ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS).

BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.

Metachronous adenocarcinoma of the remnant oesophagus 15 years following multimodal therapy.

A 53-year-old man underwent neo-adjuvant chemo-radiotherapy and a 2 stage oesophagectomy for a junctional oesophageal tumour in 1996. In March 2012, a metachronous oesophageal tumour was identified, 7cm above the anastomotic margin, on a background of non-inflamed squamous mucosa. He is currently being managed with chemo-radiotherapy. Oesophageal cancer is associated with a historically poor survival rate, with primary concerns being local recurrence or death from disseminated disease. This case highlights the challenges which must be faced, as treatment strategies improve and consequently survival rates increase.

Outcomes in gastric and junctional cancer using neoadjuvant and adjuvant chemotherapy (epirubicin, oxaliplatin, and capecitabine) and radical surgery.

BACKGROUND: The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. METHODS: Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. RESULTS: Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34%, (16/47). Disease recurrence occurred in 19 patients (19/47, 40%). Median overall survival was 22 months, with 4-year survival of 47%. Chemotoxicities were consistent with those previously reported for this regimen. CONCLUSION: This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF.

Value of CT-PET after neoadjuvant chemoradiation in the prediction of histological tumour regression, nodal status and survival in oesophageal adenocarcinoma.

BACKGROUND: The role of CT-PET after neoadjuvant chemoradiation (nCRT) for prediction of pathological response and oncological outcome in oesophageal and junctional adenocarcinoma (OAC) is unclear. The relationship between complete metabolic response (cMR), pathological complete response (pCR) and nodal status has not been clarified. METHODS: Patients with locally advanced OAC selected to receive nCRT and surgery with curative intent, on the basis of staging that included CT-PET positivity, were included. Repeat scanning (PET2) with an identical protocol was performed 2-4 weeks after completion of nCRT (cisplatin and 5-fluorouracil plus 44 Gy radiation). Changes in [(18) F]fluorodeoxyglucose uptake, considered as either a maximum standardized uptake value (SUVmax) or a relative reduction (%ΔSUVmax), and PET-predicted nodal status following nCRT were compared with histopathological response, histological node positivity and survival. RESULTS: One hundred consecutive patients with PET-positive OAC were studied. Following nCRT, PET2 identified M1 disease in 2·0 per cent of patients. There were no significant associations between PET2 SUVmax or %ΔSUVmax with respect to primary tumour stage (ypT) (P = 0.216 and P = 0·975 respectively), tumour regression grade (P = 0·109 and P = 0·232), pCR (P = 0·633 and P = 0·870) or complete resection (R0) (P = 0·440 and P = 0·235). The sensitivity of PET2 for ypN was 10 per cent. %ΔSUVmax was not associated with disease-free or overall survival (P = 0·162 and P = 0·154 respectively). Of 46 patients with a cMR on PET2, 37 (80 per cent) had histological evidence of residual tumour in the resected specimen, and cMR was not associated with overall survival benefit (P = 0·478). CONCLUSION: CT-PET following nCRT for OAC has poor prognostic and discriminatory value for clinical application.

Leptin and adiponectin receptor expression in oesophageal cancer.

BACKGROUND: Oesophageal adenocarcinoma is an exemplar model of an obesity-associated adenocarcinoma. Altered secretion of adipokines by visceral fat is believed to play a key role in tumorigenesis. This study examined leptin receptor (ObR) and adiponectin receptor (AdipoR1 and AdipoR2) expression in oesophageal cancer, and its relationship with patient obesity status, clinicopathological data and patient survival. METHODS: Tissue microarrays were constructed from paraffin-embedded oesophagectomy specimens. ObR, AdipoR1 and AdipoR2 expression was quantified by immunohistochemistry. Anthropometric data were measured at the time of diagnosis, and obesity status was assessed using visceral fat area determined by computed tomography and body mass index. Receptor expression was correlated with various clinicopathological and anthropometric variables. Patient survival was estimated using the Kaplan-Meier method, and results compared between those with low versus high receptor expression. A Cox multivariable regression model was used to assess the relationship between survival and a number of co-variables. RESULTS: All 125 tumours analysed expressed AdipoR1 and AdipoR2, whereas 96·8 per cent expressed ObR. There was no significant difference in tumour pathological features or patient obesity status between tumours with low versus high ObR expression. A high level of AdipoR1 expression was significantly associated with increased patient age, obesity and less advanced tumour (T) category. Expression of AdipoR2 was inversely associated with T category (P = 0.043). Low AdipoR1 expression was an independent predictor of improved overall survival (hazard ratio 0.56, 95 per cent confidence interval 0.35 to 0.90; P = 0.017). CONCLUSION: The association between adiponectin receptor expression, obesity status and tumour category and survival suggests a potential mechanism linking obesity and oesophageal cancer.

Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction.

BACKGROUND: Neuroepithelial transforming gene 1 (NET1) mediates tumour invasion and metastasis in a number of cancers, including gastric adenocarcinoma. It is an indicator of poor prognosis in breast cancer and glioma. This study examined NET1 expression and its prognostic significance in patients with adenocarcinoma of the oesophagogastric junction (AOG). METHODS: NET1 expression was measured by immunohistochemistry in a tissue microarray, constructed from biobanked tissue collected over a 10-year interval, and linked to a prospectively maintained clinical database. RESULTS: Using the Siewert classification for AOG, type I tumours expressed significantly higher levels of NET1, with lowest expression in type III and intermediate levels in type II (P = 0.001). In patients with AOG type III, NET1-positive patients were more likely to be female (P = 0.043), have advanced stage cancer (P = 0.035), had a higher number of transmural cancers (P = 0.006) and had a significantly higher median number of positive lymph nodes (P = 0.029). In this subgroup, NET1-positive patients had worse median overall (15 versus 23 months; P = 0·025) and disease-free (11 versus 36 per cent; P = 0.025) survival compared with NET1-negative patients. CONCLUSION: Although existing data show differences in clinical and prognostic indices across AOG subtypes, there are no studies showing differences in tumour biology. These data suggest NET1, a known mediator of an aggressive tumour phenotype in a number of gastrointestinal cancers, is expressed differentially across AOG subtypes and may be of prognostic significance in the clinical management of this condition.

Presentation and management of gastrointestinal stromal tumours.

Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the gastrointestinal tract. The aim of this study was to present the experience of a single centre. A prospective GIST database from 1997 to 2011 in a tertiary referral centre wa reviewed. 78 patients (36 male/42 female) with a median age of 66 (range 10-93) were diagnosed with GIST during this period. Surgery was the primary treatment for 70 patients (90%); 19 (24%) resections were laparoscopic. Nineteen patients (24%) received Imatinib therapy. At a median follow up of 3 years, 10 patients (15%) had recurrence. Five-year survival was 89%. Surgery remains the mainstay of treatment. Minimally invasive approaches may be carried out with high cure rates. This study highlights the changing presentation and treatment approach, as well as the excellent outcomes achievable for GIST tumours.

Lack of independent significance of a close (<1 mm) circumferential resection margin involvement in esophageal and junctional cancer.

BACKGROUND: For rectal cancer, an involved circumferential resection margin (CRM), defined as tumor cells within 1 mm of the CRM, is of established prognostic significance. This definition for the esophagus, however, is controversial, with the UK Royal College of Pathologists (RCP) recommending the 1 mm definition, while the College of American Pathologists (CAP) advises that only tumor cells at the cut margin (0 mm) define an incomplete (R1) resection. The aim of this study was to compare the clinical significance of both definitions in patients with pT3 tumors. METHODS: CAP- and RCP-defined CRM status in patients treated by surgery only or by multimodal therapy was recorded prospectively in a comprehensive database from May 2003 to May 2011. Kaplan-Meier survival curves were generated, and factors affecting survival were assessed by univariate and multivariate analysis. RESULTS: A total of 157 of 340 patients had pT3 esophageal tumors, with RCP-positive CRM in 60 %, and 18 % by CAP. There were no significant differences between RCP-positive CRM and negative margins for node-positive disease, local recurrence, and survival. CAP-positive CRM was associated with positive nodes (P = 0.036) and poorer survival (P = 0.023). Multivariate analysis revealed nodal invasion to be the only independent prognostic variable (P = 0.004). CONCLUSIONS: A CRM margin of <1 mm is common in pT3 esophageal tumors, a finding consistent with other reports. The <1 mm definition was not associated with node positivity, local recurrence, or survival, in contrast to actual involvement at the margin, suggesting lack of independent prognostic significance of the RCP definition and possible superiority of the CAP criteria for prospective registration of CRM.

Evolving changes in the management of early oesophageal adenocarcinoma in a tertiary centre.

OBJECTIVES: Series from high volume oesophageal centres highlight an increasing prevalence of early malignant (EM) lesions. The advent of endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) offer alternatives to traditional surgery. The evolution of this pattern of care in a high volume centre is analysed. METHODS: Data were collected from a prospectively maintained database. 96 patients were treated with an EM lesion from 2000 to 2011. Surgery was the standard approach during the initial period (2000-2006). In 2007, with the introduction of EMR±RFA to our Centre, a rising trend toward definitive endoscopic treatment was seen. This study details the selection of cases into treatment groups and their outcomes. RESULTS: From 2000 to 2006, 23 patients were treated with EM lesions, 96% by surgery. Seventy-three were treated from 2007 to 2011, 55% surgically and 45% by EMR±RFA. In the entire experience, there was one death from surgery and morbidity was higher in the surgery group compared with EMR±RFA (p<0.001). Three surgical patients (4.8%) relapsed with HGD or cancer, and one patient with T1N1 disease died of disease recurrence. At a median of 13 months, EMR±RFA offered 100% disease control, 72% had no endoscopic or histological evidence of Barrett's oesophagus and one patient represented with low grade dysplasia. CONCLUSIONS: This study highlights the changing pattern of care in the management of early oesophageal cancer. EMR±RFA appears an acceptable alternative to surgery in carefully selected cases. However, long-term outcome analysis using these methods is required and close interdisciplinary collaboration of specialists in gastroenterology, surgery, pathology and radiology is mandatory to achieve optimum outcomes.

Metastatic paediatric colorectal carcinoma.

A 16-year-old girl presented to our unit with crampy abdominal pain, change in bowel habit, a subjective impression of weight loss and a single episode of haematochezia. She was found to have a rectosigmoid adenocarcinoma and proceeded to laparoscopic anterior resection, whereupon peritoneal metastases were discovered. She received chemotherapy and is alive and well ten month later with no radiological evidence of disease. Colorectal carcinoma is rare in the paediatric population but is increasing in incidence. Early diagnosis is critical to enable optimal outcomes.

Hypoglycaemia in an adult male: a surprising finding in pursuit of insulinoma.

A 50-year-old man who had suffered several episodes of early morning sweats and tremors was diagnosed as having hyperinsulinaemic hypoglycaemia. Cross-sectional imaging and endoscopic ultrasound revealed no pancreatic lesion. A selective intra-arterial calcium infusion study showed a two-fold increase of insulin secretion after infusion of the splenic and superior mesenteric arteries. Laparotomy was performed, no lesion was identified after full mobilisation of the pancreas, and nothing was evident with intra-operative ultrasound. A distal pancreatectomy was performed. Microscopically, the pancreas exhibited diffuse islet cell hyperplasia consistent with nesidioblastosis. The patient remains euglycaemic eight months post-operatively.

(18)FDG uptake during induction chemoradiation for oesophageal cancer fails to predict histomorphological tumour response.

To determine whether [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) could predict the pathological response in oesophageal cancer after only the first week of neoadjuvant chemoradiation. Thirty-two patients with localised oesophageal cancer had a pretreatment PET scan and a repeat after the first week of chemoradiation. The change in mean maximum standardised uptake value (SUV) and volume of metabolically active tissue (MTV) was compared with the tumour regression grade (TRG) in the final histology. Those who achieved a TRG of 1 and 2 were deemed responders and 3-5 nonresponders. In the responders (28%), the SUV fell from 12.6 (+/-6.3) to 8.1 (+/-2.9) after 1 week of chemoradiation (P=0.070). In nonresponders (72%), the results were 9.7 (+/-5.4) and 7.1 (+/-3.8), respectively (P=0.003). The MTV in responders fell from 36.6 (+/-22.7) to 22.3 (+/-10.4) cm(3) (P=0.180), while in nonresponders, this fell from 35.9 (+/-36.7) to 31.9 (+/-52.7) cm(3) (P=0.405). There were no significant differences between responders and nonresponders. The hypothesis that early repeat FDG-PET scanning may predict histomorphologic response was not proven. This may reflect an inflammatory effect of radiation that obscures tumour-specific metabolic changes at this time. This assessment may have limited application in predicting response to multimodal regimens for oesophageal cancer.

Onset of sucrase-isomaltase deficiency in late adulthood.

Sucrase-isomaltase deficiency is a rare disorder usually manifested as diarrhea in infancy. The presentation of such a deficiency in adulthood is even more rare, particularly when the individual has no history of childhood diarrhea. After a literature search, the 59-yr-old patient we report is the oldest to have been identified with this condition. The difficulties encountered in diagnosis when such a case occurs at this age that have not previously been reported are highlighted.

Leukaemia inhibitory factor (LIF) production in a mouse model of spinal trauma.

A model of spinal trauma was developed where spinal neurones of adult mice were exposed to the excitotoxic glutamate analogue beta-N-oxylamino-L-alanine (L-BOAA). After 24 h, the injured neurones received a single dose of [125I]-LIF at the same site of the spinal cord, and 2 h later, tissues were removed to assess the distribution of leukaemia inhibitory factor (LIF). There was a significant increase in LIF binding to the injured region of the spinal cord over saline controls, and this corresponded with a significant increase in LIF mRNA expression in the same region of the cord. There was a change in the expression of ciliary neurotrophic factor, but the expression of cardiotrophin-1 (CT-1) and the common receptor subunit LIF receptor beta (LIFRbeta) did not change after neurotoxin treatment. The results add to the evidence that LIF plays a significant role in the response of adult neuronal tissue to injury.

Controlled release of leukaemia inhibitory factor (LIF) to tissues.

Leukaemia inhibitory factor (LIF) has been shown to effectively enhance skeletal muscle regeneration after mechanical injury and it may have potential therapeutic use in the muscular dystrophies as well as peripheral nerve repair after injury. When LIF is applied systemically to an animal, it is rapidly removed with a biological half life of only a few minutes, and at high doses it exhibits toxic effects. Calcium alginate rods have been developed for the purpose of insertion adjacent to skeletal muscles. These rods, when charged with LIF will release the growth factor to the muscle at a rate of less than 1% per day and for a period extending to several months. In addition, tubes of alginate are described which will be suitable for the continuous supply of LIF to repaired peripheral nerve.

The safety and tolerability of citalopram.

Since citalopram was first approved in 1989, it has been prescribed to an estimated > 600 000 patients. An integrated safety database has been prepared, including data from 3107 patients from 24 clinical trials. In placebo-controlled trials, nausea, dry mouth, somnolence, increased sweating, tremor, diarrhoea, and ejaculation failure, mostly of mild to moderate severity, occurred significantly (p < 0.05) more frequently with citalopram. The excess incidence of these events over placebo was always less than 10%. In pooled comparative studies, citalopram's tolerability profile was similar to that of other selective serotonin reuptake inhibitors (SSRIs) and superior to that of tricyclic antidepressants (TCAs). Spontaneous adverse event reports arising from clinical use have confirmed the safety profile defined during the trials programme. Specific monitoring of all serious adverse events from around 10 000 patients receiving citalopram in clinical trials (including small open studies) has indicated a low potential for convulsions and extrapyramidal effects. There is no evidence of withdrawal phenomena on abrupt discontinuation, no clinically relevant effects on cardiac or laboratory parameters, and little or no effect on psychomotor function. When taken in overdose alone, citalopram appears to have a relatively wide margin of safety. Citalopram has been well tolerated in both short- and long-term use, and the profile seen in trials has been confirmed in the clinic.