Intrabiliary Metastasis of Colorectal Mucinous Adenocarcinoma Mimicking Choledocholithiasis 18 Years After the Primary Tumor

This case report presents a 62-year-old male who had previously undergone curative colectomy and neoadjuvant chemotherapy in 2005 for colorectal cancer. He presented with jaundice, which was initially attributed to choledocholithiasis. After cholecystectomy and repeat ERCPs, hyperbilirubinemia persisted. There was persistent dilation of the right posterior duct on imaging, concerning for biliary stricture, possibly due to cholangiocarcinoma or intraductal papillary neoplasm. During a right posterior hepatectomy, a peripheral liver lesion was found in association with the dilated bile duct. On frozen evaluation, the lesion was found to be invasive adenocarcinoma. The final pathology was compatible with a metastatic mucinous adenocarcinoma of colonic origin. A repeat colonoscopy was done with no recurrence or new lesion in the colon. This case underscores the challenges associated with diagnosing biliary issues and assessing liver lesions in patients with a remote history of cancer. It raises the question of when and whether, after primary cancer treatment, it becomes safe to explore alternative diagnoses without immediately suspecting metastasis. Another significant challenge arises in ascertaining the most suitable therapeutic approaches for these patients. This is because these extremely late recurrences might be linked to an indolent, slow-growing type of tumor, but also have been linked to cancer stem cells, and as any recurrence, demands attention

A rare case of anal carcinosarcoma with human papilloma virus infection in both biphasic tumor elements: An immunohistochemical, molecular and ultrastructural study

AbstractCarcinosarcoma of the anus is rare and has yet to be reportedly associated with the keratinocyte-specific Human Papilloma Virus (HPV). We describe a case of anal carcinosarcoma with HPV infection in both the epithelial and mesenchymal components of the tumor by immunohistochemistry, chromogenic in-situ hybridization (CISH) and further supported by electron microscopy (EM). Microscopic examination of the tumor showed nests of poorly-differentiated invasive squamous cell carcinoma with basaloid features intermixed with a hypercellular, atypical spindle cell proliferation. Immunohistochemistry demonstrated that the epithelial component was positive for AE1/AE3, p63, CK5/6 and p16, whilst the mesenchymal component was positive for smooth muscle actin, vimentin, and focally positive for desmin and p16, consistent with carcinosarcoma. The tumor was negative for GATA-3, CK7 and CK20. CISH demonstrated that the tumor was positive for high risk HPV (subtype 16/18) in both tumor components. EM further supported the presence of intracellular virus particles (~50nm) that is compatible with HPV infection. Infection of both epithelial and mesenchymal tumor components by HPV has not been previously observed in the gastrointestinal tract. This finding may represent initial epithelial HPV infection with subsequent divergent tumoral differentiation and suggests the presence of viral replication in both biphasic tumor components

Mitochondrial Somatic Mutations and the Lack of Viral Genomic Variation in Recurrent Respiratory Papillomatosis

Recurrent Respiratory Papillomatosis (RRP) is a rare disease of the aerodigestive tract caused by the Human Papilloma Virus (HPV) that manifests as profoundly altered phonatory and upper respiratory anatomy. Current therapies are primarily symptomatic; enhanced insight regarding disease-specific biology of RRP is critical to improved therapeutics for this challenging population. Multiplex PCR was performed on oral rinses collected from twenty-three patients with adult-onset RRP every three months for one year. Twenty-two (95.6%) subjects had an initial HPV positive oral rinse. Of those subjects, 77.2% had an additional positive oral rinse over 12 months. A subset of rinses were then compared to tissue samples in the same patient employing HPViewer to determine HPV subtype concordance. Multiple HPV copies (60-787 per human cell) were detected in RRP tissue in each patient, but a single dominant HPV was found in individual samples. These data confirm persistent oral HPV infection in the majority of patients with RRP. In addition, three novel HPV6 isolates were found and identical HPV strains, at very low levels, were identified in oral rinses in two patients suggesting potential HPV subtype concordance. Finally, somatic heteroplasmic mtDNA mutations were observed in RRP tissue with 1.8 mutations per sample and two nonsynonymous variants. These data provide foundational insight into both the underlying pathophysiology of RRP, but also potential targets for intervention in this challenging patient cohort

Effects of Image Quantity and Image Source Variation on Machine Learning Histology Differential Diagnosis Models

Aims: Histology, the microscopic study of normal tissues, is a crucial element of most medical curricula. Learning tools focused on histology are very important to learners who seek diagnostic competency within this important diagnostic arena. Recent developments in machine learning (ML) suggest that certain ML tools may be able to benefit this histology learning platform. Here, we aim to explore how one such tool based on a convolutional neural network, can be used to build a generalizable multi-classification model capable of classifying microscopic images of human tissue samples with the ultimate goal of providing a differential diagnosis (a list of look-alikes) for each entity. Methods: We obtained three institutional training datasets and one generalizability test dataset, each containing images of histologic tissues in 38 categories. Models were trained on data from single institutions, low quantity combinations of multiple institutions, and high quantity combinations of multiple institutions. Models were tested against withheld validation data, external institutional data, and generalizability test images obtained from Google image search. Performance was measured with macro and micro accuracy, sensitivity, specificity, and f1-score. Results: In this study, we were able to show that such a model\u27s generalizability is dependent on both the training data source variety and the total number of training images used. Models which were trained on 760 images from only a single institution performed well on withheld internal data but poorly on external data (lower generalizability). Increasing data source diversity improved generalizability, even when decreasing data quantity: models trained on 684 images, but from three sources improved generalization accuracy between 4.05% and 18.59%. Maintaining this diversity and increasing the quantity of training images to 2280 further improved generalization accuracy between 16.51% and 32.79%. Conclusions: This pilot study highlights the significance of data diversity within such studies. As expected, optimal models are those that incorporate both diversity and quantity into their platforms

Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a

Pluripotent embryonic stem cells (ESCs) self-renew or differentiate into all tissues of the developing embryo and cell-specification factors are necessary to balance gene expression. Here we delineate the function of the PHD-finger protein 5a (Phf5a) in ESC self-renewal and ascribe its role in regulating pluripotency, cellular reprogramming, and myoblast specification. We demonstrate that Phf5a is essential for maintaining pluripotency, since depleted ESCs exhibit hallmarks of differentiation. Mechanistically, we attribute Phf5a function to the stabilization of the Paf1 transcriptional complex and control of RNA polymerase II elongation on pluripotency loci. Apart from an ESC-specific factor, we demonstrate that Phf5a controls differentiation of adult myoblasts. Our findings suggest a potent mode of regulation by the Phf5a in stem cells, which directs their transcriptional program ultimately regulating maintenance of pluripotency and cellular reprogramming

Algumas observaçoes sobre a estimulaçao cardíaca no Brasil entre 2000 e 2014: 25 anos do RBM - Registro Brasileiro de Marcapassos, Desfibriladores e Ressincronizadores Cardíacos

INTRODUÇAO: Desde que foi iniciado, há 25 anos, o Registro Brasileiro de Marcapassos, Desfibriladores e Ressincronizadores Cardíacos (RBM) cadastrou 306.886 cirurgias até 31 de dezembro de 2014, das quais 216.537 foram primeiro implante (190.747 marcapassos, 13.725 cardiodesfibriladores, 6.683 ressincronizadores, 4.052 cardiodesfibriladores com ressincronizadores e 1.330 sem informaçoes) e 90.349, trocas de dispositivos. MÉTODO: Analisamos o número de cirurgias e suas variedades entre 2000 e 2014 (dados de 31 de dezembro de 2015) e comparamos com alguns países, com a média europeia e com informaçoes populacionais do Instituto Brasileiro de Geografia e Estatística. RESULTADOS: O número do RBM referente às cirurgias realizadas no Brasil (129/1.000.000) foi comparado com a média europeia (960/1.000.000), verificando-se valores 7,4 vezes menores (mesmo estimando-se proporcionalmente, os valores sao 4,5 vezes menores). A modificaçao na etiologia da primeira cirurgia entre 2009 e 2014 revelou aumento da incidência de fibrose do sistema de conduçao (de 32,58% para 38,05%) e reduçao da doença de Chagas (de 18% para 11,70%), sem grandes modificaçoes nas outras causas. Considerando-se o número total de cirurgias, nota-se pequeno aumento em todas as regioes, exceto a Norte, com discreto aumento das cirurgias de cardiodesfibrilador implantável e cardiodesfibrilador implantável multissítio em todo o País. Houve pequeno aumento dos hospitais que realizaram cirurgias com a utilizaçao desses dispositivos. O número total de médicos que fazem implantes de dispositivos aumentou discretamente, especialmente nas regioes Sul e Sudeste, com queda discreta nas outras. O grupo que realizou até 10 cirurgias por ano cresceu 19,28% e o de 11-50 cirurgias por ano, 12,84%. CONCLUSAO: Houve discreto aumento do número de cirurgias, com prevalência insatisfatória, e pequeno e insuficiente aumento dos procedimentos mais complexos e modernos. Quanto à etiologia que motivou as cirurgias, ocorreu aumento da incidência de fibrose do sistema de conduçao e reduçao da doença de Chagas. Observou-se aumento do número de hospitais que realizaram até 50 cirurgias por ano, além de concentraçao de profissionais nas regioes com maior densidade populacional, com pequeno aumento do número de médicos que realizaram os procedimentos, especialmente daqueles que realizaram até 10 cirurgias por ano. Nao houve modificaçao significativa na proporçao médica por regiao, à exceçao de queda na regiao Norte

Principales medidas de profilaxis en endoscopia bariátrica. Guía Española de Recomendación de Expertos

Bariatric endoscopy (BE) encompasses a number of techniques -some consolidated, some under development- aiming to contribute to the management of obese patients and their associated metabolic diseases as a complement to dietary and lifestyle changes. To date different intragastric balloon models, suture systems, aspiration methods, substance injections and both gastric and duodenal malabsorptive devices have been developed, as well as endoscopic procedures for the revision of bariatric surgery. Their ongoing evolution conditions a gradual increase in the quantity and quality of scientific evidence about their effectiveness and safety. Despite this, scientific evidence remains inadequate to establish strong grades of recommendation allowing a unified perspective on prophylaxis in BE. This dearth of data conditions leads, in daily practice, to frequently extrapolate the measures that are used in bariatric surgery (BS) and/or in general therapeutic endoscopy. In this respect, this special article is intended to reach a consensus on the most common prophylactic measures we should apply in BE. The methodological design of this document was developed while attempting to comply with the following 5 phases: Phase 1: delimitation and scope of objectives, according to the GRADE Clinical Guidelines. Phase 2: setup of the Clinical Guide-developing Group: national experts, members of the Grupo Español de Endoscopia Bariátrica (GETTEMO, SEED), SEPD, and SECO, selecting 2 authors for each section. Phase 3: clinical question form (PICO): patients, intervention, comparison, outcomes. Phase 4: literature assessment and synthesis. Search for evidence and elaboration of recommendations. Based on the Oxford Centre for Evidence-Based Medicine classification, most evidence in this article will correspond to level 5 (expert opinions without explicit critical appraisal) and grade of recommendation C (favorable yet inconclusive recommendation) or D (inconclusive or inconsistent studies). Phase 5: External review by experts. We hope that these basic preventive measures will be of interest for daily practice, and may help prevent medical and/or legal conflicts for the benefit of patients, physicians, and BE in general

Psychopharmacotherapy of panic disorder: 8-week randomized trial with clonazepam and paroxetine

The objective of the present randomized, open-label, naturalistic 8-week study was to compare the efficacy and safety of treat- ment with clonazepam (N = 63) and paroxetine (N = 57) in patients with panic disorder with or without agoraphobia. Efficacy assessment included number of panic attacks and clinician ratings of the global severity of panic disorders with the clinical global impression (CGI) improvement (CGI-I) and CGI severity (CGI-S) scales. Most patients were females (69.8 and 68.4% in the clonazepam and paroxetine groups, respectively) and age (mean ± SD) was 35.9 ± 9.6 years for the clonazepam group and 33.7 ± 8.8 years for the paroxetine group. Treatment with clonazepam versus paroxetine resulted in fewer weekly panic attacks at week 4 (0.1 vs 0.5, respectively; P < 0.01), and greater clinical improvements at week 8 (CGI-I: 1.6 vs 2.9; P = 0.04). Anxiety severity was significantly reduced with clonazepam versus paroxetine at weeks 1 and 2, with no difference in panic disorder severity. Patients treated with clonazepam had fewer adverse events than patients treated with paroxetine (73 vs 95%; P = 0.001). The most common adverse events were drowsiness/fatigue (57%), memory/concentration difficulties (24%), and sexual dysfunction (11%) in the clonazepam group and drowsiness/fatigue (81%), sexual dysfunction (70%), and nausea/vomiting (61%) in the paroxetine group. This naturalistic study confirms the efficacy and tolerability of clonazepam and paroxetine in the acute treatment of patients with panic disorder

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURO bservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Aims: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. Methods and results: We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (~20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA 2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. Conclusion: The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal. © The Author 2013