Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

A single nucleotide polymorphism in codon F31I and V57I of the AURKA gene in invasive ductal breast carcinoma in Middle East.

Although few studies have suggested a carcinogenic role for polymorphism of F31I and V57I codons of AURKA gene in invasive ductal carcinoma, contradictory results from different populations mandates regional investigations. We aimed to determine polymorphisms of F31I and V57I codons of AURKA gene and their association with cancer prognosis in patients compared with controls in an eastern population of Iran.A case-control study was conducted on specimens from 100 patients and 100 age- and gender-matched controls. DNA was extracted and the codons F31I and V57I were amplified. The different genotypes were analyzed by PCR-RFLP and electrophoresis.In codon F31I, the frequency of Phe/Ile was 70% and 82% in patients and healthy controls respectively, whereas (Ile/Ile) was 30% in patients and 18% in healthy (P = .047). Analyzing V57I genotypes showed a higher homozygote Val/Val genotype in patients compared with controls (76% vs 68%), whereas the frequency of heterozygous Val/Ile genotype was lower in patients (17%) than controls (30%), yielding a marginal association between breast cancer and Val/Val genotype (P = .048). No association was observed between SNPs of either F31I or V57I genotypes and histological grades. However, there was a significant association between tumor stages and F31I genotype (P for trend = .003).This is the first report of F31I and V57I polymorphisms in AURKA gene in breast cancer in Iran. Determination of allelic polymorphism of those codons will help to understand background genetic predisposition and could have prognostic value in management of breast cancer in the target population.

ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.

OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.

The gastric acid pocket is attenuated in H. pylori infected subjects.

OBJECTIVE: Gastric acid secretory capacity in different anatomical regions, including the postprandial acid pocket, was assessed in Helicobacter pylori positive and negative volunteers in a Western population. DESIGN: We studied 31 H. pylori positive and 28 H. pylori negative volunteers, matched for age, gender and body mass index. Jumbo biopsies were taken at 11 predetermined locations from the gastro-oesophageal junction and stomach. Combined high-resolution pH metry (12 sensors) and manometry (36 sensors) was performed for 20 min fasted and 90 min postprandially. The squamocolumnar junction was marked with radio-opaque clips and visualised radiologically. Biopsies were scored for inflammation and density of parietal, chief and G cells immunohistochemically. RESULTS: Under fasting conditions, the H. pylori positives had less intragastric acidity compared with negatives at all sensors >1.1 cm distal to the peak lower oesophageal sphincter (LES) pressure (p<0.01). Postprandially, intragastric acidity was less in H. pylori positives at sensors 2.2, 3.3 and 4.4 cm distal to the peak LES pressure (p<0.05), but there were no significant differences in more distal sensors. The postprandial acid pocket was thus attenuated in H. pylori positives. The H. pylori positives had a lower density of parietal and chief cells compared with H. pylori negatives in 10 of the 11 gastric locations (p<0.05). 17/31 of the H. pylori positives were CagA-seropositive and showed a more marked reduction in intragastric acidity and increased mucosal inflammation. CONCLUSIONS: In population volunteers, H. pylori positives have reduced intragastric acidity which most markedly affects the postprandial acid pocket.

The Pretreatment Systemic Inflammatory Response is an Important Determinant of Poor Pathologic Response for Patients Undergoing Neoadjuvant Therapy for Rectal Cancer.

BACKGROUND: Not all patients respond equally to neoadjuvant chemoradiotherapy (nCRT), with subsequent effects on survival. The systemic inflammatory response has been shown to predict long-term outcomes in colorectal cancer. The current study examined the association between systemic inflammation and nCRT in patients with rectal cancer. METHODS: Between 1999 and 2010, patients who underwent nCRT were identified. Serum measurements of hemoglobin, C-reactive protein, albumin, modified Glasgow prognostic score (mGPS), and differential white cell counts were obtained before and after nCRT. The Rödel scoring system measured pathologic tumor regression, and magnetic resonance imaging and computed tomography determined radiologic staging. RESULTS: The study included 79 patients. Of these patients, 37% were radiologically downstaged, and 44% were categorized as showing a good pathologic response (Rödel scores 3 and 4). As a validated measure of the systemic inflammatory response, mGPS (P = 0.022) was associated with a poor pathologic response to nCRT. A radiologic response was associated with a good pathologic response to treatment (P = 0.003). A binary logistic regression model identified mGPS (odds ratio [OR] 0.27; 95% confidence interval [CI] 0.07-0.96; P = 0.043) and radiologic response (OR 0.43; 95% CI 0.18-0.99; P = 0.048) as strong independent predictors of a pathologic response to treatment. CONCLUSION: The current study showed that a systemic inflammatory response before nCRT is associated with a poor pathologic response. Further study in a prospective controlled trial setting is warranted.

Hiatus hernia in healthy volunteers is associated with intrasphincteric reflux and cardiac mucosal lengthening without traditional reflux.

BACKGROUND AND AIMS: Hiatus hernia (HH) is a key mediator of gastro-oesophageal reflux disease but little is known about its significance in the general population. We studied the structure and function of the gastro-oesophageal junction in healthy volunteers with and without HH. METHODS: We compared 15 volunteers with HH, detected by endoscopy or MRI scan, but without gastro-oesophageal reflux disease with 15 controls matched for age, gender and body weight. Jumbo biopsies were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed upright and supine, before and after a meal. The SCJ was marked with an endoscopically placed clip and visualised fluoroscopically. RESULTS: Cardiac mucosa was longer in volunteers with HH (3.5 vs 2.5 mm, p=0.01). There was no excessive acid reflux 5 cm above the upper border of the lower oesophageal sphincter (LOS) in either group but those with HH had short segment reflux 11 mm above the pH transition point after the meal when supine (pH<4 for 5.5% vs 0.3% of time, p=0.01). The SCJ and pH transition point were proximally displaced within the gastro-oesophageal junction in those with HH versus controls (p<0.05). The pH transition point was proximal to the peak LOS pressure point in HH subjects but distal to it in controls after the meal (p<0.05). When supine, the postprandial pH transition point crossed the SCJ in those with HH (p=0.03). CONCLUSIONS: Healthy volunteers with HH have increased intrasphincteric reflux and lengthening of cardiac mucosa in the absence of traditional transsphincteric reflux.

The relationship between tumour budding, the tumour microenvironment and survival in patients with primary operable colorectal cancer.

BACKGROUND: Tumour budding has been reported to reflect invasiveness, metastasis and unfavourable prognosis in colorectal cancer. The aim of the study was to examine the relationship between tumour budding and clinicopathological characteristics, tumour microenvironment and survival in patients with primary operable colorectal cancer. METHODS: A total of 303 patients from a prospective data set of patients with primary operable colorectal cancer were included in the study. The presence of budding was determined through assessment of all tumour-containing H&E slides and the number of tumour buds was counted using a 10 high-powered field method. Routine pathologic sections were used to assess: tumour necrosis, the tumour inflammatory cell infiltrate using Klintrup-Makinen (KM) grade and tumour stroma percentage (TSP) combined as the Glasgow Microenvironment Score (GMS). RESULTS: High-grade tumour budding was present in 39% of all tumours and in 28% of node-negative tumours respectively. High-grade budding was significantly associated with T stage (P<0.001), N stage (P<0.001), TNM stage (P<0.001), serosal involvement (P<0.001), venous invasion (P<0.005), KM grade (P=0.022), high tumour stroma (P<0.001) and GMS (P<0.001). Tumour budding was associated with reduced cancer-specific survival (CSS) (HR=4.03; 95% confidence interval (CI), 2.50-6.52; P<0.001), independent of age (HR=1.47; 95% CI, 1.13-1.90; P=0.004), TNM stage (HR=1.52; 95% CI, 1.02-2.25; P=0.040), venous invasion (HR=1.73; 95% CI, 1.13-2.64; P=0.012) and GMS (HR=1.54; 95% CI, 1.15-2.07; P=0.004). CONCLUSIONS: The presence of tumour budding was associated with elements of the tumour microenvironment and was an independent adverse prognostic factor in patients with primary operable colorectal cancer. Specifically high tumour budding stratifies effectively the prognostic value of tumour stage, venous invasion and GMS. Taken together, tumour budding should be assessed routinely in patients with primary operable colorectal cancer.

Worldwide Inverse Association between Gastric Cancer and Esophageal Adenocarcinoma Suggesting a Common Environmental Factor Exerting Opposing Effects.

OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) is increasing while adenocarcinoma of the stomach is decreasing. We have investigated whether the incidences of these two cancers and their time trends might be inversely related pointing to a common environmental factor exerting opposite effects on these cancers. METHODS: For cross-sectional analyses data were abstracted from "Cancer Incidence in Five Continents" (CI5) Volume X and GLOBOCAN 2012. Relevant ICD-10 codes were used to locate esophageal and gastric cancers anatomically, and ICD-O codes for the histological diagnosis of EAC. For longitudinal analyses, age standardized rates (ASRs) of EAC and total gastric cancer (TGC) were extracted from CI5C-Plus. RESULTS: Estimated (2012) ASRs were available for 51 countries and these showed significant negative correlations between EAC and both TGC (males: correlation coefficient (CC)=-0.38, P=0.006, females: CC=-0.41, P=0.003) and non-cardia gastric cancer rates (males: CC=-0.41, P=0.003 and females: CC=-0.43, P=0.005). Annual incidence trends were analyzed for 38 populations through 1989-2007 and showed significant decreases for TGC in 89% and increases for EAC in 66% of these, with no population showing a fall in the latter. Significant negative correlation between the incidence trends of the two cancers was observed in 27 of the 38 populations over the 19-50 years of available paired data. Super-imposition of the longitudinal and cross-sectional data indicated that populations with a current high incidence of EAC and low incidence of gastric cancer had previously resembled countries with a high incidence of gastric cancer and low incidence of EAC. CONCLUSIONS: The negative association between gastric cancer and EAC in both current incidences and time trends is consistent with a common environmental factor predisposing to one and protecting from the other.

Aneusomy detected by fluorescence in-situ hybridization has high positive predictive value for Barrett's dysplasia.

AIMS: The goal of this study was to pilot a commercial four-colour fluorescence in-situ hybridization (FISH) probe set as a marker of dysplasia in surveillance biopsies. METHODS AND RESULTS: FISH probes to 9p12 (CDKN2A), 17q11.2-12 (HER2), 8q24.12-13 (CMYC) and 20q13.2 (ZNF217) in 20 cases of Barrett's oesophagus. Dysplastic and non-dysplastic mucosa were compared for each case. Two observers independently counted 50 cells in each region of interest (ROI), and the mean score taken. Wilcoxon's signed-rank test was used to determine the significance of differences between dysplastic and non-dysplastic tissue. Predictive power was determined by logistic regression and receiver operator characteristic (ROC) curves were plotted to examine sensitivity and specificity of each gene to detect dysplasia. Interobserver agreement was excellent. HER2, CMYC and ZNF217 showed significant (P < 0.0005) increases in copy number in dysplastic mucosa; CDKN2A had an insignificant (P = 0.852) decrease when compared to non-dysplastic mucosa. While aneusomy was strongly predictive of dysplasia, eusomy did not rule it out. CONCLUSIONS: Increased HER2, CMYC and ZNF217 copy number distinguished dysplastic from non-dysplastic mucosa, but non-detection of aneusomy did not exclude dysplasia. Further studies are justified to determine whether FISH-positive dysplasia might justify earlier treatment by radio-frequency ablation.

In healthy volunteers, immunohistochemistry supports squamous to columnar metaplasia as mechanism of expansion of cardia, aggravated by central obesity.

INTRODUCTION: Recently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine whether it may be due to columnar metaplasia of the distal oesophagus. METHODS: We used the squamocolumnar junction (SCJ), antral and body biopsies from the 52 Helicobacter pylori-negative healthy volunteers who had participated in our earlier physiological study and did not have hiatus hernia, transsphincteric acid reflux, Barrett's oesophagus or intestinal metaplasia (IM) at cardia. The densities of inflammatory cells and reactive atypia were scored at squamous, cardiac and oxyntocardiac mucosa of SCJ, antrum and body. Slides were stained for caudal type homeobox 2 (CDX-2), villin, trefoil factor family 3 (TFF-3) and liver-intestine (LI)-cadherin, mucin MUC1, Muc-2 and Muc-5ac. In addition, biopsies from 15 Barrett's patients with/without IM were stained and scored as comparison. Immunohistological characteristics were correlated with parameters of obesity and high-resolution pH metry recording. RESULTS: Cardiac mucosa had a similar intensity of inflammatory infiltrate to non-IM Barrett's and greater than any of the other upper GI mucosae. The immunostaining pattern of cardiac mucosa most closely resembled non-IM Barrett's showing only slightly weaker CDX-2 immunostaining. In distal oesophageal squamous mucosa, expression of markers of columnar differentiation (TFF-3 and LI-cadherin) was apparent and these correlated with central obesity (correlation coefficient (CC)=0.604, p=0.001 and CC=0.462, p=0.002, respectively). In addition, expression of TFF-3 in distal oesophageal squamous mucosa correlated with proximal extension of gastric acidity within the region of the lower oesophageal sphincter (CC=-0.538, p=0.001). CONCLUSIONS: These findings are consistent with expansion of cardia in healthy volunteers occurring by squamo columnar metaplasia of distal oesophagus and aggravated by central obesity. This metaplastic origin of expanded cardia may be relevant to the substantial proportion of cardia adenocarcinomas unattributable to H. pylori or transsphincteric acid reflux.

Microscopic enteritis: Bucharest consensus.

Microscopic enteritis (ME) is an inflammatory condition of the small bowel that leads to gastrointestinal symptoms, nutrient and micronutrient deficiency. It is characterised by microscopic or sub-microscopic abnormalities such as microvillus changes and enterocytic alterations in the absence of definite macroscopic changes using standard modern endoscopy. This work recognises a need to characterize disorders with microscopic and submicroscopic features, currently regarded as functional or non-specific entities, to obtain further understanding of their clinical relevance. The consensus working party reviewed statements about the aetiology, diagnosis and symptoms associated with ME and proposes an algorithm for its investigation and treatment. Following the 5(th) International Course in Digestive Pathology in Bucharest in November 2012, an international group of 21 interested pathologists and gastroenterologists formed a working party with a view to formulating a consensus statement on ME. A five-step agreement scale (from strong agreement to strong disagreement) was used to score 21 statements, independently. There was strong agreement on all statements about ME histology (95%-100%). Statements concerning diagnosis achieved 85% to 100% agreement. A statement on the management of ME elicited agreement from the lowest rate (60%) up to 100%. The remaining two categories showed general agreement between experts on clinical presentation (75%-95%) and pathogenesis (80%-90%) of ME. There was strong agreement on the histological definition of ME. Weaker agreement on management indicates a need for further investigations, better definitions and clinical trials to produce quality guidelines for management. This ME consensus is a step toward greater recognition of a significant entity affecting symptomatic patients previously labelled as non-specific or functional enteropathy.

Gastric neo-adenocarcinoma arising in a gastric tube after Ivor Lewis oesophagectomy for oesophageal adenocarcinoma.

A 69-year-old man, seven years post Ivor-Lewis oesophagectomy for oesophageal adenocarcinoma, was diagnosed to have a moderately differentiated 4 cm, malignant ulcer within the gastric tube remnant on an endoscopic biopsy. His original presentation was with a T1N0 oesophageal adenocarcinoma, histologically intestinal in type with inflammatory features. He presented with anaemia and melena due to a malignant ulcer in the mid body of his gastric tube on an endoscopy which was confirmed to be a gastric neo-adenocarcinoma on biopsy. He underwent right posterolateral thoracotomy and a wedge resection of the gastric tube including the tumour. Pathology confirmed a T3 N0 (0/7 lymph nodes) with clear margins moderately differentiated adenocarcinoma of intestinal phenotype with papillary features and was reported to be a histopathologically new tumour. Proposed surgical treatments in such patients are dependent on patient's fitness for major resection and may vary from Endoscopic Mucosal Resection to partial resection with preservation of right gastroepiploic vessels or total gastrectomy with intestinal interposition via a retromediastinal route. We suggest that regular endoscopic surveillance may be indicated in such post-oesophagectomy patients as the number of patients developing gastric tube cancers may increase with improve survival of those patients.

Immunohistochemical detection improves the prognostic value of lymphatic and blood vessel invasion in primary ductal breast cancer.

BACKGROUND: Lymphovascular invasion (LBVI) including lymphatic (LVI) and blood (BVI) vessel invasion is a critical step in cancer metastasis. In breast cancer, the optimal detection method of LBVI remains unclear. This research aimed to compare the prognostic value of different assessments of the LVI and BVI in patients with early breast cancer. METHODS: The study cohort included 360 patients with a median follow-up of 168 months. LBVI on H&E sections (LBVIH&E) was reviewed centrally and blinded to the pathology report. Immunohistochemical staining for D2-40 and Factor VIII was performed to identify LVID2-40 and BVIFVIII. RESULTS: LBVIH&E, LVID2-40 and BVIFVIII were present in 102 (28%), 127 (35%) and 59 (16%) patients respectively. In node-negative patients (206), LBVIH&E, LVID2-40 and BVIFVIII were present in 41 (20%), 53 (26%) and 21 (10%) respectively. In triple-negative patients (120), LBVIH&E, LVID2-40 and BVIFVIII were present in 35 (29%), 46 (38%) and 16 (13%) respectively. LBVIH&E was significantly associated with tumour recurrence in the whole cohort (P < 0.001), node-negative patients (P = 0.001) and triple-negative patients (P = 0.004). LVID2-40 and BVIFVIII were significantly associated with tumour recurrence in whole cohort, node-negative (all P < 0.001) and triple-negative patients (P = 0.002). In multivariate survival analysis, only LVID2-40 and BVIFVIII were independent predictors of cancer specific survival in the whole cohort (P = 0.023 and P < 0.001 respectively), node-negative patients (P = 0.004 and P = 0.001 respectively) and triple-negative patients (P = 0.014 and P = 0.001 respectively). CONCLUSION: Assessment of LVI and BVI by IHC using D2-40 and Factor VIII improves prediction of outcome in patients with node-negative and triple-negative breast cancer.

The role of lymphatic and blood vessel invasion in predicting survival and methods of detection in patients with primary operable breast cancer.

Lymphovascular invasion (LBVI) has long been recognized as an essential step of metastases in patients with cancer. However, the process of invasion into lymphatic and blood vessels is still not well defined in breast cancer. To examine the evidence for LBVI, lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) in predicting survival in patients with primary operable breast cancer, and to evaluate the detection methods of vessel invasion. A systematic review of data published from 1964 to 2012 was undertaken according to a pre-defined protocol. There is robust evidence that general LBVI and LVI are independent prognostic factors of poorer survival. The prognostic role of BVI remains unclear. Most studies detected LBVI using H&E stained sections. The overall weighted average of the LBVI rate using immunostaining was higher (35%) than H&E (24%). The LBVI rate using H&E was variable (9-50%) and less variable using immunostaining (32-41%). The overall weighted average of the LVI rate was similar using H&E and immunostaining (33% vs. 25%). The LVI rate using H&E was variable (10-49%) and less variable using immunostaining (21-42%). The overall weighted average of the BVI rate was similar using H&E and/or classical staining and immunostaining (16% vs. 10%). The BVI rates using H&E and/or classical staining approach (4-46%) and immunostaining (1-29%) were both variable. The LBVI and LVI are powerful prognostic factors in primary operable breast cancer. However, BVI was rarely specifically examined and its role in predicting survival is not clear. Further work is required using reliable specific staining to establish the routine use of LVI and BVI in the prediction of outcome in patients with primary operable breast cancer.

The relationship between lymphovascular invasion and angiogenesis, hormone receptors, cell proliferation and survival in patients with primary operable invasive ductal breast cancer.

BACKGROUND: Several well-established tumour prognostic factors are used to guide the clinical management of patients with breast cancer. Lymphovascular invasion and angiogenesis have also been reported to have some promise as prognostic factors. The aim of the present study was to examine the prognostic value of tumour lymphovascular invasion and microvessel density compared with that of established prognostic factors in invasive ductal breast cancer. METHODS: In addition to hormone receptor status and Ki-67 proliferative activity, lymphovascular invasion and microvessel density and their relationship with survival were examined in patients with invasive ductal breast cancer. Full sections and tissue microarrays (n = 384 patients) were utilised to assess these factors and were scored by appropriate methods. RESULTS: On univariate analysis tumour size (P < 0.05), lymph node involvement (P < 0.01), lymphovascular invasion (P < 0.05), microvessel density (P < 0.05) and local- regional treatment (P < 0.01) were associated with poorer survival in ER negative tumours. On multivariate analysis in ER negative tumours lymph node involvement (P < 0.01) and local- regional treatment (P < 0.05) were independently associated with poorer cancer-specific survival. On univariate analysis tumour grade (P < 0.05), lymph node involvement (P < 0.001), HER-2 (P < 0.05), Ki-67 (P < 0.01) and lymphovascular invasion (P < 0.001) were associated with poorer survival in ER positive tumours. On multivariate analysis lymph node involvement (P < 0.001), Ki-67 (P < 0.001) and lymphovascular invasion (P < 0.05) were independently associated with poorer cancer-specific survival in ER positive tumours. CONCLUSION: Lymphovascular invasion but not microvessel density was independently associated with poorer survival in patients with ER positive but not ER negative invasive ductal breast cancer.

Serum ghrelin; a new surrogate marker of gastric mucosal alterations in upper gastrointestinal carcinogenesis.

BACKGROUND: A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting. METHODS: In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared. RESULTS: Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70-44.59) for cardia and 6.58 (1.26-34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36-23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10-0.64)]. CONCLUSION: Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.

The relationship between genetic profiling, clinicopathological factors and survival in patients undergoing surgery for node-negative colorectal cancer: 10-year follow-up.

PURPOSE: The introduction of the bowel cancer screening programme has resulted in increasing numbers of patients being diagnosed with node-negative disease. Unfortunately, approximately 30 % will develop recurrence following surgery. Given the toxicity associated with adjuvant chemotherapy, it is important to identify high-risk patients who may benefit from adjuvant therapy. This study aims to identify which clinicopathological factors and genetic profiling markers predict outcome in node-negative disease. METHODS: Forty-nine microsatellite stable (MSS) patients undergoing curative resection between 1991 and 1993 were included. Local immune response was assessed by Klintrup criteria and vascular invasion status assessed through Miller's elastin staining. Comparative genomic hybridisation (CGH) on a range of loci provided data on allelic imbalance. Analysis of survival included clinicopathological and CGH data in a multivariate (Cox) model. RESULTS: On binary logistical regression analysis, 4p deletion was independently associated with low Klintrup score (HR 0.16; 95 % CI (0.03-0.96); P = 0.045), venous invasion (HR 4.19; 95 % CI (1.08-16.29); P = 0.039) and higher Dukes' stage (HR 6.43; 95 % CI (1.22-33.97); P = 0.028). Minimum follow-up was 109 months and there were 24 cancer deaths. On multivariate analysis, high Klintrup score (HR 0.33; 95 % CI (0.12-0.93); P = 0.036), 4p- (HR 4.01; 95 % CI (1.58-10.21); P = 0.004) and 5q- (HR 3.81; 95 % CI (1.54-9.47); P = 0.004) were significantly associated with survival. CONCLUSION: 4p-, 5q- and low Klintrup score were independently associated with poor cancer-specific survival in node-negative MSS colorectal cancer. Confirmatory work in a larger cohort is needed to determine whether these markers may be used to identify patients who may benefit from adjuvant chemotherapy.