The feasibility of T2 mapping in the assessment of hepatic steatosis, inflammation, and fibrosis in patients with non-alcoholic fatty liver disease: a preliminary study.

AIM: To determine the feasibility of magnetic resonance imaging T2 mapping in the quantification of liver steatosis in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and to assess the effect of inflammation and fibrosis on T2 values of the liver. MATERIAL AND METHODS: Twenty-three consecutive patients with biopsy-proven NAFLD who underwent T2 mapping between December 2013 and September 2014 were included in this study. All patients underwent fast spin echo multi-echo sequence with eight echoes for T2 measurements. RESULTS: The mean liver T2 value and percentage of histological steatosis was 64.9 ± 7.4 ms and 46.5 ± 27.6%, respectively. There was a good correlation between the liver T2 value and histology-determined steatosis (r = 0.780, p<0.001) and grade of steatosis (rs = 0.779, p<0.001). The mean T2 value in patients with definitive non-alcoholic steatohepatitis (NASH) was significantly higher in comparison with patients without NASH (69 ± 7.37 versus 61.73 ± 5.99 ms, p=0.016). The correlation between T2 value and NAFLD activity score (NAS) was significant (rs = 0.443, p=0.034); however, the correlation disappeared after adjustment for hepatic steatosis and fibrosis (r=0.131, p=0.572). There was a close inverse correlation between T2 value and fibrosis stage after adjusting for hepatic steatosis (r=-0.536, p=0.012). CONCLUSION: T2 mapping can be used for quantification of hepatic steatosis, as there is a close correlation between T2 relaxation values and histology-determined steatosis. Patients with definite NASH have increased T2 values and there is an inverse correlation between the T2 value and fibrosis stage of the liver. T2 mapping in NAFLD may be a useful clinical tool for disease assessment and prognostication.

Differential diagnosis of traditional serrated adenomas and tubulovillous adenomas: a compartmental morphologic and immunohistochemical analysis.

AIM: Traditional serrated adenomas are the rarest member of the serrated polyps, that have endoscopic and morphologic similarities with conventional adenomas, tubulovillous adenomas, in particular. We aimed to compare the histopathologic and immunohistochemical features of TSAs showing overt dysplasia with conventional TVAs in a compartmental manner using digitalized images. PATIENTS AND METHODS: For 25 TSAs and 25 TVAs, extent of the morphologic features including cytoplasmic eosinophilia, mid-zonal nuclei, ECFs, slit-like serration, brush border, gastric foveolar-like epithelium and goblet cells were evaluated. Immunohistochemistry was perfomed using primary antibodies including CK7, CK20, MUC2, MUC5AC, MUC6, B-catenin, Ki67, p53, p16, MLH1, MSH2, MSH6 and PMS2. RESULTS: Eosinophilic cells, mid-zonal nuclei, slit-like serration and ECF were significantly more extensive in TSAs compared to TVAs (p<0,001) while gastric epithelium was also more extensive in TSA cohort with a lower significance (p<0,01). Cut-offs for these features yielding the highest sensitivity and specificity in discriminating TSAs from TVAs were determined ; mid-zonal nucleus resulted as the best discriminating histopathologic feature (100%, 92%) followed by eosinophilia (88%, 92%),and slit-like serration (84%, 92%) with highest sensitivity and specificities, respectively. Compartmental immunohistochemical evaluation revealed that CK20 and CK7 were mainly expressed in ECF while MUC5AC together with CK7 were found in epithelial compartment more frequently in TSAs compared to TVAs. P16 was more common in TSAs in all compartments whereas Ki67 and p53 were restricted to dysplastic compartments in both polyp groups. CONCLUSIONS: The present study demonstrated that mid-zonal nuclei, eosinophilic cells and slit-like serration followed by ECF proved to be the most discriminatory features for TSAs.The correct diagnosis of TSAs will allow to develop appropriate treatment and follow up modalities which seem to be crucial as their progression rate may be different from TVAs.

A prospectively validated nomogram for predicting the risk of chemotherapy-induced febrile neutropenia: a multicenter study.

PURPOSE: There is clinical need to predict risk of febrile neutropenia before a specific cycle of chemotherapy in cancer patients. METHODS: Data on 3882 chemotherapy cycles in 1089 consecutive patients with lung, breast, and colon cancer from four teaching hospitals were used to construct a predictive model for febrile neutropenia. A final nomogram derived from the multivariate predictive model was prospectively confirmed in a second cohort of 960 consecutive cases and 1444 cycles. RESULTS: The following factors were used to construct the nomogram: previous history of febrile neutropenia, pre-cycle lymphocyte count, type of cancer, cycle of current chemotherapy, and patient age. The predictive model had a concordance index of 0.95 (95 % confidence interval (CI) = 0.91-0.99) in the derivation cohort and 0.85 (95 % CI = 0.80-0.91) in the external validation cohort. A threshold of 15 % for the risk of febrile neutropenia in the derivation cohort was associated with a sensitivity of 0.76 and specificity of 0.98. These figures were 1.00 and 0.49 in the validation cohort if a risk threshold of 50 % was chosen. CONCLUSIONS: This nomogram is helpful in the prediction of febrile neutropenia after chemotherapy in patients with lung, breast, and colon cancer. Usage of this nomogram may help decrease the morbidity and mortality associated with febrile neutropenia and deserves further validation.

Factors predicting lapatinib efficacy in HER-2+ metastatic breast carcinoma: Does it work better in different histologic subtypes?

CONTEXT: Introduction of trastuzumab, a recombinant monoclonal antibody against the extracellular domain of HER-2, is a cornerstone in the treatment of HER-2+ breast carcinoma. However, many cancers that have an initial response to trastuzumab will progress some time later. After progression on trastuzumab-based first-line treatment, there are several options. Although TDM-1 (Trastuzumab emtansine) has prolonged progression-free survival (PFS) and overall survival in patients previously treated with trastuzumab and taxane, it is still not available in Turkey. Patients may be switched to lapatinib (an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2), or they may re-challenge with trastuzumab. There is no clear definition of the patients who should be switched to lapatinib. AIM: In this study, we investigated the factors predicting the efficacy of lapatinib. SUBJECTS AND METHODS: Totally, 94 patients treated with lapatinib for metastatic breast carcinoma was included in our study. Retrospective data including pathology, treatments and treatment results, metastatic sites, and laboratory tests were collected. RESULTS: Progression-free survival was 9.1 months. Histologic subtypes other than invasive ductal carcinoma and liver metastasis were inversely related with PFS. Overall survival was 22.1 months, and patients with histologic subtypes other than invasive ductal carcinoma and who progress with brain metastasis had a worse prognosis. CONCLUSION: Clinicians should give attention to histologic subtype and metastatic sites when choosing patients for lapatinib treatment.

Can positron emission tomography-computed tomography predict response in locally advanced rectal cancer patients treated with induction folinic acid and 5-florouracil?

OBJECTIVE: The aim of this study was to determine the pathological complete response rates in a group of locally advanced rectal cancer patients who underwent chemoradiotherapy (CRT) after treatment with induction folinic acid and 5-florouracil (FOLFOX) chemotherapy and the relationship between the complete response and positron emission tomography-computed tomography (PET-CT). MATERIALS AND METHODS: The files of 239 patients who were diagnosed with rectal cancer between January 2008 and January 2012 were evaluated retrospectively. Of these, there were 24 locally advanced rectal cancer patients who met the following criteria: They were administered CRT after receiving four courses induction oxaliplatin, FOLFOX and they underwent PET-CT for staging and for the evaluation of their response to FOLFOX treatment. Of these 24 patients, 20 operable patients were included in the study. RESULTS: The pathological complete response was obtained in seven patients (35%) who were operated on and then given induction four courses FOLFOX chemotherapy and CRT. We determined that age, gender, clinical stage at diagnosis and PET-CT before and after induction chemotherapy were not predictive of the pathological complete response to tumor fluorodeoxyglucose uptake activity. CONCLUSION: The rates of pathological complete response were increased in locally advanced rectal cancer patients who underwent short-term induction chemotherapy. Although the PET-CT has retained its importance in predicting pathological complete response, there is still a need for studies with a larger number of patients and long-term follow-ups.

Diagnosing oesophagitis in children: how discriminative is histology?

BACKGROUND AND STUDY AIMS: We set out to evaluate the discriminatory value of currently available histologic criteria in the differential diagnosis of reflux oesophagitis and eosinophilic oesophagitis in children. PATIENTS AND METHODS: We evaluated the oesophageal biopsies of 145 children and selected 28 demonstrative cases of clinically confirmed eosinophilic oesophagitis (n = 7), and reflux oesophagitis (n = 11) with a control group with normal histology (n = 10). Histological assessment was performed for the presence of papillary elongation, dilatation of intercellular spaces, basal cell hyperplasia and the number of intraepithelial eosinophils, lymphocytes and neutrophils. RESULTS: Among 28 children, there were 3 boys and 4 girls in eosinophilic oesophagitis group, 8 boys and 3 girls in reflux group, and 5 boys and 5 girls in normal group. The mean age was 10,4 years. Basal cell hyperplasia was observed in 12 cases while papillary elongation was found in 25, and dilated intercellular spaces were present in 20 cases. Lymphocyte and neutrophil counts were significantly higher in reflux group when compared to eosinophilic oesophagitis and normal group. Eosinophil counts were significantly higher in eosinophilic group. CONCLUSIONS: Results of the present study suggest that, basal cell hyperplasia, papillary elongation, and dilated intercellular spaces all seem to be markers of oesophagitis regardless of the underlying pathology and etiology, thereby, highlighting their rather nonspecific nature in the differential diagnosis of various types of oesophagitis. The additional information on inflammatory cell counts may help to distinguish reflux oesophagitis from other causes of oesophagitis including EoO.

The importance of COX-2 expression as prognostic factor in early breast cancer.

PURPOSE: A number of studies have been carried out, showing that the risk for breast carcinoma is decreased in those using non-steroidal anti-inflammatory drugs (NSAIDs). Increased cyclooxygenase-2 (COX-2) level is considered as a factor indicating poor prognosis and responsible for angiogenesis, increased cellular proliferation, apoptotic defect and aromatase enzyme induction. For this reason the level of COX-2 might have a prognostic and predictive value in breast cancer as well. This question has become the basis of the present study. METHODS: Eighty-eight female patients with early stage breast cancer being under adjuvant anthracycline based chemotherapy were prospectively recruited. The patient age, body weight, menopausal status, tumor size and grade as well as axillary lymph node involvement were recorded. Routine pathological examination was performed, and COX-2, CerbB2 (HER2), estrogen (ER) and progesterone receptors (PR) levels in breast cancer tissue were determined immunohistochemically. RESULTS: Multivariate analysis confirmed the independent predictive value of both menopausal status and ER expression for overall survival (OS) (p=0.009, HR=1.92, and p=0.014, HR=0.20, respectively). A negative correlation was observed between COX-2 levels and the levels of ER and PR (p=0.006, R= -0.303, and p=0.004, R=-0.312, respectively) whereas no significant correlation was observed concerning CerbB2. No statistically significant correlation was determined between COX-2 levels and the disease-free (DFS) and OS rates. CONCLUSION: Further studies investigating the role of COX- 2 levels in breast cancer progression are needed.

The role of VEGF and other parameters in tracking the clinical course in metronomic chemotherapy.

PURPOSE: The purpose of this study was to investigate the effect of metronomic chemotherapy on serum vascular endothelial growth factor (VEGF) levels in cancer patients. METHODS: The study included 11 metastatic cancer patients who received daily 50 mg cyclophosphamide and biweekly 5 mg methotrexate per os as metronomic chemotherapy. Bevacizumab together with FOLFIRI chemotherapy was administered as anti-angiogenic treatment in another group of 16 metastatic colorectal carcinoma patients. Furthermore, VEGF levels of 10 healthy individuals and 5 cord blood samples served for comparisons. VEGF levels of patients before therapy and 3 months after treatment were analyzed and compared. RESULTS: Serum VEGF levels prior to metronomic chemotherapy were higher compared with the healthy controls (p=0.0001). Similarly, serum VEGF levels prior to the bevacizumab-based chemoimmunotherapy were significantly higher compared with the healthy controls (p=0.005). In patients on metronomic chemotherapy VEGF levels showed non significant decrease (p=0.075). On the contary, VEGF levels decreased significantly (p=0.002) with bevacizumab treatment. CONCLUSION: Serum VEGF levels may be used for assessing of the efficacy of anti-angiogenic therapies.

Evaluation of Barrett's esophagus with CK7, CK20, p53, Ki67, and COX2 expressions using chromoendoscopical examination.

Barrett's esophagus (BE) is a complication of chronic gastroesophageal reflux disease and can be diagnosed when there is an endoscopically irregular Z-line and intestinal metaplasia (IM) in a biopsy obtained lower esophagus. It is still not clear whether IM in the gastric cardia or columnar mucosa without IM in the lower esophagus have any significance as BE, which is considered as preneoplastic. The aim of the study was to determine the immunohistochemical features of BE and columnar mucosa in the distal esophagus and also to evaluate the value of chromoendoscopy in the diagnosis of BE in a prospective manner. A total of 12 chromoendoscopic biopsies (six from normal-looking unstained esophagus and six from esophageal mucosa stained with methyl blue suspicious of BE) were taken from 111 cases who underwent endoscopy because of a variety of upper gastrointestinal symptoms. Immunohistochemical analysis was performed using CK7, CK20, p53, Ki67, and cyclooxygenase 2 (COX2). Of the 111 cases, 19 cases with carcinoma (nine adeno, six squamous, four undifferentiated carcinomas) and 17 cases with normal squamous epithelium were excluded, while 75 cases showing columnar epithelium, including 46 (61.3%) with IM and 29 (38,7%) without IM, were further evaluated immunohistochemically. CK7 was observed in surface, crypt, and glandular epithelium, whereas CK20 was expressed in surface and superficial crypt epithelium. No significant difference was observed between the Barrett and non-Barrett type of CK7/20 staining pattern (P > 0,05). Expression of p53 did not show any difference between BE and columnar mucosa without IM, whereas COX2 expression was significantly increased in BE (P < 0.05) in comparison with columnar mucosa without IM. Ki67 expression was significiantly higher both in upper and lower crypts in BE (P < 0.05). The present study showed that a Barrett pattern does not seem to exist; however, the analysis of COX2 expression and the Ki67 proliferation fraction by immunohistochemistry can be used to separate BE from non-Barrett's metaplasia of the distal esophagus. In our point of view, the immunohistochemical detection of p53 expression in Barrett's metaplasia stage is useless as a marker for early detection of high-risk patients.

Malign peritoneal mesothelioma with nephrotic syndrome.

Nephrotic syndrome may occur in malignancies like Hodgkin Disease and other solid tumors due to glomerulonephritis, amyloidosis or other causes. However, it is rare in peritoneal mesothelioma. We report a 42-year old female patient with peritoneal mesothelioma and nephrotic syndrome together with a review of literature (Tab. 1, Fig. 3, Ref. 7).

Quantitative endoscopic and histologic activity assessment of ulcerative colitis.

BACKGROUND: Correct assessment of the severity and activity of ulcerative colitis (UC) is necessary for determining effective treatment and predicting prognosis. The correlation between histologic activity and endoscopic activity, however, has not yet been determined by using a quantitative scoring system. STUDY AIMS: To compare the endoscopic activity index (EAI), detected during colonoscopy, with the histologic activity index (HAI) detected in biopsy samples taken from the same colon segments of UC patients in order to determine the degree of agreement between both assessments. PATIENTS AND METHODS: Ninety-six UC patients participated in this prospective study. EAIs and HAIs were obtained by summing the scores given for each mucosal/histological change to produce a total score between 1 and 12. The correlation between EAI and HAI was calculated. RESULTS: There was a positive correlation between HAI and EAI (r = 0.78; p < 0.001). There was no statistical inconsistency between the EAI and HAI results (p = 0.625, using the McNemar test). The whole group kappa coefficient was 0.607 (p < 0.001). CONCLUSION: Endoscopic and histologic activity of mucosal disease in patients with UC are generally consistent. Measuring both histologic and endoscopic activity with a quantitative scoring system during patient follow-up would be a more accurate method for monitoring UC patients.

The usefulness of chromoendoscopy with methylene blue in Barrett's metaplasia and early esophageal carcinoma.

BACKGROUND: Barrett's esophagus is a condition that is premalignant for adenocarcinoma of the esophagus and the esophagogastric junction. Early detection of Barrett's metaplasia and dysplasia is very important to decrease the mortality and morbidity from esophageal adenocarcinoma cancer. This study aimed to evaluate the effectiveness of methylene blue-targeted biopsies in the differential diagnosis of intestinal metaplasia, dysplasia, and superficial esophageal carcinoma. METHODS: A total of 109 patients (43 women and 66 men; average age, 62.32 +/- 10.61 years; range, 33-82 years) were enrolled for the study. Four groups were designed before endoscopic examinations. The patients for these groups were selected at the conventional endoscopy, and then chromoendoscopy was performed. The esophagus was stained with methylene blue, after which six biopsies were taken from stained and unstained areas. RESULTS: Conventional and chromoendoscopic assessments were compared with histopathologic examination. The sensitivity of chromoendoscopy for Barrett's epithelium was superior to that of conventional endoscopy (p < 0.05). However, there was no statistical difference between the two methods in the diagnosis of esophagitis or esophageal carcinoma (p > 0.05). Stained biopsies were superior to unstained biopsies in terms of sensitivity for Barrett's epithelium and esophageal carcinoma (p < 0.001). CONCLUSION: Chromoendoscopy is useful for delineating Barrett's epithelium and for indicating the correct location for securing biopsies where dysplasia or early esophageal cancer is suspected.

The development of papillary serous carcinoma of the peritoneum subsequent to endometrial carcinoma: a case report and review of the literature.

Metachronous papillary serous carcinoma of the peritoneum (PSCP) after endometrial carcinoma (EC) is an extremely rare condition. Only three patients have been reported in the English literature. We present the fourth patient who had a more aggressive and fatal clinical course. A 79-year-old multiparous woman complained of progressive abdominal pain and distension after 5 years, subsequent to total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrioid type EC. Serum CA-125 level being followed routinely rose above 500 IU/mL. Abdominal and pelvic computed tomography demonstrated ascites, omental thickening, and nodularity. Paracentesis showed malignant cells resembling papillary adenocarcinoma. Omentectomy and bilateral pelvic lymphadenectomy were performed as cytoreductive surgery. The histologic slides of the totally sampled ovaries obtained from the first operation were reexamined and the corresponding paraffin blocks were re-sectioned but no tumor was detected. The microscopic appearance of the tumor in the omentum differed from that of the previous EC. Immunohistochemically, while the tumor showed reactivity for low and high molecular weight cytokeratin (CK) cocktail, epithelial membrane antigen, CK7, CA-125, and Ber-EP4, the immunostains for calretinin, monoclonal carcinoembryonic antigen, and CK20 were negative. On the basis of these results and the criteria proposed by the Gynecologic Oncology Group, the tumor was diagnosed as metachronous PSCP developed after EC, which corresponded to stage IIIC according to FIGO criteria for ovarian carcinoma. The patient received two cycles of carboplatin and paclitaxel and died 2 months after the cytoreductive surgery.

Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study.

BACKGROUND: Insulin resistance (IR) is commonly associated with non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) may also play a role in the pathogenesis of NASH. A pivotal role in NASH pathogenesis depends on the hypothesis of increased oxidative stress. The aim of our study was to evaluate the effects of supplemental oral vitamin E, a potent antioxidant, on liver functions, PPAR-alpha expression and IR in patients with NASH. METHODS: Nine patients with biopsy-proven NASH were given oral vitamin E 800 mg daily for 24 weeks. Liver functions, lipid parameters, IR index with homeostatic metabolic assessment and liver histology and PPAR-alpha staining index in biopsy specimens were detected before and after the treatment. RESULTS: Seven patients (78%) had IR initially. After 6 months of therapy in nine patients, fasting insulin improved (P = 0.01), but serum cholesterol, triglyceride, fasting blood glucose levels and body mass index remained unchanged. Aspartate aminotransferase and alanine aminotransferase levels decreased (P = 0.01 and P = 0.01, respectively). IR index with homeostatic metabolic assessment resistance improved (P = 0.01), but PPAR-alpha staining index did not change (P = 0.37). Although the histological grade of steatosis decreased (P = 0.01), necroinflammation and fibrosis remained unchanged. In seven patients with IR, however, necroinflammation and PPAR-alpha staining index were improved (P = 0.04 and P = 0.02). CONCLUSION: Vitamin E treatment, in addition to its previously shown beneficial effect by suppressing oxidative stress, may also achieve improvement by reducing IR and PPAR-alpha expression in NASH.