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1.  Silencing of MGMT expression by promoter hypermethylation in the metaplasia–dysplasia–carcinoma sequence of Barrett’s esophagus 
Cancer letters  2008;275(1):117-126.
To determine the relevance of MGMT in Barrett’s carcinogenesis, we analyzed promotor hypermethylation and expression of MGMT in Barrett’s adenocarcinomas and its paired precursor lesions from 133 patients using a methylation-specific PCR, real-time RT-PCR and immunohistochemistry. Hypermethylation was detected in 78.9% of esophageal adenocarcinomas, in 100% of Barrett’s intraepithelial neoplasia, in 88.9% of Barrett’s metaplasia, but only in 21.4% of normal esophageal mucosa samples (P < 0.001) and correlated significantly with downregulation of MGMT transcripts (P = 0.048) and protein expression (P = 0.02). Decrease of protein expression was significantly correlated with progressed stage of disease, lymph node invasion and tumor size. We conclude, that aberrant promoter methylation of MGMT is a frequent and early event during tumorigenesis of Barrett’s esophagus. High prevalence of MGMT hypermethylation may represent a candidate marker for improved diagnosis and targeted therapy in Barrett’s adenocarcinoma.
doi:10.1016/j.canlet.2008.10.009
PMCID: PMC4028828  PMID: 19027227
O6-methylguanine-DNA methyltransferase (MGMT); Hypermethylation; Carcinogenesis; Barrett’s metaplasia; Barrett’s adenocarcinoma
2.  Endoscopic papillectomy: Data of a prospective observational study 
AIM: To investigate the clinical value of endoscopic papillectomy indicated by feasibility and safety of the procedure in various diseases of the papilla in a representative number of patients in a setting of daily clinical and endoscopic practice and care by means of a systematic prospective observational study.
METHODS: Through a defined time period, all consecutive patients with tumor-like lesions of the papilla, who were considered for papillectomy, were enrolled in this systematic bicenter prospective observational study, and subdivided into 4 groups according to endoscopic and endoscopic ultrasonography (EUS) findings as well as histopathological diagnosis: adenoma; carcinoma/neuroendocrine tumor (NET)/lymphoma; papilla into which catheter can not be introduced; adenomyomatosis, respectively. Treatment results and outcome were characterized by R0 resection, complication, recurrence rates and tumor-free survival.
RESULTS: Over a 7-year period, 58 patients underwent endoscopic papillectomy. Main symptoms prompting to diagnostic measures were unclear abdominal pain in 50% and cholestasis with and without pain in 44%. Overall, 54/58 patients [inclusion rate, 93.1%; sex ratio, males/females = 25/29 (1:1.16); mean age, 65 (range, 22-88) years] were enrolled in the study. Prior to papillectomy, EUS was performed in 79.6% (n = 43/54). Group 1 (adenoma, n = 24/54; 44.4%): 91.6% (n = 22/24) with R0 resection; tumor-free survival after a mean of 18.5 mo, 86.4% (n = 19/22); recurrence, 13.6% (n = 3/22); minor complications, 12.5% (n = 3/24). Group 2 (carcinoma/NET/lymphoma, n = 18/54; 33.3%): 75.0% (n = 10/18) with R0 resection; tumor-free survival after a mean of 18.5 (range, 1-84) mo, 88.9% (n = 8/9); recurrence, 11.1% (n = 1/9). Group 3 (adenomyomatosis, n = 4/54; 7.4%). Group 4 (primarily no introducible catheter into the papilla, n = 8; 14.8%). The overall complication rate was 18.5% (n = 10/54; 1 subject with 2 complications): Bleeding, n = 3; pancreatitis, n = 7; perforation, n = 1 (intervention-related mortality, 0%). In summary, EUS is a sufficient diagnostic tool to preoperatively clarify diseases of the papilla including suspicious tumor stage in conjunction with postinterventional histopathological investigation of a specimen. Endoscopic papillectomy with curative intention is a feasible and safe approach to treat adenomas of the papilla. In high-risk patients with carcinoma of the papilla with no hints of deep infiltrating tumor growth, endoscopic papillectomy can be considered a reasonable treatment option with low risk and an approximately 80% probability of no recurrence if an R0 resection can be achieved. In patients with jaundice and in case the catheter can not be introduced into the papilla, papillectomy may help to get access to the bile duct.
CONCLUSION: Endoscopic papillectomy is a challenging interventional approach but a suitable patient- and local finding-adapted diagnostic and therapeutic tool with adequate risk-benefit ratio in experienced hands.
doi:10.3748/wjg.v19.i27.4316
PMCID: PMC3718899  PMID: 23885142
Papilla of Vater; Papillectomy; Endoscopic ultrasonography; Adenoma; Carcinoma; Carcinoid-like tumor; Adenomyomatosis
3.  Emergency double balloon enteroscopy: a feasible and promising diagnostic as well as possible therapeutic option in recurrent midgut bleeding 
BMJ Case Reports  2011;2011:bcr0620103068.
Gastrointestinal (GI) tract bleeding, in particular originating within the long segment of the small intestine, remains a diagnostic and therapeutic challenge. The authors describe the potential utility of emergency double balloon enteroscopy (DBE) for small bowel bleeding. An elderly woman was admitted because of a hypertensive crisis to the medical department of a regional hospital. Her medical history was significant for non-steroidal anti-inflammatory drug (NSAID) abuse. While in hospital she had massive obscure GI bleeding. Upper GI endoscopy and colonoscopy for recurrent bleeding showed only thrombotic residuals in two sigmoid diverticuli, which led to segmental resection of the sigmoid colon. However, postoperatively, bleeding recurred leading to transfer to our university hospital. Immediate angiography only revealed a vascular malformation at the upper jejunum but no ongoing bleeding. Subsequent emergency DBE detected an oozing jejunal ulcer, which was coagulated using a argon beamer. Because of recurrent falls in haemoglobin with the need for repeated transfusion, the patient underwent surgical reintervention including segmental resection of the ulcerated upper jejunum with subsequent end-to-end anastomosis. Histopathology revealed NSAID-induced ulcerous jejunopathy. Postoperatively, there was no further bleeding and the patient was discharged home in a stable condition. In conclusion, this is one of the first reports of successful emergency use of DBE in a case of recurrent and occult bleeding within the small bowel which successfully located the source of bleeding and facilitated successful superficial ulcer coagulation with an argon beamer to prevent further bleeding.
doi:10.1136/bcr.06.2010.3068
PMCID: PMC3070338  PMID: 22700075
4.  Complications and nutrient deficiencies two years after sleeve gastrectomy 
BMC Surgery  2012;12:13.
Background
The aim of this systematic study was to investigate patient outcomes and nutritional deficiencies following sleeve gastrectomy (SG) during a median follow-up of two years.
Methods
Over a period of 56 months, all consecutive patients who underwent SG were documented in this prospective, single-center, observational study. The study endpoints included complication rates, nutritional deficiencies and percentage of excess weight loss (%EWL).
Results
From September 26, 2005 to May 28, 2009, 100 patients (female: male = 59:41) with a mean age of 43.6 years (range: 22–64) and a preoperative BMI of 52.3 kg/² (range: 36–77) underwent SG. The mean operative time was 86.4 min (range: 35–275). Major complications were observed in 8.0 % of the patients. During the follow-up period, 25 patients (25.0 %) underwent a second bariatric intervention (22 DS and 3 RYGBP). Out of the total 100 patients, 48 % were supplemented with iron, 33 % with zinc, 34 % with a combination of calcium carbonate and cholecalciferol, 24 % with vitamin D, 42 % with vitamin B12 and 40 % with folic acid. The patients who received only a SG (n = 75) had %EWL of 53.6, 65.8 and 62.6 % after 6, 12 and 24 months, respectively.
Conclusions
SG is a highly effective bariatric intervention for morbidly obese patients. Nutritional deficiencies resulting from the procedure can be detected by routine nutritional screening. Results of the study show that Vitamin B12 supplementation should suggested routinely.
doi:10.1186/1471-2482-12-13
PMCID: PMC3413543  PMID: 22765843
Sleeve gastrectomy; Laparoscopic sleeve gastrectomy; Obesity; Metabolic surgery; Bariatric surgery; Nutritional deficiencies
5.  Successful interdisciplinary treatment of renal cell carcinoma with tumour thrombus into inferior vena cava using multimodal protocol and organ-extending R0 resection in rare horseshoe kidney and doubled right organ 
BMJ Case Reports  2010;2010:bcr04.2009.1802.
This is the first case ever reported showing a combination of renal cell carcinoma (RCC) with tumour thrombus into inferior vena cava (IVC), horseshoe kidney and doubled right kidney that was successfully treated. Even in advanced tumour lesions of the kidney, curative treatment is a feasible and safe option by using interdisciplinary cooperation and expertise. However, this requires an adequate diagnostic work-up to clarify resectability and optimal perioperative and postoperative care, and also advanced surgical skills exhausting all potential options for complete tumour resection in a centre of excellence. Achieving R0 resection with a reasonable risk-benefit ratio for the patient, which should be the primary aim, can distinctly improve survival chances as published cases in literature have indicated. RCC-derived IVC tumour thrombus as an extra-renal tumour manifestation by continuous intravascular tumour growth (also classified as secondary IVC tumour lesion) can be considered no serious contraindication to aim for curative surgery.
doi:10.1136/bcr.04.2009.1802
PMCID: PMC3047170  PMID: 22751093
6.  Complications, Reoperations, and Nutrient Deficiencies Two Years after Sleeve Gastrectomy 
Journal of Obesity  2012;2012:828737.
Background. The aim of this study was to investigate patient outcomes and nutritional deficiencies following sleeve gastrectomy (SG) during a follow-up of two years. Methods. Over a period of 56 months, all consecutive patients who underwent SG were documented in this prospective, single-center, observational study. The study endpoints included operative time, complication rates, nutritional deficiencies and percentage of excess weight loss (%EWL). Results. From September 26, 2005 to May 28, 2009, 82 patients (female : male = 48 : 34) with a mean age of 43.3 years (range: 22–64) and a preoperative BMI of 52.5 kg/m² (range: 36.8–77.0) underwent SG. Major complications were observed in 9.8% of the patients, with 1 death. During follow up 51.2% of patients were supplemented with iron, 36.6% with zinc, 37.8% with calcium, 26.8% with vitamin D, 46.3% with vitamin B12 and 41.5% with folic acid. %EWL was 54.3, 65.3 and 62.6% after 6, 12 and 24 months. Conclusion. SG as a single step procedure is an effective bariatric intervention. Nutritional deficiencies after SG can be detected by routine nutritional screening. Our results show that Vitamin B12 supplementation should suggest routinely after SG.
doi:10.1155/2012/828737
PMCID: PMC3364598  PMID: 22685635
7.  Fourteen-Year Long-Term Results after Gastric Banding 
Journal of Obesity  2010;2011:128451.
Background. Gastric banding (GB) is a common bariatric procedure that is performed worldwide. Weight loss can be substantial after this procedure, but it is not sufficient in a significant portion of patients. Long-term rates for associated complications increase with every year of follow up, and only a few long-term studies have been published that examine these rates. We present our results after 14 years of postoperative follow up. Methods. Two hundred patients were operated upon form 01.02.1995 to 31.01.2009. Data collection was performed prospectively. In retrospective analysis, we analyzed weight loss, short- and long-term complications, amelioration of comorbidities and long-term outcome. Results. The mean postoperative follow up time was 94.4 months (range 2–144). The follow up rate was 83.5%. The incidence of postoperative complications for slippage was 2.5%, for pouch dilatation was 9.5%, for band migration was 5.5% and 12.0% for overall band removal. After 14 years, the reoperation rate was 30.5% with a reoperation rate of 2.2% for every year of follow up. Excess weight loss was 40.2% after 1 year, 46.3% after 2 years, 45.9% after 3 years, 41.9% after five years, 33.3% after 8 years, 30.8% after 10 years, 33.3% after 12 years and 15.6% after 14 years of follow up. Conclusion. The complication and reoperation rate after GB is high. Nevertheless, GB is still a therapeutic option in morbid obese patients, but the criteria for patient selection should be carefully evaluated.
doi:10.1155/2011/128451
PMCID: PMC3017910  PMID: 21234392
8.  Interleukin-1 Beta Single-Nucleotide Polymorphism’s C Allele is Associated with Elevated Risk of Gastric Cancer in Helicobacter pylori-Infected Peruvians 
Particular alleles of the interleukin-1B (IL-1B) gene have been correlated with increased risk of atrophic gastritis and gastric cancer in the populations of East Asia and Europe. No such data exist from Peru, a developing country with a population genotypically different from others studied and with a high prevalence of Helicobacter pylori infection and gastric cancer. We conducted a case-control study comparing 334 hospitalized patients with atrophic gastritis or gastric cancer with 158 nonatrophic gastritis patients (controls). Conditional logistic regression analysis revealed that an increased risk of atrophic gastritis (odds ratio, 5.60) and gastric cancer (odds ratio, 2.36) was associated with the IL-1B-511 C allele. Our study is the first to establish this allele as a risk for these conditions. Given the high prevalence of H. pylori and recurrence rate after treatment, IL-1B-511 single-nucleotide polymorphism analysis may identify those individuals who would benefit most from robust H. pylori eradication efforts in Peru.
doi:10.4269/ajtmh.2009.08-0494
PMCID: PMC2833398  PMID: 19861615
9.  Inflammatory Myofibroblastic Tumor of the Pancreatic Head: An Unusual Cause of Recurrent Acute Pancreatitis – Case Presentation of a Palliative Approach after Failed Resection and Review of the Literature 
Case Reports in Gastroenterology  2010;4(3):443-451.
Inflammatory myofibroblastic tumors (IMTs) are a rare cause of echo-poor pancreatic head enlargement. Histologically, IMTs are characterized by spindle-shaped myofibroblasts or fibroblasts accompanied by a mixed immune cell infiltration. The most common localizations of IMTs have been reported in lung, mesentery and omentum, especially in children and young adults. IMTs show infiltrating growth, multilocular appearance and also metastasis have been reported. Curative resection is the only therapeutic option so far. In the palliative situation, evident data and clear guidelines for this rare tumor entity are missing. We report on a 44-year-old male with an unresectable IMT of the pancreatic head causing recurrent episodes of acute pancreatitis that resulted in a chronic obstructive course of the disease. The patient entered a palliative therapeutic regimen including radiation therapy and antiinflammatory medication. In a regular follow-up of 12 months, he presented with stable disease after initial progression. This case of local progressive IMT of the pancreatic head was managed with a palliative therapeutic regimen and is discussed based on the current literature.
doi:10.1159/000320953
PMCID: PMC2988857  PMID: 21113286
Inflammatory myofibroblastic tumor; Pancreas; Recurrent acute pancreatitis; Chronic obstructive pancreatitis
10.  Early Involvement of Death-Associated Protein Kinase Promoter Hypermethylation in the Carcinogenesis of Barrett's Esophageal Adenocarcinoma and Its Association with Clinical Progression1 
Neoplasia (New York, N.Y.)  2007;9(3):236-245.
Esophageal Barrett's adenocarcinoma (BA) develops through a multistage process, which is associated with the transcriptional silencing of tumor-suppressor genes by promoter CpG island hypermethylation. In this study, we explored the promoter hypermethylation and protein expression of proapoptotic deathassociated protein kinase (DAPK) during the multistep Barrett's carcinogenesis cascade. Early BA and paired samples of premalignant lesions of 61 patients were analyzed by methylation-specific polymerase chain reaction and immunohistochemistry. For the association of clinicopathological markers and protein expression, an immunohistochemical tissue microarray analysis of 66 additional BAs of advanced tumor stages was performed. Hypermethylation of DAPK promoter was detected in 20% of normal mucosa, 50% of Barrett's metaplasia, 53% of dysplasia, and 60% of adenocarcinomas, and resulted in a marked decrease in DAPK protein expression (P < .01). The loss of DAPK protein was significantly associated with advanced depth of tumor invasion and advanced tumor stages (P < .001). Moreover, the severity of reflux esophagitis correlated significantly with the hypermethylation rate of the DAPK promoter (P < .003). Thus, we consider DAPK inactivation by promoter hypermethylation as an early event in Barrett's carcinogenesis and suggest that a decreased protein expression of DAPK likely plays a role in the development and progression of BA.
PMCID: PMC1838580  PMID: 17401463
Barrett's adenocarcinoma; Barrett's metaplasia; DAPK; reflux esophagitis; inflammation
11.  Selective Loss of Codon 72 Proline p53 and Frequent Mutational Inactivation of the Retained Arginine Allele in Colorectal Cancer1 
Neoplasia (New York, N.Y.)  2004;6(5):529-535.
Abstract
According to recent reports, some cancer types exhibit nonrandom allele loss at codon 72 in exon 4 of the p53 gene [coding for proline (72Pro) or arginine (72Arg)]. To clarify this phenomenon for colorectal cancer and to find out if this preferential loss might have any functional significance, p53 loss of heterozygosity (LOH) and p53 mutations were investigated in a group of 61 colorectal cancers and 28 liver metastases, and were correlated with clinicopathologic factors. A comparison of a patient's blood codon 72 status with a healthy control group did not reveal an enhanced risk of developing colorectal tumors for one of the two isoforms. p53-LOH and p53 mutations were found in 62.2% and 39.4% of primary tumors, respectively, and in 57.9% and 25% of hepatic metastases, respectively. In 14 heterozygous cases showing exon 4-LOH, only the 72Pro allele was lost and the retained 72Arg was preferentially mutated. In general, p53 mutations were significantly associated with the 72Arg tumor status (P < .001). Distal tumors showed allelic losses of the p53 gene more commonly than proximal tumors (P = .054). The prevalence of 72Arg increased in frequency with higher Dukes stage (P = .056). We suggest that either the preferential loss of 72Pro or the mutation of the 72Arg in colorectal cancer and hepatic metastases is associated with malignant potential and might reflect carcinogenic exposure, particularly in the distal part of the large intestines.
PMCID: PMC1531656  PMID: 15548361
Codon 72 polymorphism; p53-LOH; p53 mutation; colorectal cancer; allelic loss
12.  Modulation of Innate Cytokine Responses by Products of Helicobacter pylori 
Infection and Immunity  2000;68(11):6265-6272.
The gastric inflammatory and immune response in Helicobacter pylori infection may be due to the effect of different H. pylori products on innate immune mechanisms. The aim of this study was to determine whether bacterial components could modulate cytokine production in vitro and thus contribute to Th1 polarization of the gastric immune response observed in vivo. The effect of H. pylori recombinant urease, bacterial lysate, intact bacteria, and bacterial DNA on proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) from H. pylori-negative donors was examined as a model for innate cytokine responses. Each of the different H. pylori preparations induced gamma interferon (IFN-γ) and interleukin-12p40 (IL-12p40), but not IL-2 or IL-5, production, and all but H. pylori DNA stimulated release of IL-10. Addition of anti-IL-12 antibody to cultures partially inhibited IFN-γ production. In addition, each bacterial product inhibited mitogen-stimulated IL-2 production by PBMCs and Jurkat T cells. The inhibitory effect of bacterial products on IL-2 production correlated with inhibition of mitogen-stimulated lymphocyte proliferation, although urease inhibited IL-2 production without inhibiting proliferation, suggesting that inhibition of IL-2 production alone is not sufficient to inhibit lymphocyte proliferation. The results of these studies demonstrate that Th1 polarization of the gastric immune response may be due in part to the direct effects of multiple different H. pylori components that enhance IFN-γ and IL-12 production while inhibiting both IL-2 production and cell proliferation that may be necessary for Th2 responses.
PMCID: PMC97708  PMID: 11035734

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