Małgorzata Ławniczak

Endoscopic submucosal dissection for treatment of gastric subepithelial tumors (with video).

BACKGROUND Endoscopic submucosal dissection (ESD) is a well-accepted method for removing superficial mucosal tumors; however, there is limited data on the use of this method for removing subepithelial tumors. OBJECTIVE To investigate the efficacy, safety, and outcome of ESD for gastric subepithelial tumors and determine factors related to treatment success. DESIGN Retrospective analysis of a prospectively maintained database. SETTING Single tertiary academic center. PATIENTS AND INTERVENTIONS From April 2007 to November 2010, 37 patients with gastric subepithelial tumors were treated with ESD. MAIN OUTCOME MEASUREMENTS Macroscopically and microscopically complete en block resection rate (R0), complication rate, and endosonographic features predictive of R0 resection. RESULTS The median tumor diameter was 25.0 mm, (range 10-60 mm, IQR 17-37). The overall rate of R0 resections was 81.1% (30/37, 95%CI: 61.8-90.2%), including 100% (15/15, 95%CI: 78.2-100.0%) of tumors from the submucosa and 68.2% (15/22, 95%CI: 45.1-86.1%) of tumors from the muscularis propria. Seventeen patients had a final diagnosis of gastrointestinal stromal tumor. The severe complication (perforation) rate was 5.4% (2/37, 95%CI: 0.0-9.5%). One patient required surgery; the other was treated conservatively. No recurrence was observed in patients with R0 resections at a median follow up of 21.0 months (IQR 11-35). Successful R0 resections were predicted by the observation of no, or only narrow, tumor connections with the underlying muscle layer during EUS (OR=35.0, 95%CI: 3.7-334.4, p=0.001). LIMITATIONS Single-center, retrospective analysis, short follow-up. CONCLUSIONS ESD is an effective and relatively safe method for removing gastric subepithelial tumors. Endoscopic ultrasonography findings can predict complete tumor resections.

Validation of the BARD scoring system in Polish patients with nonalcoholic fatty liver disease (NAFLD)

AbtractBackgroundNonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver diseases, ranging from pure steatosis to nonalcoholic steatohepatitis (NASH), and eventually to liver cirrhosis with its complications. Identifying advanced fibrosis in patients is crucial to evaluating prognosis and possible therapeutic intervention. A novel, simple, and highly accurate scoring system called BARD, which identifies patients with NAFLD and without significant fibrosis, has been recently introduced and validated in North America..The aim of this study is to validate the BARD scoring system in a Polish cohort with NAFLD.MethodsA group of 104 Caucasians with biopsy-proven NAFLD were included in this study. Fibrosis in liver biopsies was evaluated according to the Histological Scoring System for Nonalcoholic Fatty Liver Disease. The BARD scoring system was assessed according to Harrison et al.: BMI ≥ 28 = 1 point, AST/ALT ratio (AAR) ≥ 0.8 = 2 points, type 2 diabetes mellitus = 1point.ResultsAge over 50 and AAR over 0.8 showed, respectively, a moderate and strong association with advanced fibrosis. A BARD score of 2-4 points was associated with F3 or F4 stages of fibrosis with an odds ratio of 17.333 (95% Cl; 3,639 - 82.558) and negative predictive value of 97%.ConclusionOur results demonstrate that the BARD scoring system has value in the non-invasive diagnosis of advanced fibrosis in NAFLD patients. The vast majority of patients with NAFLD would avoid liver biopsy if BARD was broadly introduced into the clinic.

A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer

Germ-line mutations in the BRCA2 gene are associated with a wide range of cancer types, including the breast, ovary, pancreas, prostate and melanoma. In this study, we evaluated the importance of a family history of stomach cancer in predicting the presence of a BRCA2 mutation in Polish patients with ovarian cancer. A BRCA2 mutation was found in eight of 34 women with ovarian cancer and a family history of stomach cancer versus three of 75 women with ovarian cancer and a family history of ovarian cancer, but not of stomach cancer (odds ratio=7.4; 95% CI 1.8–30; P=0.004). The results of this study suggest that, in the Polish population, the constellation of ovarian and stomach cancer predicts the presence of a germ-line BRCA2 mutation and confirms that stomach cancer is part of the spectrum of BRCA2 mutations. It is expected that the penetrance of BRCA2 mutations for stomach cancer will vary from country to country, reflecting local environmental and lifestyle factors.

Nodular regenerative liver hyperplasia as a complication of azathioprine-containing immunosuppressive treatment for Crohn’s disease

Nodular regenerative liver hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for autoimmune disorders, organ transplantation, and/or oncological treatment. Here we report a case of a 40-year-old female patient with Crohn’s disease and genetic hypercoagulability disorder—factor V Leiden, who in the course of azathioprine immunosuppressive treatment for inflammatory bowel disease developed NRH, which was clinically manifested by thrombocytopenia and delicate hepato-splenomegaly. Moreover, her endoscopic examination of upper gastrointestinal tract demonstrated esophageal varices. Genetic analysis revealed heterozygous genotype (*1/*3A) of thiopurine S-methyltransferase (TPMT), a key enzyme of thiopurines’ metabolism, which results in lower activity of TPMT enzyme, thereby making our patient more susceptible to azathioprine-related hepato and myelotoxicity development. Treatment was started with the immediate cessation of azathioprine therapy, and administration of propranolol as primary prophylaxis for bleeding from esophageal varices. Currently (3 years after diagnosis) remission of Crohn’s disease is achieved, however, progression of features of portal hypertension is observed. Propranolol administration is continued and the patient is constantly monitored in our Department. Our Case Study highlights the clinical difficulties and challenges associated with diagnosing of azathioprine-induced NRH, as well as, supports previous observations that hypercoagulability disorders and abnormal TPMT activity may contribute to NRH development.

CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome characterized by a high risk of diffuse stomach cancer and lobular breast cancer. HDGC is caused by germline mutations in the CDH1 gene encoding the E-cadherin which is a member of the transmembrane glycoprotein family responsible for calcium-dependent, cell-to-cell adhesion and plays a fundamental role in the maintenance of cell differentiation and the normal architecture of epithelial tissues. Mutations in the CDH1 gene are detected in 30–46% of families that fulfil strong clinical criteria for HDGC and in about 11% of families fulfilling the modified criteria. In the present study, we investigated germline mutations in the CDH1 gene in Polish patients with HDGC. The entire coding sequence of CDH1 gene was analyzed by sequencing in 86 Polish cancer patients from families fulfilling the modified criteria of HDGC. We found several silent mutations including one common variant (c.2076T>C) present in 56 patients, and three rare variants (c.2253C>T, c.1896C>T, c.2634C>T) detected in 2 patients. In addition, we found four rare sequence variants of unknown significance localized in introns. We did not detect any deleterious mutations of the CDH1 gene. CDH1 gene mutations are not present in Polish families with HDGC defined by the modified clinical criteria. Further studies of families with HDGC matching the restrictive criteria for HDGC are needed.

Synchronous and metachronous neoplasms in gastric cancer patients: A 23-year study

AIM To determine the prevalence and characteristics of additional primary malignancies in gastric cancer (GC) patients. METHODS GC patients (862 total; 570 men, 292 women; mean age 59.8 ± 12.8 years) diagnosed at the Department of Gastroenterology at Pomeranian Medical University over a period of 23 years were included in this retrospective analysis of a prospectively maintained database. Mean follow-up time was 31.3 ± 38.6 mo (range 1-241 mo). The following clinicopathological features of patients with synchronous tumors were compared to those with metachronous tumors: age, sex, symptom duration, family history of cancer, tumor site, stage (early vs advanced), histology, and blood group. GC patients with and without a second tumor were compared in terms of the same clinicopathological features. RESULTS Of 862 GC patients, 58 (6.7%) developed a total of 62 multiple primary tumors, of which 39 (63%) were metachronous and 23 (37%) synchronous. Four (6.9%) of the 58 multiple GC patients developed two or more neoplasms. The predominant tumor type of the secondary neoplasms was colorectal (n = 17), followed by lung (n = 9), breast (n = 8), and prostate (n = 7). Age was the only clinicopathological feature that differed between GC patients with synchronous vs metachronous malignancies; GC patients with synchronous neoplasms were older than those with metachronous neoplasms (68.0 ± 10.3 years vs 59.9 ± 11.1 years, respectively, P = 0.008). Comparisons between patients with and without a second primary cancer revealed that the only statistically significant differences were in age and blood group. The mean age of the patients with multiple GC was higher than that of those without a second primary tumor (63.4 ± 11.4 years vs 59.5 ± 13.0 years, respectively, P = 0.026). GC patients with a second primary tumor were more commonly blood group O than those without (56.2% vs 31.6%, respectively, P = 0.002). CONCLUSION GC patients may develop other primary cancers; appropriate preoperative and postoperative diagnostic modalities are thus required, particularly if patients are older and blood group O.

Expression of Mismatch Repair Proteins in Early and Advanced Gastric Cancer in Poland.

Background Mutations in DNA of mismatch repair (MMR) genes result in failure to repair errors that occur during DNA replication in microsatellites, resulting in accumulation of frameshift mutations in these genes and leading to DNA mismatch replication errors and microsatellite instability. Gastric cancers (GCs) with high MSI (MSI-H) are a well-defined subset of carcinomas showing distinctive clinicopathological features. In this study we investigated the rate of MSI and the correlation between MSI status and clinicopathological features of GC. Material/Methods The study included 107 patients with GCs: 61 with advanced gastric cancers (AGC) and 46 with early gastric cancer (EGC). MSI deficiency in GCs was assessed by the immunohistochemical analysis of expression of MMR proteins – MLH1, MSH2, MSH6, and PMS2 – using formalin-fixed and paraffin-embedded tissue. Results A total of 6 (5.6%) MSI-H were observed. The loss of MMR proteins expression was associated with the intestinal type of GC in Lauren classification, and tubular and papillary architecture in WHO classification. There was no statistically significant association between negative MMR expression and other selected clinical parameters: age, sex, tumor location, depth of invasion (EGC and AGC), lymph nodes status, presence of the ulceration, and lymphocytic infiltrate. Conclusions In the present era of personalized medicine, the histological type of GC and MMR proteins status in cancer cells are very important for the proper surveillance of patients with familial GC and sporadic GCs, as well as for selecting the proper follow-up and treatment. Larger collaborative studies are needed to verify the features of MSI-H GCs in Poland.

The CHEK 2 GENE mutations and the risk of Gastric cancer

Background and aims CHEK2 gene is located on chromosome 22q12.1. and encodes the human analogue of the yeast checkpoint kinases Cds1 and Rad 53. Activation of CHEK2 in response to DNA damage prevents the cell from entering into mitosis. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein IVS2+1G>A in exon 3a nd 1100 del Ci n exon 10, the other, I157T is a missense substitution of an isoleucine for a threonine in exon 3. A single founder allele of the CHEK2 has been associated with predisposition to breast and prostate cancer in North America and Europe. CHK2 alterations are associated with an increased risk of thyroid, prostate, breast, colon and kidney cancer in Polish population. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin, the del 5395 also confers an increased risk of prostate cancer in Polish men. The CHEK2 is therefore a good candidate for a multisite cancer susceptibility gene. We reasoned, that CHEK2 alterations ought to be investigate in gastric cancer cases, too. Patients and methods We have examined the frequency of the CHEK2 gene mutations in a series of randomized individuals including 749 consecutively collected stomach cancer , 166 patients with familial gastric cancer, and 5496 control patients. The 1100 del C, IVS2+1G®A, I 157 T and del

Clinicopathologic characteristics and resection rates of papillary early gastric cancer removed by endoscopic submucosal dissection

The aim of this study was to assess the: 1) clinicopathologic features of papillary early gastric cancer (PEGC) (13 cases) compared to tubular early gastric cancer (TEGC) (41 cases); 2) efficiency of endoscopic submucosal dissection (ESD) in treatment of PEGC. From January 2007 to February 2016, a total of 54 consecutive patients with early gastric cancer (EGC) underwent ESD at the Department of Gastroenterology of the Pomeranian Medical University in Poland. The histologic type of carcinoma was assessed according to the WHO histological classification of GC. The extension of GC into the submucosa was measured using the Aperio Scan Scope image analysis system tools. PEGCs were diagnosed in 24.1% of the cases of EGC. PEGCs were significantly more elevated in macroscopic examination and better demarcated tumors than TEGC. There were no significant differences between gender, tumor location, ulceration, tumor size, depth of invasion (T), presence of intestinal metaplasia and lymphocytic infiltrate. Curative resection was achieved in 87.1% of patients with EGCs treated with ESD. The lower rate of curative resection (R0) observed in PEGC (76.9%) vs TEGC (90.2%) was not statistically significant. Further studies will be necessary to confirm the clinical and morphological presentation of PEGCs.

Histomorphologic features of early gastric carcinoma treated by endoscopic submucosal dissection: relation to efficiency of endoscopic resection

Abstract Objective: Early gastric cancer (EGC) is defined as cancer invasion confined to the mucosa or submucosa, irrespective of lymph node metastasis. Recently endoscopic submucosal dissection (ESD) has been widely accepted for the treatment for dysplasia and EGC without lymph node metastases. While the method has been advanced in Far East countries, ESD is still being developed in Europe and has not gained enough popularity although it has been recommended as the treatment of choice for superficial gastric neoplastic lesions by European Society of Gastrointestinal Endoscopy (ESGE) in 2015. Methods: The aim of the study was to perform a retrospective analysis of clinical and histomorphologic features of 58 cases of EGCs removed by ESD in a university hospital in Western Pomerania in Poland and to evaluate factors related to the efficiency of ESD resection. Results: With univariate analysis, indications for ESD with the highest R0 rate were found in EGCs limited to mucosa (T1a, small mucosal, M), without muscularis mucosa invasion, localised in the middle/lower part of stomach and intestinal type in histological examination. The R0 complete resection rate was significantly (p < 0.0001) lower for T1b than that for T1a tumours (21.4% vs. 100%). Tumours with submucosal involvement were associated with lower efficiency of ESD procedure. Conclusions: Our data showed that in EGCs with favourable histomorphologic characteristics, ESD seemed to be a totally efficient and safe method of treatment in a European small-volume centre. R0 resection rate reached 81.1% of cases and median time of the ESD procedure was 61.5 min.