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Background: Breast, colorectal, ovarian, and endometrial cancers constitute approximately 30% of newly diagnosed cancer cases in Switzerland, affecting more than 12,000 individuals annually. Hundreds of these patients are likely to carry germline pathogenic variants associated with hereditary breast ovarian cancer (HBOC) or Lynch syndrome (LS). Genetic services (counseling and testing) for hereditary susceptibility to cancer can prevent many cancer diagnoses and deaths through early identification and risk management., Objective: Cascade screening is the systematic identification and testing of relatives of a known mutation carrier. It determines whether asymptomatic relatives also carry the known variant, needing management options to reduce future harmful outcomes. Specific aims of the CASCADE study are to (1) survey index cases with HBOC or LS from clinic-based genetic testing records and determine their current cancer status and surveillance practices, needs for coordination of medical care, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to serve as advocates for cancer genetic services to blood relatives, (2) survey first- and second-degree relatives and first-cousins identified from pedigrees or family history records of HBOC and LS index cases and determine their current cancer and mutation status, cancer surveillance practices, needs for coordination of medical care, barriers and facilitators to using cancer genetic services, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to participate in a study designed to increase use of cancer genetic services, and (3) explore the influence of patient-provider communication about genetic cancer risk on patient-family communication and the acceptability of a family-based communication, coping, and decision support intervention with focus group(s) of mutation carriers and relatives., Methods: CASCADE is a longitudinal study using surveys (online or paper/pencil) and focus groups, designed to elicit factors that enhance cascade genetic testing for HBOC and LS in Switzerland. Repeated observations are the optimal way for assessing these outcomes. Focus groups will examine barriers in patient-provider and patient-family communication, and the acceptability of a family-based communication, coping, and decision-support intervention. The survey will be developed in English, translated into three languages (German, French, and Italian), and back-translated into English, except for scales with validated versions in these languages., Results: Descriptive analyses will include calculating means, standard deviations, frequencies, and percentages of variables and participant descriptors. Bivariate analyses (Pearson correlations, chi-square test for differences in proportions, and t test for differences in means) will assess associations between demographics and clinical characteristics. Regression analyses will incorporate generalized estimating equations for pairing index cases with their relatives and explore whether predictors are in direct, mediating, or moderating relationship to an outcome. Focus group data will be transcribed verbatim and analyzed for common themes., Conclusions: Robust evidence from basic science and descriptive population-based studies in Switzerland support the necessity of cascade screening for genetic predisposition to HBOC and LS. CASCADE is designed to address translation of this knowledge into public health interventions., Trial Registration: ClinicalTrials.gov NCT03124212; https://clinicaltrials.gov/ct2/show/NCT03124212 (Archived by WebCite at http://www.webcitation.org/6tKZnNDBt)., (©Maria C Katapodi, Valeria Viassolo, Maria Caiata-Zufferey, Christos Nikolaidis, Rosmarie Bührer-Landolt, Nicole Buerki, Rossella Graffeo, Henrik Csaba Horváth, Christian Kurzeder, Manuela Rabaglio, Michael Scharfe, Corinne Urech, Tobias E Erlanger, Nicole Probst-Hensch, Karl Heinimann, Viola Heinzelmann-Schwarz, Olivia Pagani, Pierre O. Chappuis. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 20.09.2017.)

The vitamin D system is deregulated during development and progression of several cancer types. Data on the expression of the vitamin D system in the diseased pancreas are missing. The aim of this study was to investigate the expression of the vitamin D receptor (VDR), 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1), and the calcium-sensing receptor (CaSR), a vitamin D target gene, in the different regions of the pancreas in patients with chronic pancreatitis (n=6) and pancreatic ductal adenocarcinomas (PDAC) (n=17). We analyzed the expression of these genes at mRNA and protein level with quantitative real-time RT-PCR and immunostaining. mRNA expression of CYP24A1 and VDR was significantly increased in tumors compared with the adjacent non-tumorous tissue (p<0.01), while CaSR mRNA expression decreased. Both the VDR and the CaSR protein were highly expressed in the endocrine compared with the exocrine pancreas. In CP the CYP24A1 expression was highest in the endocrine pancreas, while in PDACs in the transformed ducts. In the PDAC patients CYP24A1 expression in the islets was significantly lower than in CP patients. Our data suggest that during ductal adenocarcinoma development the vitamin D system in the pancreas becomes deregulated on two levels: in the islets CYP24A1 expression decreases weakening the negative feedback regulation of the vitamin D-dependent insulin synthesis/secretion. In the transformed ducts CYP24A1 expression increases, impairing the antiproliferative effect of vitamin D in these cells., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Inflammatory bowel disease may show a life long persistence, while female fertility is time-limited., Aim: The aim of the authors was to obtain more knowledge about the obstetrical-gynecological aspects of this disorder., Methods: The authors evaluated 100 patients with inflammatory bowel disease and 100 healthy women with a self-composed questionnaire., Results: Menarche occurred significantly earlier in patients than in controls (p = 0,03). Either the activity of the disease, or the therapy itself may initiate irregularities in the menstrual cycle. Patients used contraceptives less frequently than controls (p = 0,002), and the time from family-planning to conception was longer in patients. Symptoms of bowel disease during pregnancy were not as severe as before and after pregnancy (p<0,001). Excess weight had a beneficial effect on symptoms during pregnancy (p = 0,042) and on the frequency of complications. Preterm birth and low birth weight were more frequent in newborns of patients (p = 0,019)., Conclusion: Pregnancy has positive effect on the symptoms of inflammatory bowel disease in case gestation occurs in a stable period of the inflammatory bowel disease.

Aim: 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits cell growth and induces apoptosis in numerous types of tumors. We aimed to examine the mRNA and protein expression of 1,25(OH)(2)D(3)-inactivating CYP24A1 and mRNA expression of the activating CYP27B1 enzymes, as well as that of vitamin D receptor (VDR), in hepatocellular carcinoma (HCC) cell cultures in response to 1,25(OH)(2)D(3) administration., Materials and Methods: Increasing amounts of 1,25(OH)(2)D(3) (0.256-10 nM) were added to cultures of HepG2, Huh-Neo, Hep3B, Huh5-15 human HCC cell lines and cells then incubated for various time periods (30 min-28 h). The mRNA expression was analyzed by real time reverse transcription-polymerase chain reaction (RT-PCR). CYP24A1 protein in HepG2 cells was detected by immuncytochemistry., Results: CYP24A1 mRNA expression significantly (p<0.0001) increased in response to 1,25(OH)(2)D(3) administration in two cell lines: in HepG2 cells, the CYP24A1 mRNA level exhibited 5,300-fold elevation, reaching a maximum value at 8 h; in Huh-Neo cells, the increase was 152-fold that of the baseline value, with the maximum being reached at 14 h. There was no significant change in Hep3B and Huh5-15 cell lines, nor was there any change in CYP27B1 and VDR gene expression in any cell cultures. Immuncytochemistry in HepG2 cells proved that gene activation was followed by CYP24A1 protein synthesis., Conclusion: Our novel data indicate that administration of 1,25(OH)(2)D(3) results in a marked increase of CYP24A1 mRNA expression in some, but not all, human HCC lines in vitro. These differences could be dependent upon the origin of the tumor cells.

25-hydroxyvitamin D3 24-hydroxylase (CYP24A1), the catabolizing enzyme of the active vitamin D3, is often overexpressed in solid tumors. The unbalanced high levels of CYP24A1 seem to be a determinant of vitamin D resistance in tumors. Splice variants of CYP450 enzymes are common. Existence of CYP24A1 isoforms has been reported recently. We have investigated the presence of CYP24A1 splicing variants (SV) in human colon cancer cell lines and tissue samples. Using a set of primer combination we have screened the entire coding sequence of CYP24A1 and identified three splice variants in colon cancer cell lines. The presence of these SVs in human colon tissue samples showed a correlation with histological type of the tissue and gender of patients. The sequencing of the alternatively spliced fragments showed that two have lost the mitochondrial target domain, while the third lacks the heme-binding domain. All SVs retained their sterol binding domain. Translation of these variants would lead to a dysfunctional enzyme without catalytic activity that still binds its substrates therefore they might compete for substrate with the synthesizing and catabolizing enzymes of vitamin D., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The main autocrine/paracrine role of the active metabolite of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)), is inhibition of cell growth and induction of cell differentiation and/or apoptosis. Synthesis and degradation of the secosteroid occurs not only in the kidney but also in normal tissue or malignant extrarenal tissues such as the colon. Because 25-hydroxyvitamin D(3) 24-hydroxylase (CYP24A1) is considered to be the main enzyme determining the biological half-life of 1,25-D(3), we have examined expression of the CYP24A1 mRNA (by real-time RT-PCR) and protein (by immunohistochemistry) in normal human colon mucosa, colorectal adenomas, and adenocarcinomas in 111 patients. Although 76% of the normal and benign colonic tissue was either completely devoid of or expressed very low levels of CYP24A1, in the majority of the adenocarcinomas (69%), the enzyme was present at high concentrations. A parallel increased expression of the proliferation marker Ki-67 in the same samples suggests that overexpression of CYP24A1 reduced local 1,25-D(3) availability, decreasing its antiproliferative effect.

Unlabelled: Until recently, only the proximal small bowel was accessible for diagnostic and therapeutic endoscopy. Endoscopic evaluation of this organ has often required open laparotomy with surgically assisted passage of the endoscope through the intestine. Recently, Yamamoto et al have developed a new method, double-balloon endoscopy (DBE) that allows high-resolution visualization and therapeutic interventions in all segments of the GI tract. Our aim was to report our early experience with the Fujinon EN-450 T5 therapeutic double-balloon endoscope., Patients and Methods: Between August 2005 and March 2006, 25 DBE was conducted in 23 consecutive patients (M/F: 13/10, age: 51.8 +/- 16.5 years) presenting at our tertiary referral hospitals (17 and 4 patients from the oral or the anal route, respectively; 2 patients from both). All procedures were done by i.v. anesthesia, at our outpatient clinic. After the procedure, the patients were monitored in a recovery room for at least 4h before discharge., Results: The main indication for DBE was suspected small-bowel GI bleeding (11), diagnosis or complications of IBD (7), polyposis syndrome (3), stenosis (1) and insertion of jejunal catheter in one case. Twelve out of 22 patients (54.5%) had a small-bowel finding, with 16 of 22 (72.7%) of the patients having a more accurate diagnostic input. The average insertion length was app. 165 cm (range 50-350 cm, SD 97). Patients' tolerance of the procedure was excellent. No severe complications were recognized., Conclusions: Based on our limited experience double-balloon enteroscopy is a safe and useful method to evaluate and treating small bowel disease in selected patients, including patients with suspected small-bowel strictures, in whom capsule endoscopy is contraindicated.

Unlabelled: The incidence of proximal tumours in Western countries has steadily increased while that of distal tumours has shown a corresponding decrease. Our aim was to investigate the prevalence, location and histology of colorectal cancers in the last twelve years in Hungarian patients., Patients and Methods: Clinical data of 1738 patients diagnosed with colorectal tumors (M/F: 940/798, mean age at diagnosis: 65.2 +/- 12.5 years) between 1st of January 1993 and 31st of December 2004 at the 1st Internal Medicine and 1st Surgery Department of Semmelweis University were enrolled. Pathology and clinical data were analysed retrospectively. The observed periods were the following 1993-1998 and 1999-2004., Results: 1694 (97.5%) of the patients had adenocarcinoma (CRC), 15 anaplastic cancers, 9 carcinoid, 6 planocellular, 5 GIST, 3 leiomyoma and 2-2 melanoma, lymphoma and shigillocellular cancers were diagnosed. 75.7% (943/1246) of the CRCs were diagnosed at locally advanced stage (T3-T4), and 47.7% (521/1093) of CRC patients had lymph node metastasis at the time of diagnosis. 11.0% of the CRCs were diagnosed in <50 year-olds (<40 years: 2.5%, <30 years: 0.5%). The location of the CRC was distal in 1186 (rectum: 53.9%, sigmoid/descending: 46.1) and proximal in 508 cases. Synchronous cancers were detected in 12 patients (age: 68.8 +/- 11.6 years, gender: 11 male/1 female, location: rectum and transverse in 6, rectum and ascending/caecum in 5 patients). Age at diagnosis was not different according to gender (M/F: 64.8 +/- 12.0 years vs. 65.8 +/- 12.9 years), but it was lower in patients with rectal cancer compared to left or right sided cancers (64.1 years vs. left: 66.1 years, right: 66.0 years, p = 0.02). Rectal CRC was more common in males, while the proportion of proximal cancers was lower (rectum, M/F: 41.2% vs. 33.5%, proximal M/F: 26.8% vs. 33.8%, p = 0.003). The proportion of rectal cancers increased over the observed period (1993-1998: rectal: 31.6% vs. 1999-2004: 42.1%, p = 0.002)., Conclusions: In contrast to Western countries, the proportion of proximal CRC did not become higher in Hungary. Still more than two-third of the patients were diagnosed to have distal cancers. The proportion of male patients was higher in this subset of CRC. The high percentage of locally advanced and metastatic cancers supports the need for colorectal screening program in Hungary.