Pathological regression of primary tumour and metastatic lymph nodes following chemotherapy in resectable OG cancer: pooled analysis of two trials.

BACKGROUND: No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. METHODS: Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. RESULTS: Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. CONCLUSIONS: Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further.

Processing Apples to Puree or Juice Speeds Gastric Emptying and Reduces Postprandial Intestinal Volumes and Satiety in Healthy Adults.

BACKGROUND: Whole apples produce greater satiety than processed apples, but the underlying mechanisms remain unclear. OBJECTIVE: Our aim was to assess the intragastric processing of apple preparations and the associated small and large bowel contents using MRI. METHODS: An open label, 3-way crossover, randomized, controlled trial. Eighteen healthy adults (mean ± SD age, 25 ± 4 y; BMI, 22.7 ± 3.5 kg/m2) underwent serial MRI scans on 3 occasions separated by 7 d, after consumption of isocaloric (178 kcal) portions of either whole apples, apple puree, or apple juice. Gastric emptying, small bowel water content (SBWC; primary endpoint), were measured at baseline and at 45 min intervals (0-270 min) postmeal ingestion. Fullness and satiety were also assessed at each time point. Treatment effects between groups were analyzed using ANOVA. RESULTS: Gastric emptying half-time (GE t50) was greater (P < 0.0001) after participants consumed whole apple (mean ± SEM), 65 (3.3) min compared with when they consumed apple puree (41 [2.8] min) or apple juice (38 [2.9] min), times that did not differ. Postprandial area under the curve (AUC) (135-270 min) SBWC was also greater for whole apples than puree (P = 0.025) and juice (P = 0.0004) but juice and puree did not differ. AUC for fullness and satiety (0-270 min) postingestion was also greater (P = 0.002 and 0.004, respectively) for whole apple compared with juice but juice and puree did not differ. CONCLUSIONS: Gastric emptying is slower after whole apple consumption causing a greater sensation of fullness and satiety than puree or juice in healthy adults. Whole apples increased small bowel and colonic contents during the later phase of the study which may be relevant for subsequent food consumption.This study was registered at clinicaltrials.gov as NCT03714464.

Glycaemic, gastrointestinal, hormonal and appetitive responses to pearl millet or oats porridge breakfasts: a randomised, crossover trial in healthy humans.

Whole-grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. The present study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomised, two-way crossover trial, twenty-six healthy participants consumed two isoenergetic/isovolumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP), peptide YY, gastric volumes and appetite ratings were collected 2 h postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental AUC (iAUC2h) for blood glucose was not significantly different between the porridges (P > 0·05). The iAUC2h for gastric volume was larger for PMP compared with SOP (P = 0·045). The iAUC2h for GIP concentration was significantly lower for PMP compared with SOP (P = 0·001). Other hormones and appetite responses were similar between meals. In conclusion, the present study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable alternative with health-promoting characteristics comparable with oats. GIP is an incretin hormone linked to TAG absorption in adipose tissue; therefore, the lower GIP response for PMP may be an added health benefit.

Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy.

BACKGROUND: Pre-operative ultrasound-guided needle sampling (UNS) of abnormal axillary lymph nodes in breast cancer can identify patients with axillary metastases and therefore rationalize patient care and inform decision-making. To obtain tissue diagnosis, UNS can be performed by either fine needle aspiration (FNA) or core needle biopsy (CNB). However, few studies have compared the sensitivity of these techniques and the majority show no difference. METHODS: All node-positive patients (those with micro- and macrometastases but not isolated tumor cells) treated at a tertiary referral center between January 2012 and December 2015 were retrospectively identified from pathology records. The result of the first axillary UNS performed on each patient was compared with postoperative histopathology results. The UNS method used was according to individual radiologist preference. RESULTS: A total of 215 patients underwent FNA (1 patient had bilateral breast cancer and underwent bilateral FNA), and 92 underwent CNB. Sensitivity of CNB was significantly higher than FNA (83.7 vs. 69.0%, P = 0.008). The false-negative rate in the FNA group was therefore higher than in the CNB group by a factor of 2.5. There was no difference in inadequacy rate between the two techniques. There were no complications in the FNA group, and only one hematoma (which did not require operative intervention) in the CNB group. CONCLUSIONS: CNB is safe and should be the preferred technique for UNS to improve sensitivity.

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.

BACKGROUND: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. METHODS: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. FINDINGS: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. INTERPRETATION: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. FUNDING: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Distinct Abnormalities of Small Bowel and Regional Colonic Volumes in Subtypes of Irritable Bowel Syndrome Revealed by MRI.

OBJECTIVES: Non-invasive biomarkers which identify different mechanisms of disease in subgroups of irritable bowel syndrome (IBS) could be valuable. Our aim was to seek useful magnetic resonance imaging (MRI) parameters that could distinguish each IBS subtypes. METHODS: 34 healthy volunteers (HV), 30 IBS with diarrhea (IBS-D), 16 IBS with constipation (IBS-C), and 11 IBS with mixed bowel habit (IBS-M) underwent whole-gut transit and small and large bowel volumes assessment with MRI scans from t=0 to t=360 min. Since the bowel frequency for IBS-M were similar to IBS-D, IBS-M and IBS-D were grouped together and labeled as IBS non-constipation group (IBS-nonC). RESULTS: Median (interquartile range): fasting small bowel water content in IBS-nonC was 21 (10-42), significantly less than HV at 44 ml (15-70), P<0.01 as was the postprandial area under the curve (AUC) P<0.01. The fasting transverse colon volumes in IBS-C were significantly larger at 253 (200-329) compared with HV, IBS-nonC whose values were 165 (117-255) and 198 (106-270) ml, respectively, P=0.02. Whole-gut transit time for IBS-C was prolonged at 69 (51-111), compared with HV at 34 (4-63) and IBS-D at 34 (17-78) h, P=0.03. Bloating score (VAS 0-10 cm) correlated with transverse colon volume at t=405 min, Spearman r=0.21, P=0.04. CONCLUSIONS: The constricted small bowel in IBS-nonC and the dilated transverse colon in IBS-C point to significant differences in underlying mechanisms of disease.

Magnetic Resonance Imaging Quantification of Fasted State Colonic Liquid Pockets in Healthy Humans.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment.

Fat emulsion intragastric stability and droplet size modulate gastrointestinal responses and subsequent food intake in young adults.

BACKGROUND: Intragastric creaming and droplet size of fat emulsions may affect intragastric behavior and gastrointestinal and satiety responses. OBJECTIVES: We tested the hypotheses that gastrointestinal physiologic responses and satiety will be increased by an increase in intragastric stability and by a decrease in fat droplet size of a fat emulsion. METHODS: This was a double-blind, randomized crossover study in 11 healthy persons [8 men and 3 women, aged 24 ± 1 y; body mass index (in kg/m(2)): 24.4 ± 0.9] who consumed meals containing 300-g 20% oil and water emulsion (2220 kJ) with 1) larger, 6-µm mean droplet size (Coarse treatment) expected to cream in the stomach; 2) larger, 6-µm mean droplet size with 0.5% locust bean gum (LBG; Coarse+LBG treatment) to prevent creaming; or 3) smaller, 0.4-µm mean droplet size with LBG (Fine+LBG treatment). The participants were imaged hourly by using MRI and food intake was assessed by using a meal that participants consumed ad libitum. RESULTS: The Coarse+LBG treatment (preventing creaming in the stomach) slowed gastric emptying, resulting in 12% higher gastric volume over time (P < 0.001), increased small bowel water content (SBWC) by 11% (P < 0.01), slowed appearance of the (13)C label in the breath by 17% (P < 0.01), and reduced food intake by 9% (P < 0.05) compared with the Coarse treatment. The Fine+LBG treatment (smaller droplet size) slowed gastric emptying, resulting in 18% higher gastric volume (P < 0.001), increased SBWC content by 15% (P < 0.01), and significantly reduced food intake by 11% (P < 0.05, equivalent to an average of 411 kJ less energy consumed) compared with the Coarse+LBG treatment. These high-fat meals stimulated substantial increases in SBWC, which increased to a peak at 4 h at 568 mL (range: 150-854 mL; P < 0.01) for the Fine+LBG treatment. CONCLUSION: Manipulating intragastric stability and fat emulsion droplet size can influence human gastrointestinal physiology and food intake.

Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is known about the time courses and distribution of water volumes in vivo in an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds.

Impact of COVID-19 on the practice of breast pathologists: a survey of breast pathologists in the UK and Ireland.

AIMS: There is little information on the impact of COVID-19 on breast pathologists. This survey assessed the effect of the COVID-19 pandemic on UK and Ireland-based breast pathologists to optimise working environments and ensure preparedness for potential future pandemics. METHODS: A 35-question survey during the first wave of COVID-19 infections in the UK including questions on workload, working practices, professional development, training, health and safety and well-being was distributed to consultant breast pathologists and responses collected anonymously. RESULTS: There were 135 responses from breast pathologists based in the UK and Ireland. Most participants (75.6%) stated that their workload had decreased and their productivity dropped. 86/135 (63.7%) were given the option of working from home and 36% of those who did reported improved efficiency. Multidisciplinary team meetings largely moved to virtual platforms (77.8%) with fewer members present (41.5%). Online education, including webinars and courses, was utilised by 92.6%. 16.3% of pathologists reported shortages of masks, visors or gowns as the the most common health and safety concern. COVID-19 had a significant negative impact on the physical and mental health of 33.3% of respondents. A small number of pathologists (10.4%) were redeployed and/or retrained. CONCLUSION: The UK and Ireland breast pathologists adapted to the rapid change and maintained service delivery despite the significant impact of the pandemic on their working practices and mental health. It is important to apply flexible working patterns and environments that improve productivity and well-being. The changes suggested should be considered for long-term shaping of breast pathology services.

Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland -on behalf of the UK national coordinating committee for breast pathology.

BACKGROUND: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer. PATIENT AND METHODS: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen's Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after a washout period. RESULTS: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Inter-observer agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. Similarly, consensus-observer agreement was substantial to almost perfect in the whole cohort and moderate to substantial in the HER2-low group. CONCLUSION: HER2-low breast cancer suffers from lower concordance among expert pathologists. While most cases can reproducibly be classified, a small proportion (10%) remained challenging. Refining the criteria for reporting and consensus scoring will help select appropriate patients for targeted therapy.

Calibrated BOLD using direct measurement of changes in venous oxygenation.

Calibration of the BOLD signal is potentially of great value in providing a closer measure of the underlying changes in brain function related to neuronal activity than the BOLD signal alone, but current approaches rely on an assumed relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF). This is poorly characterised in humans and does not reflect the predominantly venous nature of BOLD contrast, whilst this relationship may vary across brain regions and depend on the structure of the local vascular bed. This work demonstrates a new approach to BOLD calibration which does not require an assumption about the relationship between cerebral blood volume and cerebral blood flow. This method involves repeating the same stimulus both at normoxia and hyperoxia, using hyperoxic BOLD contrast to estimate the relative changes in venous blood oxygenation and venous CBV. To do this the effect of hyperoxia on venous blood oxygenation has to be calculated, which requires an estimate of basal oxygen extraction fraction, and this can be estimated from the phase as an alternative to using a literature estimate. Additional measurement of the relative change in CBF, combined with the blood oxygenation change can be used to calculate the relative change in CMRO(2) due to the stimulus. CMRO(2) changes of 18 ± 8% in response to a motor task were measured without requiring the assumption of a CBV/CBF coupling relationship, and are in agreement with previous approaches.

Preventing gastric sieving by blending a solid/water meal enhances satiation in healthy humans.

Separation of solids and liquids within the stomach allows faster gastric emptying of liquids compared with solids, a phenomenon known as sieving. We tested the hypothesis that blending a solid and water meal would abolish sieving, preventing the early rapid decrease in gastric volume and thereby enhancing satiety. We carried out 2 separate studies. Study 1 was a 2-way, crossover, satiety study of 22 healthy volunteers who consumed roasted chicken and vegetables with a glass of water (1008 kJ) or the same blended to a soup. They completed satiety visual analogue scales at intervals for 3 h. Study 2 was a 2-way, crossover, mechanistic study of 18 volunteers who consumed the same meals and underwent an MRI to assess gastric emptying, gallbladder contraction, and small bowel water content (SBWC) at intervals for 3 h. In Study 1, the soup meal was associated with reduced hunger (P = 0.02). In Study 2, the volume of the gastric contents after the soup meal decreased more slowly than after the solid/liquid meal (P = 0.0003). The soup meal caused greater gallbladder contraction (P < 0.04). SBWC showed a biphasic response with an initial "gastric" phase during which SBWC was greater when the solid/liquid meal was consumed (P < 0.001) and a later "small bowel" phase when SBWC was greater when the soup meal was consumed (P < 0.01). Blending the solid/liquid meal to a soup delayed gastric emptying and increased the hormonal response to feeding, which may contribute to enhanced postprandial satiety.

Postprandial changes in small bowel water content in healthy subjects and patients with irritable bowel syndrome.

BACKGROUND & AIMS: Postprandial symptoms are common in patients with irritable bowel syndrome with diarrhea (IBS-D) and could be diet related. We studied postprandial changes in distribution of water in the upper gastrointestinal tract of healthy volunteers (HVs) and patients with IBS-D after contrasting meals. METHODS: In study 1, 11 HVs consumed 350-mL test meals with 5% mannitol (unabsorbable) or 5% glucose (readily absorbed). In study 2, 17 HVs consumed a 331-kcal meal, with or without 15 g bran. In study 3, 26 patients with IBS-D consumed the study 2 diet with bran meal. All subjects underwent serial magnetic resonance imaging analysis. RESULTS: In study 1, subjects' small bowel water content (SBWC) increased after the mannitol but not glucose meals, reaching 381 mL (interquartile range, 343-491 mL) and 47 mL (18-78 mL), respectively, 40 minutes after eating (P < .001). In study 2, SBWC initially decreased after both meal types and then increased, plateauing at 180-405 minutes and was greater after the bran meal (P = .02). In study 3, fasting and postprandial SBWC was lower in IBS-D than in HVs (P < .05 and P < .0001, respectively). Patients with IBS-D had faster orocecal transit times (135 minutes; 90-180 minutes) compared with HVs (225 minutes; 203-293 minutes; P < .0001) and reduced terminal ileum diameter (P < .003). CONCLUSIONS: Postprandial SBWC initially decreases, because of rapid, nutrient-driven fluid absorption, and then increases after a mixed liquid/solid meal. Patients with IBS-D have reduced fasting and postprandial SBWC with faster transit, possibly indicating increased small intestinal tone.

Comparison of COX-2, Ki-67, and BCL-2 expression in normal esophageal mucosa, Barrett's esophagus, dysplasia, and adenocarcinoma with postablation mucosa and implications for ablative therapies.

BACKGROUND: The neosquamous mucosa that replaces ablated esophageal endothelium after endoscopic mucosal ablation for Barrett's metaplasia or high-grade dysplasia (HGD) may retain buried glandular tissue. This study aimed to assess the neoplastic potential, cellular proliferation, and resistance to apoptosis of this buried glandular tissue by measuring COX-2, Ki-67, and BCL-2 expression in these tissues. METHODS: A prospectively collected database was sourced for esophageal biopsy specimens with normal histologic appearance, Barrett's metaplasia, HGD, adenocarcinoma, and postablation mucosa comprising ablated Barrett's and ablated HGD. Quantitative analysis of cellular markers was achieved immunohistochemically using monoclonal antibodies for the COX-2 enzyme (suggesting increased neoplastic potential), Ki-67 antigen (suggesting cellular proliferation), and BCL-2 oncoprotein (suggesting oncogenic resistance to apoptosis). Grading was performed by independent, blinded observers, and the pre- and postablation cellular disparities were subsequently noted. RESULTS: The buried glandular elements of postablation mucosa demonstrated universally greater COX-2, Ki-67, and BCL-2 expression than normal esophagus. Barrett's esophagus and adenocarcinoma expressed significantly greater COX-2 and Ki-67 at the deep glandular level than postablation mucosa. HGD demonstrated greater Ki-67 expression than the postablation tissue but only within the superficial glands. Overall, the expression of COX-2 correlated significantly with Ki-67 expression in deep glandular tissue. CONCLUSIONS: Ablation of pathologic mucosa in Barrett's esophagus and HGD reduces the expression of some markers of neoplastic behavior. However, the buried glandular tissue of the postablation mucosa still exhibits a higher expression than normal esophageal epithelium. This has potential implications for the follow-up treatment of these patients because it is unclear whether the true risk of neoplastic progression is adequately reduced. A more comprehensive study is required to address this issue.

The effects of morphine-neostigmine and secretin provocation on pancreaticobiliary morphology in healthy subjects: a randomized, double-blind crossover study using serial MRCP.

BACKGROUND: Secretin-stimulated magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis of sphincter of Oddi dysfunction (SOD), but it does not correlate well with sphincter of Oddi manometry. Serial MRCP following morphine-neostigmine provocation may be of value in the assessment of SOD, but the effects of these pharmacological agents on pancreaticobiliary morphology in healthy subjects have not been studied. The aim of the present study was to use serial MRCP to characterize the effects of morphine-neostigmine and secretin provocation on serum pancreatic enzyme responses and pancreaticobiliary ductal morphology in healthy subjects. METHODS: Following a baseline scan and serum lipase and amylase assays, 10 healthy subjects were randomized in a double-blind manner to receive morphine (10 mg intramuscularly [IM]), neostigmine (1 mg IM) and saline (intravenously [IV]); OR saline (IM), saline (IM) and secretin (1 U/kg IV). A MRCP study was performed at 5, 30, 60, 90, 120, 150, and 180 min thereafter, with blood samples taken every 60 min for 4 h. Pancreatic duct (PD) diameter, visible PD length, common bile duct (CBD) diameter, and gallbladder volume were recorded. Crossover studies were performed 10 days later. RESULTS: Serum pancreatic enzyme concentrations were significantly greater (amylase, P = 0.003; lipase, P = 0.04) after morphine-neostigmine than after secretin. Following morphine-neostigmine and secretin provocation, the mean (SEM) percentage increase in PD diameter was 28.7 (7.2) versus 12.9 (3.3); P < 0.0001, and visible PD length was 49.4 (11.5) versus 28.1 (8.2); P < 0.0001, respectively. CONCLUSIONS: The effects of morphine-neostigmine were more pronounced than those of secretin in healthy subjects. The diagnostic utility of morphine-neostigmine stimulated serial MRCP for SOD merits further evaluation.

Tumour budding and a low host inflammatory response are associated with a poor prognosis in oesophageal and gastro-oesophageal junction cancers.

AIMS: Tumour budding and host inflammatory response are parameters easily assessed histologically that have prognostic significance in many cancers. There have been few studies examining these parameters in oesophageal or gastro-oesophageal cancers. This study aims to address that deficiency. METHODS AND RESULTS: A two-centre, retrospective study was carried out on 356 patients. Tumour budding and host inflammatory response at the invasive front were assessed histologically. Statistical analysis was performed to determine the prognostic significance of these factors. The median number of tumour buds was four (range 0-50) with 172 of 356 cases having five or more buds at the invasive front. The presence of five or more buds was associated with a poor prognosis on univariate analysis (P = 0.0001), as was a sparse or moderate host inflammatory response (P = 0.001). Tumour budding retained prognostic significance when tumours were separated into adenocarcinomas (n = 287) and squamous cell carcinomas (n = 69), but host inflammatory response was a significant prognostic factor only for adenocarcinomas. On multivariate analysis the presence of five or more buds retained significance (P = 0.002). CONCLUSIONS: Tumour budding and host inflammatory response are important prognostic factors in patients with oesophageal/gastro-oesophageal cancer and can be used to identify high-risk patients who would benefit from closer follow-up and adjuvant therapies.

The influence of surgical excision margins on keloid prognosis.

Keloid disease is known to have variable clinical behavior in response to therapy and there is no clinicopathologic classification that predicts such varied behavior. The aim of this study was to study the effect of excision margins and other histopathologic characteristics on keloid prognosis.Seventy-five multiethnic patients presenting with keloid scars at a department of plastic and reconstructive surgery during an 11-year period were included in this study. Clinical data was collected and detailed histologic analyses using light microscopy were carried out on archived patient specimens.A detailed histopathologic examination of all tissue samples identified keloid border or margin characteristics which were classified into "circumscribed" (borders clearly-demarcated) and "infiltrative" (borders not clearly-demarcated and not easily-definable). The specific histologic findings were correlated with keloid recurrence which revealed that incomplete peripheral (P < 0.001) and deep excision margins (P < 0.001), as well as infiltrative borders (P < 0.05) were associated with higher 1-year reported recurrence rates.This study has given evidence that incomplete surgical excision are associated with higher recurrence and this may justify the practice of routine histopathologic reporting of keloid excision margins.

Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion.

BACKGROUND: Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS). METHODS: In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival. RESULTS: Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT. CONCLUSION: This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.