The microbiota of the bilio-pancreatic system: A cohort, STROBE-compliant study

Background: The gut microbiota play an essential role in protecting the host against pathogenic microorganisms by modulating immunity and regulating metabolic processes. In response to environmental factors, microbes can hugely alter their metabolism. These factors can substantially impact the host and have potential pathologic implications. Particularly pathogenic microorganisms colonizing pancreas and biliary tract tissues may be involved in chronic inflammation and cancer evolution. Purpose: To evaluate the effect of bile microbiota on survival in patients with pancreas and biliary tract disease (PBD). Patients and Methods: We investigated 152 Italian patients with cholelithiasis (CHL), cholangitis (CHA), cholangiocarcinoma (CCA), gallbladder carcinoma (GBC), pancreas head carcinoma (PHC), ampullary carcinoma (ACA), and chronic pancreatitis (CHP). Demographics, bile cultures, therapy, and survival rates were analyzed in cohorts (T1 death <6 months; T2 death <12 months; T3 death <18 months, T3S alive at 18 months). Results: The most common bacteria in T1 were E. coli, K. pneumoniae, andP. aeruginosa. In T2, the most common bacteria were E. coli and P. aeruginosa. InT3, there were no significant bacteria isolated, while in T3S the most common bacteria were like those found in T1. E. coli and K. pneumoniae were positive predictors of survival for PHC and ACA, respectively. E. coli, K. pneumoniae, andP. aeruginosa showed a high percentage of resistant bacteria to 3CGS, aminoglycosides class, and quinolone group especially at T1 and T2 in cancer patients. Conclusions: An unprecedented increase of E. coli in bile leads to a decrease in survival. We suggest that some strains isolated in bile samples may be considered within the group of risk factors in carcinogenesis and/or progression of hepato-biliary malignancy. A better understanding of bile microbiota in patients with PBD should lead to a multifaceted approach to rapidly detect and treat pathogens before patients enter the surgical setting in tandem with the implementation of the infection control policy

TTF-1/p63-positive poorly differentiated NSCLC: A histogenetic hypothesis from the basal reserve cell of the terminal respiratory unit

TTF-1 is expressed in the alveolar epithelium and in the basal cells of distal terminal bronchioles. It is considered the most sensitive and specific marker to define the adenocarcinoma arising from the terminal respiratory unit (TRU). TTF-1, CK7, CK5/6, p63 and p40 are useful for typifying the majority of non-small-cell lung cancers, with TTF and CK7 being typically expressed in adenocarcinomas and the latter three being expressed in squamous cell carcinoma. As tumors with coexpression of both TTF-1 and p63 in the same cells are rare, we describe different cases that coexpress them, suggesting a histogenetic hypothesis of their origin. We report 10 cases of poorly differentiated non-small-cell lung carcinoma (PD-NSCLC). Immunohistochemistry was performed by using TTF-1, p63, p40 (∆Np63), CK5/6 and CK7. EGFR and BRAF gene mutational analysis was performed by using real-time PCR. All the cases showed coexpression of p63 and TTF-1. Six of them showing CK7+ and CK5/6− immunostaining were diagnosed as “TTF-1+ p63+ adenocarcinoma”. The other cases of PD-NSCLC, despite the positivity for CK5/6, were diagnosed as “adenocarcinoma, solid variant”, in keeping with the presence of TTF-1 expression and p40 negativity. A “wild type” genotype of EGFR was evidenced in all cases. TTF1 stained positively the alveolar epithelium and the basal reserve cells of TRU, with the latter also being positive for p63. The coexpression of p63 and TTF-1 could suggest the origin from the basal reserve cells of TRU and represent the capability to differentiate towards different histogenetic lines. More aggressive clinical and morphological features could characterize these “basal-type tumors” like those in the better known “basal-like” cancer of the breast

Successful intravenous immunoglobulin treatment for steroid-resistant eosinophilic enteritis in a patient with systemic lupus erythematosus.

Eosinophilic gastroenteritis is a rare condition of unknown etiology characterized by eosinophilic infiltration of the bowel. Corticosteroids are the mainstay of EG therapy. Although rare, steroid-resistant EG could be a life-threatening condition with tissue destructive evolution. Associations of eosinophilic gastroenteritis with systemic lupus erythematosus have rarely been reported. In this report we describe a case of successful IVIG treatment in a patient with systemic lupus erythematosus and steroid-refractory eosinophilic gastroenteritis

MULTIPLE PLURIPOTENT STEM CELL MARKERS IN HUMAN ANAPLASTIC THYROID CANCER: THE PUTATIVE UPSTREAM ROLE OF SOX-2

Background: Anaplastic Thyroid Carcinoma (ATC) is a rare and aggressive endocrine tumor, with highly undifferentiated morphology. It has been suggested that cancer stem cells (CSCs) might play a central role in ATC. The objectives of this study were the following: 1) to characterize CSCs from ex vivo ATC specimens by investigating the expression of several pluripotent stem cell markers; 2) to evaluate in vitro drug resistance modifications after specific CSC transcription factor switch off. Methods: Ex vivo: eight formalin-fixed, paraffin-embedded ATC specimens were analyzed by RT and qRT-PCR and immunohistochemistry. In vitro: in ATC SW1736 cells the expression levels of OCT-4, NANOG and ABCG2 and the sensitivity to either cisplatin or doxorubicin were evaluated after silencing. Results: OCT-4, KLF4 and SOX2 transcription factors and C-KIT and THY-1 stem surface antigens showed variable up-regulation in all ATC cases. The SW1736 cell line was characterized by a high percentage of stem population (10.4 \ub1 2.1 % of cells were aldehyde dehydrogenase positive) and a high expression of several CSC markers (SOX2, OCT4, NANOG, C-MYC, SSEA4). SOX2 silencing down-regulated OCT-4, NANOG and ABCG2. SOX2 silencing sensitized SW1736 cells, causing a significant cell death increase (1.8 fold) in comparison to control cells with 10 \ub5M cisplatin (93.9\ub13.4% vs. 52.6\ub19.4%, p<0.01) and 2.7 fold with 0.5\ub5M doxorubicin (45.8\ub19.9% vs. 17.1\ub13.4% p<0.01). ABCG2 silencing caused increased cell death with both cisplatin (74.9\ub11.4%) and doxorubicin treatment (74.1\ub10.1%) vs. no-target-treated cells (respectively, 45.8\ub11.0% and 48.6\ub11.0%, p<0.001). Conclusions: The characterization of CSCs in ATC through the analysis of multiple pluripotent stem cell markers might be useful in identifying cells with a stem-like phenotype capable of resisting conventional chemotherapy. In addition, our data demonstrate that SOX2 switch-off through ABCG2 transporter down-regulation has a major role in overcoming CSC chemotherapy resistance

Significance of P16INK4A hypermethylation gene in primary head/neck and colorectal tumors: it is a specific tissue event? Results of a 3-year GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study

BACKGROUND: Methylation of the p16 promoter is one of the most frequent mechanisms of gene inactivation; its incidence is extremely variable according to the type of tumor involved. Our purpose was to analyze the hypermethylation of the p16 promoter in laryngeal squamous cell carcinomas (LSCC), salivary gland (SG) tumors and in colorectal cancer (CRC), to detect any possible association with the clinicopathological features and to determine the prognostic significance of the p16 gene in the tumors analyzed. PATIENTS AND METHODS: The hypermethylation of the p16 promoter was prospectively analyzed, by MSP, in a consecutive series of 64 locally advanced LSCC patients, in a consecutive series of 33 SG tumor patients and in a consecutive series of 66 sporadic CRC patients. RESULTS: Hypermethylation was observed in 9% of the LSCC cases, in all cases of SG cancer and in 21% of the CRC cases. No significant association was observed between p16 hypermethylation and clinicopathological variables in all the tissue samples analyzed. Moreover at univariate analysis p16 mutations were not independently related at disease relapse and death in LSCC and CRC. CONCLUSIONS: The results of this study suggest that the lack of p16 function could happen in advanced stage of SG tumors

Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that are believed to originate from a neoplastic transformation of the intestinal pacemaker cells (interstitial cells of Cajal) normally found in the bowel wall or their precursors. Although the microscopic features have been known for a long time, the defining characteristic of GIST is the presence of the cell-surface antigen CD117 (KIT), which is demonstrated by immunohistochemistry. KIT, which is a growth factor transmembrane receptor, is the product of the proto-oncogene c-kit (chromosome 4). Surgical removal remains the only curative treatment for patients with GISTs. Tumor size, mitotic index, anatomic location, tumor rupture and disease-free interval are the classic characteristics used to predict the clinical course of patients who undergo complete gross resection. Most GISTs express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. Imatinib mesylate is a rationally designed, molecularly specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer and which has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant GISTs. More recently Sunitinib, a new KIT/PDGFRA kinase inhibitor, has been tested in patients with GIST resistant to imatinib, with promising results. Key words: gastrointestinal stromal tumors, histopathological diagnosis, molecular biology, novel therapie

Fever with perinasal and tongue lesions: A diagnostic challenge

The diagnosis may be challenging, and high suspicion index should be maintained in immunosuppressed patients with unusual mucocutaneous lesions, even in non-endemic areas for mucocutaneous leishmaniasis

A solitary fibrous tumor of the parotid gland: Case report

Introduction: Solitary fibrous tumor is a rare neoplasm that can affect any part of the body, also head and neck region. Etiology is unknown. The incidence is slightly higher in males, the age ranges from 11 to 79&nbsp;years. Presentation of case: It's the first case in our country of left parotid solitary fibrous tumor, removed by partial parotidectomy with facial nerve preservation. Histology examination showed diffuse spindle-shaped cells proliferation, moderate polymorphism, low mitotic index (&lt;4 mitoses per 10 HPF), partially bordered by fibrous capsule. Immunohistochemistry showed STAT6, CD34, CD99 positivity. Six-months follow-up didn't show sign of recurrence. Discussion: Solitary fibrous tumor is a mesenchymal spindle cell neoplasm with fibroblastic differentiation ubiquitous in soft tissues, that involved the head and neck region in 6&nbsp;% of cases. Etiology is unknown. The possible pathogenesis is NAB2-STAT6 gene fusion. It's asymptomatic or symptoms are related to space-occupying mass. Diagnostic work up involves imaging, immunohistochemistry, histology. Radiographic finding may lead to incorrect assessment of the mass: the same imaging features are present in pleomorphic adenoma, the most frequent tumor of salivary glands. Conclusion: This case report aims to stress that, although rare, solitary fibrous tumor should be considered in differential diagnosis in case of indolent salivary gland mass, since it may require more invasive approach (e.g., total parotidectomy, adjuvant radiotherapy). It would like to highlight the role of multidisciplinary team to define the best therapy, tailored for the patient, as well as to give awareness to a rare but sometimes aggressive tumor

FUS MUTATIONS IN SPORADIC AMYOTROPHIC LATERAL SCLEROSIS: CLINICAL AND GENETIC ANALYSIS

Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 patients: R521G and R521C respectively; P525L mutation has been found in 2 additional cases. Most of the patients with FUS mutations showed early symptom onset and had short disease survival. We also detected 4 different polymorphic variants (3=-untranslated region [UTR] variant, c.*41G.A; c.52313ins[GAGGTG]; c.335-15del[TTTT]; and rs13331793) in 9 patients from within our cohort. This study underlines the importance of population-based mutation screening of newly identified genes. \ua9 2011 Elsevier Inc. All rights reserved

PathVisio Analysis: An Application Targeting the miRNA Network Associated with the p53 Signaling Pathway in Osteosarcoma

MicroRNAs (miRNAs) are small single-stranded, non-coding RNA molecules involved in the pathogenesis and progression of cancer, including osteosarcoma. We aimed to clarify the pathways involving miRNAs using new bioinformatics tools. We applied WikiPathways and PathVisio, two open-source platforms, to analyze miRNAs in osteosarcoma using miRTar and ONCO.IO as integration tools. We found 1298 records of osteosarcoma papers associated with the word "miRNA". In osteosarcoma patients with good response to chemotherapy, miR-92a, miR- 99b, miR-193a-5p, and miR-422a expression is increased, while miR-132 is decreased. All identified miRNAs seem to be centered on the TP53 network. This is the first application of PathVisio to determine miRNA pathways in osteosarcoma. MiRNAs have the potential to become a useful diagnostic and prognostic tool in the management of osteosarcoma. PathVisio is a full pathway editor with the potentiality to illustrate the biological events, augment graphical elements, and elucidate all the physical structures and interactions with standard external database identifiers