohistochemical stains. The SLCT showed positive staining for calretinin, inhibin, CD99, and androgen receptor. MART-1 immunostain highlighted the Leydig cells. The SBT showed classic features including hierarchically branching papillae lined by stratified serous epithelium. This pediatric case is the first reported case of a Sertoli-Leydig cell tumor arising in association with a serous borderline tumor.

Anal cancer screening results from 18-to-34-year-old men who have sex with men living with HIV.

Men who have sex with men living with HIV (MSM LWH) are at highest risk for human papillomavirus (HPV)-associated anal cancer. There is no consensus on the optimal screening initiation age. This study aimed to assess the prevalence and severity of anal HPV disease among MSM LWH under the age of 35, which is a currently proposed screening age threshold. Between 2014 and 2020, 1255 18-to-34-year-old MSM LWH underwent anal cytology screening. 916 were co-tested for high-risk HPV (HR-HPV). 467 underwent high-resolution anoscopy (HRA) and biopsy. Cancer registry data were queried. Predictors of abnormal cytology (ie, ≥ASCUS) and histological high-grade squamous intraepithelial lesions (HSIL) were evaluated using unadjusted logistic regression models. Median age was 28 years (range, 18-34). 19% received at least one dose of HPV vaccine. Abnormal cytology rate was 65%. HR-HPV and HPV16 prevalence were 87% and 30%. Biopsy results were benign (10%), LSIL (43%) and HSIL (47%). No cases of prevalent or incident anal cancers were detected. Findings were similar between age subgroups (18-24, 25-29 and 30-34) except for a higher prevalence of AIN 3 in the 30-34 group (19%). Abnormal cytology was significantly associated with HR-HPV infection. Histological HSIL was associated with HR-HPV infection and cytological LSIL or worse. The absence of anal cancer in a large cohort of MSM LWH under the age of 35, despite high prevalence of anal HR-HPV infection and precancer, supports an age-based anal cancer screening strategy for MSM LWH.

Low Complex CORDIC-based Hand Movement Recognition Design Methodology for Rehabilitation and Prosthetic Applications.

Hand movement recognition using Electromyography (EMG) signals have gained much significance lately and is extensively used for rehabilitation and prosthetic applications including stroke-driven disability and other neuromuscular disorders. Herein, quantitative analysis of EMG signals is very crucial. However, such applications are constrained by power consumption limitations due to the battery backup necessitating low-complex system design and the on-chip area requirement. Existing hand movement recognition methodologies using single-channel EMG signal involve computationally intensive stages, including Ensemble Empirical Mode Decomposition (EEMD), Fast Independent Component Analysis (FastICA), feature extraction, and Linear Discriminant Analysis (LDA) classification, which can not be mapped onto the low-complex architecture directly from the algorithmic level. The high computational complexity of LDA classification makes it difficult to be used for low-complex applications. In this paper, we introduce a low-complex CORDIC-based hand movement recognition design methodology targeting resource-constrained rehabilitation applications. This work explores replacing LDA classification with K-Means clustering due to its reduced complexity and efficient clustering algorithm. CORDIC-based K-Means clustering is used to further reduce the overall computational complexity of the system. The proposed low complex, K-Means clustering-based hand movement recognition for classifying seven hand movements using single-channel EMG data is found to be 99.77 % less complex and 1.28% more accurate than the conventional LDA-based classification.

India's tryst with salt: Dandi march to low sodium salts.

Salt plays a critical role in India's past as well as its present, from Dandi March to its role as a vehicle for micronutrient fortification. However, excess salt intake is a risk factor for high blood pressure and cardiovascular diseases (CVDs). Indians consume double the World Health Organization recommended daily salt (<5 g). India has committed to a 30 per cent reduction in sodium intake by 2025. Evidence based strategies for population sodium intake reduction require a moderate reduction in salt in - home cooked foods, packaged foods and outside-home foods. Reducing the sodium content in packaged food includes policy driven interventions such as front-of-package warning labels, food reformulation, marketing restrictions and taxation on high sodium foods. For foods outside of the home, setting standards for foods purchased and served by schemes like mid-day meals can have a moderate impact. For home cooked foods (the major source of sodium), strategies include advocacy for reducing salt intake. In addition to mass media campaigns for awareness generation, substituting regular salt with low sodium salt (LSS) has the potential to reduce salt intake even in the absence of a major shift in consumer behaviour. LSS substitution effectively lowers blood pressure and thus reduces the risk of CVDs. Further research is required on the effect of LSS substitutes on patients with chronic kidney disease. India needs an integrated approach to sodium reduction that uses evidence based strategies and can be implemented sustainably at scale. This will be possible only through scientific research, governmental leadership and a responsive evidence-to-action approach through a multi-stakeholder coalition.

'Stealth' Prostate Tumors.

BACKGROUND: The aim of this study was to determine the false negative rates of prebiopsy magnetic resonance imaging (MRI) and MRI-ultrasound (US) 12-core systematic prostate biopsy (PBx) by analyzing radical prostatectomy specimens. METHODS: This retrospective study included 3600 prostate cancer (PCa) patients who underwent robot-assisted laparoscopic radical prostatectomy. Based on comparison of lobe-specific data on final pathology with preoperative biopsy and imaging data, the study population was subdivided into group I-contralateral (CL) benign PBx (n = 983), group II-CL and/or bilateral (BL) non-suspicious mpMRI (n = 2223) and group III-CL benign PBx + non-suspicious mpMRI (n = 688). This population was studied for the presence of PCa, clinically significant PCa (csPCa), extracapsular extension (ECE) (pathological stage pT3), positive frozen section and final positive surgical margin (PSM) in the CL lobe. Descriptive statistics were performed. RESULTS: In subgroups I, II and III, PCa was respectively detected in 21.5%, 37.7% and 19.5% of cases, and csPCa in 11.3%, 16.3% and 10.3% of cases. CL pT3 disease was seen in 4.5%, 4% and 5.5%, and CL surgical margins and/or frozen section analysis were positive in 6%, 7% and 5% of cases in subgroups I, II and III, respectively. CONCLUSIONS: There are still significant rates of false negatives in the standard care diagnostics of PCa. Further strategies are required to improve the accuracy of diagnosis and determination of tumor location.

Melanotic medullary thyroid carcinoma: A case report with review of the literature.

Melanotic medullary thyroid carcinoma is morphologically defined by the presence of melanin deposits in the cytoplasm of tumor cells. It is an extremely rare variant with only 15 cases described in the literature to date and only one report of diagnosis by fine needle aspiration (FNA) biopsy. A 51-year-old woman presented with neck swelling. An ultrasound examination revealed a single solid nodule in the right thyroid lobe that measured 5.4 × 4.7 × 4.3 cm. Laboratory examination revealed elevated levels of serum calcitonin (8643.0 pg/ml), carcinoembryonic antigen (CEA) (86.2 ng/ml), and chromogranin A (123.2 ng/ml). An FNA biopsy of the thyroid nodule revealed predominantly single plasmacytoid cells with round to oval eccentric nuclei and dark brown intracytoplasmic granules. Immunohistochemical studies with Melan-A performed on a cell block slide confirmed that the granules contained melanin. The tumor cells were also positive for calcitonin, CEA, synaptophysin, AE1/AE3, CAM5.2, and HMB-45(focal); the tumor cells were negative for chromogranin, thyroglobulin, PAX8 and TTF-1. The diagnosis was reported as melanotic variant of medullary thyroid carcinoma. The patient underwent a total thyroidectomy which revealed tumor cell expression of insulinoma-associated protein 1 and confirmed neuroendocrine differentiation. Shortly after she presented with tumor recurrence in the thyroidectomy bed. The tumor cells were positive for only S100, SOX10, and Melan-A. Molecular analysis with the SEMA4 Solid Tumor Panel revealed mutations in the HRAS, PIK3CA, PIK3R1, MYC, and CCND3 genes. The final diagnosis was reported as melanocytic medullary thyroid carcinoma with high grade transformation and loss of epithelial and neuroendocrine expression.

Primary renal glomus tumor with concurrent papillary renal cell carcinoma and multiple papillary adenomas in a patient with end stage renal disease: a case report and clinicopathologic analysis.

Glomus tumors are mesenchymal tumors commonly seen in the extremities, and rarely seen in deep visceral organs. This is due to the lack of glomus bodies in visceral organs. Here, we describe an unusual association between glomus tumor and co-existing papillary renal cell carcinoma, multiple papillary adenomas, and end stage renal disease. We discuss our diagnostic approach and differential diagnoses, along with an extensive review of all reported benign and malignant primary glomus tumors. A 63-year-old male with a known history of a kidney transplant, end-stage renal disease, and previous nephrectomy of his right kidney due to a renal mass (papillary renal cell carcinoma) presented with a renal mass. Microscopic examination showed papillary carcinoma, multiple papillary adenomas, and a small nodule with uniform, round to oval cells. Immunohistochemical work-up revealed the small nodule to be a glomus tumor. Only 28 cases of primary renal glomus tumors have been reported in the literature. Most were discovered incidentally. None of the reported cases have occurred along with other renal tumors. This is the first case of the unusual combination of primary renal glomus tumor arising in the native kidney of a renal transplant patient with concurrent papillary renal cell carcinoma and multiple papillary adenomas (renal adenomatosis). We also explore the possible genetic basis behind this association.

Hardware-Algorithm Codesign for Fast and Energy Efficient Approximate String Matching on FPGA for Computational Biology.

Myers bit-vector algorithm for approximate string matching (ASM) is a dynamic programming based approach that takes advantage of bit-parallel operations. It is one of the fastest algorithms to find the edit distance between two strings. In computational biology, ASM is used at various stages of the computational pipeline, including proteomics and genomics. The computationally intensive nature of the underlying algorithms for ASM operating on the large volume of data necessitates the acceleration of these algorithms. In this paper, we propose a novel ASM architecture based on Myers bit-vector algorithm for parallel searching of multiple query patterns in the biological databases. The proposed parallel architecture uses multiple processing engines and hardware/software codesign for an accelerated and energy-efficient design of ASM algorithm on hardware. In comparison with related literature, the proposed design achieves 22× better performance with a demonstrative energy efficiency of  âˆ¼ 500×109 cell updates per joule.

Impacted gutkha presenting as an intrabronchial mass lesion leading to post-obstructive pneumonia.

A 66-year-old man presented with a chief complaint of difficulty breathing and productive cough. CT scan of the chest revealed an endobronchial mass with associated "tree-in-bud" opacities. A bronchoscopic biopsy of the mass was performed due to clinical suspicion of malignancy. Microscopic examination revealed inflamed endobronchial mucosa, granulation tissue and abundant fragments of uncharacterized organic material, compatible with aspiration. Detailed history revealed a history of chewing "gutkha", a form of smokeless tobacco comprising a mixture of betel nut and other condiments. Microscopic sections of a betel nut and the "gutkha mix" processed subsequently in the histology laboratory were found to be similar to the organic material found in the mass. Thus, a diagnosis of impacted betel nut mixture leading to post-obstructive pneumonia was rendered.

Constrictive and Hypertrophic Strictures in Ileal Crohn's Disease.

BACKGROUND & AIMS: Strictures in Crohn's disease (CD) are classically attributed to fibromuscular hypertrophy of the intestinal wall. We have identified and characterized CD-related ileal strictures that result instead from mural constriction (ie, reduced external circumference). METHODS: Twenty-four strictures and internal controls from 17 adults with obstructive CD were analyzed by cross-sectional morphometry. RESULTS: The stricture-to-control circumference ratios (CRs) ranged from 0.53 to 1.7. Six strictures with CR ≥1.0, designated hypertrophic, had concentrically thickened walls, mean 3-fold increases in cross-sectional area and stainable fibromucular tissue, and high transmural inflammation scores. In contrast, 18 strictures with CR <1.0, designated constrictive, had thin, pliant walls, cross-sectional areas and stainable fibromuscular tissue comparable with control values, and low transmural inflammation scores. Eight mildly constrictive strictures also showed mild fibromuscular mural expansion that fell short of statistical significance. Twelve of 18 constrictive strictures (67%) occurred multiply (2-4 strictures per specimen) in contrast with hypertrophic strictures, all of which occurred singly (P = .01). Constriction correlated quantitatively with circumferential serosal fat wrapping (P = .003) and was associated with myenteric lymphocytic plexitis (P = .02). Disease duration was shortest among subjects with constrictive strictures and correlated with increasing circumference (CR ≤0.8, 6.3 ± 6.2 years; CR >0.8, 8.7 ± 6.4 years; and CR ≥1.00, 13.7 ± 5.0 years, respectively; P = .03). CONCLUSIONS: Constrictive ileal strictures in CD differ pathologically and clinically from hypertrophic strictures, featuring little or no fibromuscular mural expansion, frequent multiplicity, and earlier onset. Mesenteric fat wrapping and myenteric plexitis may contribute to their pathogenesis. Pathologic manifestations of constriction and hypertrophy can coexist, suggesting that stricture heterogeneity may be shaped in part by the dynamics of constrictive and hypertrophic processes.

Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis.

BACKGROUND: Data on therapy and outcome of dense deposit disease (DDD), C3 glomerulonephritis (C3GN), and immune-complex MPGN (IC-MPGN) in children are limited. METHODS: In this retrospective single-center study from 2007 to 2019, kidney biopsies were reviewed to include patients aged <18-years with C3 glomerulopathy and IC-MPGN. Initial immunosuppression comprised prednisolone, mycophenolate mofetil (n = 51), tacrolimus (n = 11), and/or IV cyclophosphamide (n = 20). Clinicopathological features, response to therapy, and adverse outcome (eGFRcr < 15 mL/min/1.73 m2 or death) were evaluated. RESULTS: A total of 92 patients were classified as DDD (n = 48, 52.2%), C3GN (n = 26, 28.3%), and IC-MPGN (n = 18, 19.6%) by immunohistochemistry and electron microscopy; 8 patients with DDD were misclassified as IC-MPGN on immunofluorescence. At last follow-up (median 4.3 years), complete or partial remission occurred in 28.5, 36.1, and 16.7% patients with DDD, C3GN, and IC-MPGN, respectively. Serum albumin at onset < 2.5 g/dL (HR = 0.29, P = 0.005) and persistently low serum C3 (HR = 0.34, P = 0.02) were associated with lack of remission. The 5-year kidney survival was 62.6, 85.5, and 88.5% in patients with DDD, C3GN, and IC-MPGN, respectively (log-rank, P = 0.006). Presentation as rapidly progressive GN (HR = 11.2, P < 0.001), age > 10 years at onset (HR = 4.0, P = 0.004), and DDD (HR = 4.2, P = 0.02) were independently associated with adverse outcome; achieving remission was protective (HR = 0.04; P < 0.001). CONCLUSION: Outcome in patients with C3 glomerulopathy and IC-MPGN was unsatisfactory, and only a small proportion of patients achieved complete or partial remission. Patients with DDD were more likely to present with rapidly progressive GN and were at higher risk of adverse outcomes, including kidney failure.

Comparative Diagnostic Accuracy of Frozen Sections and Scrape Cytology in Ovarian Neoplasms.

INTRODUCTION: Frozen section is a well-established method for providing rapid and accurate intraoperative diagnosis. Cytological techniques such as imprint and scrape cytology and intraoperative fine-needle aspiration cytology are conventionally considered as less accurate alternatives to the frozen section. However, inexperienced hands, scrape cytology has been shown to provide remarkably accurate results comparable to the frozen section. AIMS: The aims of this study are as follows: (1) To evaluate the diagnostic utility of scrape cytology in the intraoperative diagnosis of ovarian neoplasms. (2) To compare the accuracy of scrape cytology with frozen section in the intraoperative diagnosis of ovarian neoplasms. MATERIALS AND METHODS: This study was conducted over a period of 3 years from 2014 to 2017. A total of 60 cases of clinically and radiologically suspected ovarian masses were included in the study. Thirty cases were evaluated using frozen section and 30 cases using scrape cytology alone. The intraoperative diagnosis of both was compared with the final paraffin section histopathology. RESULTS: The diagnostic accuracy of scrape cytology and frozen section in determining a benign and malignant nature of neoplasm was 96% and 100%, respectively. In 93% of cases, scrape cytology enabled correct categorization of the tumor as surface epithelial, germ-cell tumor, sex cord-stromal, or others. CONCLUSION: Scrape cytology is an adjunct to frozen section for providing an intraoperative diagnosis; however, in resource-poor settings, it can be used as a stand-alone method for aiding intraoperative decision-making.

Urbanized South Asians' susceptibility to coronary heart disease: The high-heat food preparation hypothesis.

OBJECTIVE: Known risk factors do not fully explain the comparatively high susceptibility to coronary heart disease (CHD) in South Asians (Indian, Pakistani, Bangladeshi, and Sri Lankan populations in South Asia and overseas). The search for explanatory hypotheses and cofactors that raise susceptibility of South Asians to CHD continues. The aim of this study was to propose "the high-heat food preparation hypothesis," where neo-formed contaminants (NFCs) such as trans-fatty acids (TFAs) and advanced glycation end-products (AGEs) are the cofactors. METHODS: We reviewed the actions of AGEs and TFAs, the burden of these products in tissues and blood in South Asians, the relationship between these products and CHD, the effects of preparing food and reheating oils at high temperatures on NFCs, and the foods and mode of preparation in South Asian and Chinese cuisines. RESULTS: Animal and human studies show NFCs increase the risk for CHD. Evidence on the consumption and body burden of these products across ethnic groups is not available, and comparable data on the NFC content of the cuisine of South Asians and potential comparison populations (e.g., the Chinese with lower CHD rates) are limited. South Asians' cuisine is dominated by frying and roasting techniques that use high temperatures. South Asian foods have high TFA content primarily through the use of partially hydrogenated fats, reheated oils, and high-heat cooking. Reheating oils greatly increases the TFA content. In comparison, Chinese cuisine involves mostly braising, steaming, and boiling rather than frying. CONCLUSION: We hypothesize that South Asians' susceptibility to CHD is partly attributable to high-heat treated foods producing high NFCs. Research to accrue direct evidence is proposed.

A randomized controlled trial to evaluate the effects of high Protein Complete (lActo) VEgetaRian (PACER) diet in non-diabetic obese Asian Indians in North India.

In view of the increasing prevalence of obesity in largely vegetarian Asian Indians, it is important to research a high protein, low carbohydrate vegetarian diet. The present study was designed to evaluate the effects of a "High Protein Complete (lacto) VEgetaRian Diet (Acronym; 'PACER diet'), on weight, body composition and metabolic profiles in non-diabetic obese Asian Indians living in north India. In this 8-week randomized control trial, 102 vegetarian subjects with body mass index (BMI) >25 kg/m2 were randomized to either a test diet (PACER diet; high protein, high fat and moderately low carbohydrate, lacto-vegetarian diet) or control diet (standard vegetarian diet formulated as the dietary guidelines for Asian Indians) after 4 weeks of diet and exercise run-in period. A standard exercise protocol was followed for both groups. Body weight, BMI, waist circumference (WC), blood pressure, fasting plasma glucose (FPG), fasting serum insulin and lipid profile were assessed before and after the intervention. There was significant weight loss along with improvements in cardio-metabolic risk factors among both the groups post intervention. Percent reductions in the intervention group for weight (6.1± 2.9; p < 0.001), WC (3.9 ± 1.7; p < 0.001), FPG (5.9 ± 3.2; p < 0.001), total cholesterol (10.2 ± 6.3: p < 0.001), serum triacylglycerol (13.6 ± 10.6; p < 0.001) and low-density lipoprotein cholesterol (11.9 ± 7.1; p < 0.001]) were significantly greater than the control diet group. In summary, intervention with a PACER diet (high protein, high fat and moderately low carbohydrate, lacto-vegetarian diet) showed significant improvement in weight loss, body composition and cardio-metabolic profile as compared to a standard vegetarian diet among obese Asian Indians in north India.