Gastric and colonic metastases of malignant melanoma diagnosed during endoscopic evaluation of symptomatic anemia presenting as angina: a case report.

A 72-year-old man visited cardiology for exertional chest pain, lightheadedness, and fatigue. Six years prior, he was surgically treated for cutaneous malignant melanoma of the lower back. After a negative cardiac work-up, primary care diagnosed severe iron deficiency anemia. Emergent upper and lower gastrointestinal (GI) endoscopy revealed simultaneous melanoma metastases to the stomach and colon with discrete macroscopic features. Metastatic disease, including brain, lung, and bone, was discovered on imaging. Treatment included immunotherapy with nivolumab and stereotactic radiosurgery of the brain metastases, and our patient has remained in continued remission even after 2 years. Melanoma with GI tract (GIT) metastasis has a poor prognosis and rarely presents symptomatically or with synchronous gastric and colonic lesions. This case illustrates the importance of early primary care involvement to expedite work-up for multifocal GI metastases in patients with a remote melanoma history presenting with symptoms related to iron deficiency anemia (IDA).

Medicina prepagada: problemas bioéticos evidentes en la atención de sus pacientes / Prepaid medicine: Evident bioethical problems in patient care

El sistema de salud en Colombia hace parte del Sistema de Seguridad Social Integral (SGSS) creado por la Ley 100 de 1993. La medicina prepagada existe como un contrato comercial de seguro de personas desde antes del SGSS, para mejorar la comodidad y el lujo, con libertad de elección de profesionales, sin trámites burocráticos para autorizaciones, oportunidad de citas, resolución rápida, eficiencia por ahorro en tiempo, dinero, efectividad y calidad en la atención. La naturaleza del vínculo comercial da pie para que los usuarios puedan tomar ventaja ilegítima del contrato y cambien las relaciones de poder y líneas de autoridad, amparados por el derecho que sienten que les confiere la compra con el fin de ver su inversión en resultados. Se generan así relaciones no idóneas, que transforman la relación médico-paciente, dando lugar a toda clase de conflictos, perversiones y vicios con consecuencias nefastas desde el punto de vista clínico, bioético y jurídico. El caso, analizado desde la metodología de análisis en ética clínica de Diego Gracia para resolver dilemas bioéticos, se aplica para hacer evidentes los conflictos y problemas bioéticos que surgieron en este contexto.

The health system in Colombia is part of the General Social Security System (GSSS) created by Law 100 of 1993. Prepaid medicine exists as a Personal Insurance Commercial Contract since before the SGSS, to improve comfort, luxury, with freedom of choice of professionals, without bureaucratic procedures for authorizations, opportunity for appointments, decisiveness, efficiency due to savings in time, money, effectiveness, and quality of care. The nature of the commercial relationship allows users to take illegitimate advantage of the contract and change the power relationships and lines of authority protected by the right they feel the purchase confers on them to see their investment in results. Inappropriate relationships are thus generated, which transform the doctor-patient relationship, giving rise to all kinds of conflicts, perversions, and vices with disastrous consequences from the clinical, bioethical and legal point of view. The case, analyzed from Diego Gracia's clinical ethics analysis methodology to resolve bioethical dilemmas, is applied to make evident the conflicts and bioethical problems that arose in this context.

Cytomegaloviral colitis in primary CMV viraemia in a young immunocompetent adult.

A man in his 20s presented with a 2-week history of fever, fatigue and diarrhoea. On arrival to the emergency department, he had clinical findings of sepsis. The care team initially suspected sepsis secondary to bacterial colitis and administered antibiotics. Further workup including a stool PCR assay for gastrointestinal pathogens failed to establish a diagnosis, and he had no evidence of immune compromise. Colonoscopy revealed mucosal ulceration presumed to be ulcerative colitis. Histopathology obtained after discharge revealed severe colitis with cytomegalovirus (CMV) inclusions. Serological studies indicated a primary CMV infection. To our knowledge, this is the first report of a primary CMV infection presenting as severe colitis and systemic disease in a young immunocompetent patient without underlying disease.

Unusual Presentation of Cow's Milk Protein Allergy.

Cow's milk protein allergy (CMPA) is an abnormal immunologic response to bovine protein that can result in various gastrointestinal and cutaneous manifestations including diarrhea, failure to thrive, malabsorption, and even protein-losing enteropathy. We describe a case of a 7-month-old breastfed male who presented with severe atopic dermatitis, emesis, oily diarrhea, failure to thrive, electrolyte disturbance, and hemodynamic instability. Following stabilization, additional evaluation revealed concern for abetalipoproteinemia. Ultimately, the patient's symptoms resolved with introduction of an elemental formula and returned with reinitiation of cow's milk protein, confirming the diagnosis of severe CMPA. It is important for the general practitioner to be aware of the various presentations and have a high index of suspicion for CMPA as no symptom or diagnostic test is pathognomonic for diagnosis. Even though it can mimic other causes of malabsorption, a trial with extensively hydrolyzed or elemental formula should be attempted before undertaking invasive testing.

Locoregional Therapy Protocols With and Without Radioembolization for Hepatocellular Carcinoma as Bridge to Liver Transplantation.

OBJECTIVE: The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). MATERIALS AND METHODS: Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. RESULTS: One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. CONCLUSIONS: Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo.

Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4','5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis.

Desmoplasia and Detached Papillae in Early Esophageal Adenocarcinoma: A Histologic Study on Endoscopic Submucosal Dissection Specimens.

BACKGROUND: Desmoplasia and detached papillae were only rarely mentioned in intramucosal adenocarcinoma of esophagus or stomach. This study aimed to examine these two features in early esophageal adenocarcinoma. METHODS: All endoscopic submucosal dissections specimens performed for Barrett's esophagus neoplasm during the year 2013 to 2016 were reviewed. These 44 cases included in this study were eight Barrett's esophagus with high-grade dysplasia, 21 intramucosal adenocarcinoma, and 15 submucosally or beyond invasive adenocarcinoma. RESULTS: Desmoplasia occurred in 73% submucosally or beyond invasive adenocarcinoma, higher than intramucosal adenocarcinoma (24%) and high-grade dysplasia (0%) (P < 0.00001 for each). The frequency of detached papillae in intramucosal adenocarcinoma and submucosally or beyond invasive adenocarcinoma specimens was 71.4% and 73.3%, higher than high-grade dysplasia (0%, P < 0.0001 for both). Univariate analysis identified desmoplasia as risk factors for lymphovascular invasion in intramucosal adenocarcinoma specimens (odds ratio 12, P = 0.048), and desmoplasia and tumor thickness for lymphovascular invasion in intramucosal adenocarcinoma and submucosally or beyond invasive adenocarcinoma specimens combined (odds ratio 9.0, P = 0.005; odds ratio 2.7, P = 0.01, respectively). Age, gender, the largest dimension and the average thickness of endoscopic submucosal dissection specimens, tumor size, detached papillae, and poor differentiation were not associated with lymphovascular invasion (P ≥ 0.05 for all). Multivariate analysis confirmed that only desmoplasia was predictive of lymphovascular invasion (odds ratio 8.0, P = 0.02) in intramucosal adenocarcinoma and submucosally or beyond invasive adenocarcinoma specimens combined. CONCLUSIONS: In conclusion, desmoplasia occurs in about a quarter of esophageal intramucosal adenocarcinomas and three quarters of submucosally or beyond invasive adenocarcinomas, and is associated with lymphovascular invasion in early esophageal adenocarcinoma.

Gastric Plexiform Fibromyxoma: A Great Mimic of Gastrointestinal Stromal Tumor (GIST) and Diagnostic Pitfalls.

Through a multicenter study, we collected seven cases of gastric plexiform fibromyxoma including four females and three males, 21 to 79 y old (46.1 ± 10.1). All cases showed a unilocular lesion measuring 0.3 to 17 cm (5.3 ± 2.4), arising from antrum (5/7) or body (2/7). Six of the seven cases had intraoperative frozen sections and/or endoscopic ultrasound fine needle aspiration (EUS-FNA), and all of them were preoperatively or intraoperatively diagnosed as gastrointestinal stromal tumor (GIST). EUS-FNA material showed markedly elongated spindle cells with streaming oval to elongated nuclei with rounded ends. Histologically, the tumors exhibited a plexiform growth pattern and were composed of a rich myxoid stroma and cytologically bland uniform spindle cells without mitotic figures, with the exception of one case which displayed nuclear pleomorphism and increased mitosis. Immunostains showed the tumor cells to be focally positive for SMA (6/6), focally and weakly positive for desmin (3/6) and caldesmon (2/3), negative for CD117 (0/7), CD34 (0/7), DOG1 (0/4), and S100 (0/5). No mutations were identified on Next-Generation Sequencing test, and no loss of SDHB immunoreactivity was identified in the tumor with nuclear pleomorphism. One case was treated with Gleevec because of the initial diagnosis of GIST. All patients had a follow-up for up to 11 y, with no tumor recurrence or metastasis reported. Our results suggest that gastric plexiform fibromyxoma is rare and may be underrecognized and misinterpreted as GIST during intraoperative frozen section or preoperative EUS-FNA diagnosis without immunostains leading to inappropriate treatment.

Risk factors for colorectal neoplasia in patients with underlying inflammatory bowel disease: a multicenter study.

BACKGROUND: This study sought to evaluate the risk factors for the development of colitis-associated neoplasia (CAN) in Chinese patients with inflammatory bowel disease (IBD). METHODS: IBD patients who developed CAN between 1999 and 2016 were identified from eight medical centers. In addition to initial pathology evaluation, a CAN diagnosis was confirmed by two expert pathologists. Patients with CAN (n = 29) were compared with non-CAN controls (n = 87). Matching was performed for gender and IBD type with a ratio of three controls to one subject. RESULTS: Of the 29 patients with CAN, 8 (27.6%) had colorectal cancer (CRC), 20 (69.0%) had a final diagnosis of low-grade dysplasia and 1 (3.4%) had high-grade dysplasia. Multivariate analysis revealed that an older age at the time of IBD diagnosis and a longer IBD duration were independent risk factors for the development of CAN, with odds ratios of 1.09 [95% confidence interval (CI): 1.04-1.14, P < 0.001] and 1.14 (95% CI: 1.03-1.27, P = 0.013), respectively. Comparison between IBD patients with CRC and those with dysplasia indicated that the former were older at the time of IBD diagnosis (P = 0.012) and had longer IBD durations (P = 0.019). CONCLUSIONS: Older age at the time of IBD diagnosis and longer IBD duration were found to be associated with the development of CAN in IBD patients.

A case of extensive hepatic adenomatosis in a renal transplant patient.

Hepatic adenomatosis (HA) is a rare condition that is traditionally associated with oral contraceptive use, glycogen storage diseases or metabolic syndrome. Here we present a renal transplant recipient that was diagnosed with HA and has none of the traditional risk factors. We review the literature on diagnosing and managing HA.

Stroma-derived extracellular vesicles deliver tumor-suppressive miRNAs to pancreatic cancer cells.

The biology of tumor-associated stroma (TAS) in pancreatic ductal adenocarcinoma (PDAC) is not well understood. The paradoxical observation that stroma-depletion strategies lead to progression of PDAC reinforced the need to critically evaluate the functional contribution of TAS in the initiation and progression of PDAC. PDAC and TAS cells are unique in their expression of specific miRNAs, and this specific miRNA expression pattern alters host to tumor microenvironment interactions. Using primary human pancreatic TAS cells and primary xenograft PDAC cells co-culture, we provide evidence of miRNA trafficking and exchanging between TAS and PDAC cells, in a two-way, cell-contact independent fashion, via extracellular vesicles (EVs) transportation. Selective packaging of miRNAs into EVs led to enrichment of stromal specific miR-145 in EVs secreted by TAS cells. Exosomes, but not microvesicles, derived from human TAS cells demonstrated a tumor suppressive role by inducing PDAC cell apoptosis. This effect was mitigated by anti-miR-145 sequences. Our data suggest that TAS-derived miRNAs are delivered to adjacent PDAC cells via exosomes and suppress tumor cell growth. These data highlight that TAS cells secrete exosomes carrying tumor suppressive genetic materials, a possible anti-tumor capacity. Future work of the development of patient-derived exosomes could have therapeutic implications for unresectable PDAC.

Steatohepatitic Variant of Hepatocellular Carcinoma: A Focused Review.

The incidence of hepatocellular carcinoma (HCC) has steadily increased over the past three decades and currently ranks as the fifth most common cancer worldwide. Likewise, non-alcoholic fatty liver disease (NAFLD), a known risk factor for the development of HCC, has emerged as the most common liver disease in Western countries. The underlying pathogenesis of NAFLD-related HCC remains unclear. The steatohepatitic variant of HCC (SH-HCC) typically presents in patients with metabolic risk factors and either cirrhotic or non-cirrhotic NAFLD and shares many of the histological features found in non-alcoholic steatohepatitis (NASH). Given their similar morphological features, distinguishing SH-HCC from background fatty liver can be a diagnostic challenge. Immunohistochemical studies to characterize and assist in the diagnosis are relatively limited. Whether the steatotic phenotype of SH-HCC results from the tumor's adaptive response to an environment rich in fatty acids or from an independent pathogenic pathway remains to be seen. This review aims to summarize what is currently known regarding the pathogenesis and clinicopathological features of SH-HCC.

Mucinous Cystadenoma: A Rare Hepatic Tumor in a Child.

Mucinous cystadenomas (MCAs) of the liver (also called hepatic biliary cystadenomas) are rare tumors that comprise about 5% of cystic masses of the liver in adults. These slow-growing lesions most commonly occur in middle-aged individuals, with a female sex predominance. Herein, we present a MCA in a 6-year-old male, one of only very few such cases described in the pediatric literature to date. Although MCAs are generally considered benign lesions, malignant transformation rarely occurs. The recurrence rate is high when partial cyst excision is performed. Therefore, complete surgical cyst resection with clinical follow-up, including imaging, is warranted.

The pancreatic tumor microenvironment drives changes in miRNA expression that promote cytokine production and inhibit migration by the tumor associated stroma.

The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS.

Common Inflammatory Disorders and Neoplasia of the Ileal Pouch: A Review of Histopathology.

Ileal pouch-anal anastomosis (IPAA) is the standard restorative procedure after proctocolectomy in patients with ulcerative colitis (UC) who require colectomy. The ileal pouch is susceptible to a variety of insults including mechanical injury, ischemia, fecal stasis, and infectious agents. In addition, the development of recurrent and idiopathic inflammatory bowel disease and neoplasia may occur in the ileal pouch. Although clinical, endoscopic, and radiographic examination can diagnose many ileal pouch diseases, histologic examination plays an essential role in diagnosis and management, particularly in cases with antibiotic refractory chronic pouchitis and pouch neoplasia.

Influence of Cushioning Variables in the Workplace and in the Family on the Probability of Suffering Stress.

Stress at work and in the family is a very common issue in our society that generates many health-related problems. During recent years, numerous studies have sought to define the term stress, raising many contradictions that various authors have studied. Other authors have attempted to establish some criteria, in subjective and not very quantitative ways, in an attempt to reduce and even to eliminate stressors and their effects at work and in the family context. The purpose of this study was to quantify so-called cushioning variables, such as control, social support, home/work life conciliation, and even sports and leisure activities, with the purpose of, as much as possible, reducing the negative effects of stress, which seriously affects the health of workers. The study employs data from the Fifth European Working Conditions Survey, in which nearly 44,000 interviewees from 34 countries in the European Union participated. We constructed a probabilistic model based on a Bayesian network, using variables from both the workplace and the family, the aforementioned cushioning variables, as well as the variable stress. If action is taken on the above variables, then the probabilities of suffering high levels of stress may be reduced. Such action may improve the quality of life of people at work and in the family.

Clinical significance and management of Barrett's esophagus with epithelial changes indefinite for dysplasia.

Barrett's esophagus (BE) is defined as the extension of salmon-colored mucosa into the tubular esophagus ≥ 1 cm proximal to the gastroesophageal junction with biopsy confirmation of intestinal metaplasia. Patients with BE are at increased risk of esophageal adenocarcinoma (EAC), and undergo endoscopic surveillance biopsies to detect dysplasia or early EAC. Dysplasia in BE is classified as no dysplasia, indefinite for dysplasia (IND), low grade dysplasia (LGD) or high grade dysplasia (HGD). Biopsies are diagnosed as IND when the epithelial abnormalities are not sufficient to diagnose dysplasia or the nature of the epithelial abnormalities is uncertain due to inflammation or technical issues. Specific diagnostic criteria for IND are not well established and its clinical significance and management has not been well studied. Previous studies have focused on HGD in BE and led to changes and improvement in the management of BE with HGD and early EAC. Only recently, IND and LGD in BE have become focus of intense study. This review summarizes the definition, neoplastic risk and clinical management of BE IND.

Cystoisospora belli Infection of the Gallbladder in Immunocompetent Patients: A Clinicopathologic Review of 18 Cases.

Cystoisospora belli, previously known as Isospora belli, is an obligate intracellular coccidian parasite that is most often associated with gastrointestinal disease in immunocompromised patients. In this study, we detail the clinicopathologic features of 18 cases of Cystoisospora infection affecting the gallbladder in immunocompetent individuals and compare them with a control group. Each case was reviewed for cholecystitis (none, acute, chronic), epithelial disarray, presence of intraepithelial lymphocytes (none, rare [≤5 per 20 epithelial cells], present [>5 per 20 epithelial cells]), architectural distortion, intramucosal eosinophilia, and mural thickening/serositis. The mean age of patients with Cystoisospora infection was 33 years and the male to female ratio 1:4.3. Cholecystectomy was performed for biliary dyskinesia (n=7), abdominal pain (n=7), suspected cholelithiasis (n=5), and cholecystitis (n=3). In 2 cases, Cystoisospora was found in donor gallbladders resected at the time of liver transplantation. Each case was characterized by eosinophilic, oval or banana-shaped intraepithelial parasites within perinuclear parasitophorous vacuoles. Most cases showed epithelial disarray and minimal intraepithelial lymphocytosis. Of the 11 cases with an average follow-up of 15 months, none had evidence of disease related to Cystoisospora infection within the biliary tract or elsewhere in the gastrointestinal tract. We present the largest series of gallbladder cystoisosporiasis in immunocompetent patients to date. Cystoisospora infection is underrecognized in the gallbladders of immunocompetent patients, in part due to the subtle findings in routine cholecystectomy specimens. On the basis of the clinical follow-up, gallbladder cystoisosporiasis in immunocompetent individuals appears to be a self-limited infection.