Postoperative survival following perioperative MAGIC versus neoadjuvant OE02-type chemotherapy in oesophageal adenocarcinoma.

The optimal management of resectable oesophageal adenocarcinoma is controversial, with many centres using neoadjuvant chemotherapy following the Medical Research Council (MRC) oesophageal working group (OE02) trial and the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. The more intensive MAGIC regimen is used primarily in gastric cancer but some also use it for oesophageal cancer. A database of cancer resections (2001-2013) provided information on survival of patients following either OE02 or MAGIC-type treatment. The data were compared using Kaplan-Meier analysis. Straight-to-surgery patients were also reviewed and divided into an 'early' cohort (2001-2006, OE02 era) and a 'late' cohort (2006-2013, MAGIC era) to estimate changes in survival over time. Subgroup analysis was performed for responders (tumour regression grade [TRG] 1-3) versus non-responders (TRG 4 and 5) and for anatomical site (gastro-oesophageal junction [GOJ] vs oesophagus). An OE02 regimen was used for 97 patients and 275 received a MAGIC regimen. Those in the MAGIC group were of a similar age to those undergoing OE02 chemotherapy but the proportion of oesophageal cancers was higher among MAGIC patients than among those receiving OE02 treatment. MAGIC patients had a significantly lower stage following chemotherapy than OE02 patients and a higher median overall survival although TRG was similar. On subgroup analysis, this survival benefit was maintained for GOJ and oesophageal cancer patients as well as non-responders. Analysis of responders showed no difference between regimens. 'Late' group straight-to-surgery patients were significantly older than those in the 'early' group. Survival, however, was not significantly different for these two cohorts. Although the original MAGIC trial comprised few oesophageal cancer cases, our patients had better survival with MAGIC than with OE02 chemotherapy in all anatomical subgroups, even though there was no significant change in operative survival over the time period in which these patients were treated. The use of the MAGIC regimen should therefore be encouraged in cases of operable oesophagogastric adenocarcinoma.

Routine non-thyroid head and neck cytology in a large UK centre: clinical utility and pitfalls.

OBJECTIVE: This study aimed to examine the performance of head and neck cytology at Nottingham University Hospitals between 2009 and 2010. METHODS: Cases were extracted from the Winpath pathology reporting system and correlations were investigated between results and the histological and clinical outcomes. Specimen adequacy and the sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of the cytology tests were calculated. RESULTS: In all, 19.7 per cent of aspirates were judged to be inadequate. The absolute and relative sensitivities of head and neck cytology were 87.0 per cent and 89.0 per cent, respectively, and the absolute and relative specificities were 99.0 per cent and 97.0 per cent, respectively. The positive predictive values were 99.0 per cent and 96.0 per cent and the negative predictive values were 92.0 per cent and 92.0 per cent for a diagnostic accuracy of 94.5 per cent and 93.0 per cent. The performance was consistent with previous reports and superior to that of a recent UK series. The high rate of inadequate samples is, however, a concern. CONCLUSION: Head and neck cytology is a robust technique at our institution, although there are certain problem areas. There is room for improvement in the technical quality of fine needle aspiration.

An inter-observer agreement study of autofluorescence endoscopy in Barrett's esophagus among expert and non-expert endoscopists.

BACKGROUND: Autofluorescence imaging (AFI), which is a "red flag" technique during Barrett's surveillance, is associated with significant false positive results. The aim of this study was to assess the inter-observer agreement (IOA) in identifying AFI-positive lesions and to assess the overall accuracy of AFI. METHODS: Anonymized AFI and high resolution white light (HRE) images were prospectively collected. The AFI images were presented in random order, followed by corresponding AFI + HRE images. Three AFI experts and 3 AFI non-experts scored images after a training presentation. The IOA was calculated using kappa and accuracy was calculated with histology as gold standard. RESULTS: Seventy-four sets of images were prospectively collected from 63 patients (48 males, mean age 69 years). The IOA for number of AF positive lesions was fair when AFI images were presented. This improved to moderate with corresponding AFI and HRE images [experts 0.57 (0.44-0.70), non-experts 0.47 (0.35-0.62)]. The IOA for the site of AF lesion was moderate for experts and fair for non-experts using AF images, which improved to substantial for experts [κ = 0.62 (0.50-0.72)] but remained at fair for non-experts [κ = 0.28 (0.18-0.37)] with AFI + HRE. Among experts, the accuracy of identifying dysplasia was 0.76 (0.7-0.81) using AFI images and 0.85 (0.79-0.89) using AFI + HRE images. The accuracy was 0.69 (0.62-0.74) with AFI images alone and 0.75 (0.70-0.80) using AFI + HRE among non-experts. CONCLUSION: The IOA for AF positive lesions is fair to moderate using AFI images which improved with addition of HRE. The overall accuracy of identifying dysplasia was modest, and was better when AFI and HRE images were combined.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. METHODS AND RESULTS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). CONCLUSIONS: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

High-resolution endoscopy and endoscopic ultrasound for evaluation of early neoplasia in Barrett's esophagus.

BACKGROUND: Endoscopic ultrasound (EUS) is useful for detecting depth of invasion and nodal involvement in patients with early Barrett's neoplasia (EBN), precluding endoscopic management. This study aimed to determine whether the lesion morphology of the EBN shown on high-resolution endoscopy predicts EUS and histologic tumor stage. METHODS: Retrospective series from two tertiary referral centers were studied. Patients with EBN referred for EUS evaluation before treatment were identified, and data were collected from endoscopies, a database, and case notes. All patients had high-resolution endoscopy followed by radial EUS. RESULTS: This study included 50 patients (22 men) with a median age of 69 years (interquartile range, 60-79 years). Visible lesions in the Barrett's segment were described as Paris types 0-1 (n = 9), 0-IIb (n = 12), 0-IIa (n = 12), 0-IIa + IIc (n = 6), and 0-IIc (n = 5). Of the 50 patients, 46 (92%) had either EMR (n = 17), esophagectomy (n = 23), or both (n = 6). All 12 patients (100%) with Paris 0-IIb lesions had T0/T1 m staging on EUS confirmed with resection histology. The sensitivity for EUS T-staging for Paris classification was 71.4% for type 0-I, 100% for type 0-IIb, 83% for type 0-IIa, 66.7% for type 0-IIa + IIc, and 66.7% for type IIc. Overall, 8 (17%) of the 46 patients were understaged and 2 (4%) were overstaged. For detecting submucosal invasion, EUS had a sensitivity of 66%, a specificity of 93%, a negative predictive value of 85%, and a diagnostic accuracy of 84.4%. CONCLUSION: Submucosal invasion is detected by EUS for 26% of patients with EBN. The value of EUS staging before resection for type 0-IIb early Barrett's cancer (flat lesions) is limited because 100% of these lesions are limited to the mucosa. For the management algorithm in this selected cohort, the use of EUS should be reconsidered.

Endoscopic-ultrasound-guided mural trucut biopsy in the investigation of unexplained thickening of esophagogastric wall.

BACKGROUND AND AIMS: Esophageal and/or gastric wall thickening raises the possibility of malignancy. Endoscopic-ultrasound-(EUS-)guided targeted biopsy of the thickened wall is possible. We aimed to evaluate the efficacy and safety of EUS-guided mural trucut biopsies (TCB) in detecting underlying malignancy in patients with thickened esophagogastric wall and negative mucosal biopsies. METHODS: Patients with alarm symptoms referred for EUS-guided sampling after negative endoscopy and mucosal biopsy were included in the study. All patients had radial EUS reporting abnormal thickening of the esophageal/gastric wall. A linear-array echoendoscope and a 19-gauge trucut needle were used for sampling. Clinical and investigatory data were collected prospectively between 2004 and 2008. RESULTS: Thirty-one patients (20 men) aged 60 - 74 years (median 67 years) were included. All patients had thickened esophageal wall (n = 10), gastric wall (n = 21), or both on radial EUS. Prior to EUS, patients had undergone 1 - 5 endoscopies (median 1.2) and 2 - 8 mucosal biopsies (median 4). The median esophageal and gastric wall thicknesses were 12 and 18 mm respectively. During sampling 1 - 5 needle punctures (median 3) were made. On EUS-TCB, an adequate specimen for histology was obtained in 28/31 patients (90 %). The size of the tissue cores was 4 - 10 mm (median 6mm). Malignancy was confirmed in 16/31 patients (54 %) on histology, and in 11/31 patients (35.4 %) an underlying malignancy was excluded. There was no significant correlation between wall thickness and biopsy size (rho = 0.11, 95 %CI- 0.25 to - 0.45, two-sided P = 0.53). EUS-TCB had sensitivity, specificity, and positive and negative predictive values of 85 %, 100 %, 100 %, and 74 % respectively. There were no immediate or late complications. CONCLUSIONS: EUS-guided mural TCB is a safe and effective technique in the investigation of esophagogastric wall thickening in patients with alarm symptoms and has high sensitivity and specificity for the diagnosis of a cancer.

Narrow-band imaging with magnification in Barrett's esophagus: validation of a simplified grading system of mucosal morphology patterns against histology.

BACKGROUND AND STUDY AIMS: Validation of a simplified classification of mucosal morphology in prediction of histology in Barrett's esophagus using narrow-band imaging with magnification (NBI-Z) and assessing its reproducibility by endoscopists experienced in the use of NBI (NBI-experts) and by endoscopists who were new to NBI (non-NBI-experts). PATIENTS AND METHODS: In a prospective cohort study of 109 patients with Barrett's esophagus at a single tertiary referral center, mucosal patterns visualized in Barrett's esophagus on NBI-Z were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI-Z grading was compared with the final histopathological diagnosis, and positive (PPV) and negative predictive values (NPV) were calculated. The reproducibility of the grading was then assessed by NBI-expert and non-NBI-expert endoscopists, and interobserver and intraobserver agreement were calculated using kappa statistics. RESULTS: Per-biopsy analysis: In 903 out of 1021 distinct areas (87.9%) the NBI-Z grading corresponded to the histological diagnosis. Per-patient analysis: The PPV and NPV for type A pattern (columnar mucosa without intestinal metaplasia) were 100% and 97% respectively; for types B and C (intestinal metaplasia) they were 88% and 91% respectively, and for type D (high-grade dysplasia) 81% and 99% respectively. Inter- and intraobserver agreement: The mean kappa values in assessing the various patterns were 0.71 and 0.87 in the non-expert group; 0.78 and 0.91 in the expert group. CONCLUSIONS: This study has validated a simplified classification of the various morphologic patterns visualized in Barrett's esophagus and confirmed its reproducibility when used by NBI-expert and non-NBI-expert endoscopists.

Non-steroidal anti-inflammatory drug (NSAID)-induced colonic strictures and perforation: a case report.

Although non-steroidal anti-inflammatory drug-induced colopathy is well described, colonic perforations complicating non-steroidal anti-inflammatory drug intake are rare. We report a patient with rheumatoid arthritis who was on long-term diclofenac and presented with early colonic stricture formation and a caecal perforation, which to the best of our knowledge, has only been reported once before. It is important to suspect this diagnosis in patients on non-steroidal anti-inflammatory drug therapy who present with an acute abdomen.

Colonic angiomyolipoma with a monotypic expression and a predominant epithelioid component.

Angiomyolipomas are rare lesions, often arising in the kidney, and are part of a group of tumours with a diverse appearance and evidence of dual melanocytic and smooth muscle differentiation known as PEComas (tumours of perivascular epithelioid cell origin). This report describes an unusual case of a colonic PEComa in a 40 year old woman. Unlike most of the previous colonic angiomyolipomas/PEComas reported in the literature, this case formed a large, mainly extrinsic mass and was monotypic, and composed entirely of the myomatous component with no adipose tissue or typical vasculature.

Expression of p53 and p21waf1/cip1 in gastric carcinoma: lack of inter-relationship or correlation with prognosis.

AIMS: The cell cycle regulators p53 and p21waf1/cip1 are expressed variably in human cancers. We investigated their expression in gastric carcinoma and determined their inter-relationship and prognostic significance. METHODS: Immunohistochemistry was used to determine their expression in material from 100 resected specimens of gastric carcinoma, and comparison was then made of the degree of expression between each, with conventional clinicopathological indices and with survival. RESULTS: Positivity was found with p53 (40%) and p21 (75%). There was no significant correlation between the expression of each individual marker, nor between each marker and 5-year survival. There appeared to be an association between p53 expression and lymph node metastases, and a higher frequency of p21waf1/cip1 expression in males. CONCLUSIONS: The expression of p53 and p21waf1/cip1 as detected by immunohistochemistry were of no value in predicting the prognosis of patients with gastric carcinoma.

Management of the thyroid gland with laryngectomy for cT3 glottic carcinomas.

Is routine hemithyroidectomy justified in laryngectomy for laryngeal carcinoma? Hemithyroidectomy with laryngectomy causes hypothyroidism in up to 25% of patients, and if combined with radiotherapy, in up to 70%. In this review of 102 total laryngectomies with routine hemithyroidectomy for cT3 glottic carcinoma, laryngeal carcinoma involved the thyroid gland in two. Both had subglottic tumour extension. The tumour approached within 3 mm of the thyroid capsule in seven. It is proposed that thyroidectomy should be performed only in selected laryngeal carcinomas. Intraoperative assessment of the thyroid gland should determine the need for thyroidectomy in glottic and transglottic carcinomas. Carcinoma invasion of the thyroid gland should be confirmed by frozen section before proceeding to thyroidectomy. In the absence of thyroid gland involvement, both thyroid lobes may be preserved. Total thyroidectomy should be performed if the thyroid gland has been invaded. Total thyroidectomy should be routinely performed with subglottic carcinomas.

Absence of mutations in exon 3 of the GnRH receptor in human gonadotroph adenomas.

BACKGROUND AND OBJECTIVE: The mechanisms of tumourogenesis for the majority of pituitary tumours are unknown. Mutations of G-protein coupled receptors (GPCRs) have recently been described as important in diverse human diseases, including thyroid adenomas. To test this hypothesis in pituitary gonadotroph adenomas, we amplified and sequenced the GnRH receptor gene in 12 human tumours. We restricted our analysis to the third exon, since this represents the hotspot for activating mutations in other GPCRs. PATIENTS: Pituitary adenoma tissue was identified from patients who had tumours resected and where a diagnosis of gonadotroph adenoma had been made on the basis of immunohistochemical demonstration of LH and/or FSH. METHODS: Genomic DNA was extracted from paraffin-embedded tissue of 18 gonadotroph adenomas. The third exon was successfully amplified by PCR in 12 cases and directly sequenced. RESULTS: We found no missense point mutations or even silent polymorphisms in any tumour studied. CONCLUSION: We conclude that activating mutations of the GnRH receptor gene do not represent an important mechanism of pituitary gonadotroph tumourogenesis.

Arachidonic acid-induced LH release is ATP-independent and insensitive to N-ethyl maleimide.

The mechanism of arachidonic acid (AA)-induced LH release was characterized using sheep pituitary cells in primary culture permeabilized with Staphylococcal alpha-toxin. In intact cells, exogenous AA evoked release of LH in a manner which was partially dependent on extracellular Ca2+. At similar concentrations, AA also caused cell permeabilization as monitored by efflux of [3H]2-deoxyglucose metabolites. In alpha-toxin-permeabilized cells where cytosolic Ca2+ was clamped at resting levels, AA retained its ability to cause LH release. Unlike the stimulation of exocytosis produced by Ca2+, phorbol ester or cyclic AMP, AA-evoked release was independent of ATP and was not inhibited by pretreatment with N-ethyl maleimide. These findings indicated that exogenous AA does not cause LH release by Ca2+ influx or mobilization or by activating protein kinase C. The results suggest that LH release induced by exogenous AA is probably due to its detergent-like properties, and does not represent true exocytosis.