Meta-analysis of the effect of extending the interval after long-course chemoradiotherapy before surgery in locally advanced rectal cancer.

BACKGROUND: The current standard of care in locally advanced rectal cancer (LARC) is neoadjuvant long-course chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). Surgery is conventionally performed approximately 6-8 weeks after nCRT. This study aimed to determine the effect on outcomes of extending this interval. METHODS: A systematic search was performed for studies reporting oncological results that compared the classical interval (less than 8 weeks) from the end of nCRT to TME with a minimum 8-week interval in patients with LARC. The primary endpoint was the rate of pathological complete response (pCR). Secondary endpoints were recurrence-free survival, local recurrence and distant metastasis rates, R0 resection rates, completeness of TME, margin positivity, sphincter preservation, stoma formation, anastomotic leak and other complications. A meta-analysis was performed using the Mantel-Haenszel method. RESULTS: Twenty-six publications, including four RCTs, with 25 445 patients were identified. A minimum 8-week interval was associated with increased odds of pCR (odds ratio (OR) 1·41, 95 per cent c.i. 1·30 to 1·52; P < 0·001) and tumour downstaging (OR 1·18, 1·05 to 1·32; P = 0·004). R0 resection rates, TME completeness, lymph node yield, sphincter preservation, stoma formation and complication rates were similar between the two groups. The increased rate of pCR translated to reduced distant metastasis (OR 0·71, 0·54 to 0·93; P = 0·01) and overall recurrence (OR 0·76, 0·58 to 0·98; P = 0·04), but not local recurrence (OR 0·83, 0·49 to 1·42; P = 0·50). CONCLUSION: A minimum 8-week interval from the end of nCRT to TME increases pCR and downstaging rates, and improves recurrence-free survival without compromising surgical morbidity.

ANTECEDENTES: El tratamiento estándar actual del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) consiste en quimiorradioterapia neoadyuvante de ciclo largo (neoadjuvant, long-course chemoradiation, nCRT) seguida de exéresis total del mesorrecto (total mesorectal excision, TME). De forma convencional, la cirugía se realiza a las 6-8 semanas después de la nCRT. Este estudio tuvo como objetivo determinar el efecto sobre los resultados de ampliar este intervalo. MÉTODOS: Se realizó una búsqueda sistemática de los estudios que analizaban los resultados oncológicos, comparando el intervalo clásico (< 8 semanas) desde el final de la nCRT hasta la TME con un intervalo mínimo de 8 semanas, en pacientes con LARC. El criterio de valoración principal fue la tasa de respuesta patológica completa (pathologic complete response, pCR). Los criterios de valoración secundarios fueron las tasas de supervivencia sin recidiva (recurrence-free survival, RFS), recidiva local (local recurrence, LR) y metástasis a distancia (distant metastasis, DM), tasas de resección R0, integridad (completeness) del mesorrecto, afectación del margen de resección, preservación esfinteriana, formación de estoma, fuga anastomótica y otras complicaciones. Se realizó un metaanálisis utilizando el método de Mantel-Haenszel. RESULTADOS: Se identificaron 26 publicaciones, incluidos cuatro ensayos clínicos aleatorizados, con 17.220 pacientes. Un intervalo mínimo de 8 semanas se asoció con un aumento de la razón de oportunidades (odds ratio, OR) de pCR (OR, 1,68, i.c. del 95% 1,37-2,06, P < 0,001) y de disminución del estadio tumoral (OR 1,18, i.c. del 95% 1,05-1,32, P = 0,004). Los porcentajes de resección R0, integridad del mesorrecto, ganglios linfáticos identificados, preservación esfinteriana, formación de estoma y complicaciones fueron similares entre los dos grupos. El aumento del porcentaje de pCR se tradujo en una disminución de las DM (OR 0,71, i.c. del 95% 0,54-0,93, P = 0,01) y de la recidiva global (OR 0,76, i.c. del 95% 0,58-0,98, P = 0,04), pero no de la LR (OR 0,83, i.c. del 95% 0,49-1,42, P = 0,50). CONCLUSIÓN: Un intervalo mínimo de 8 semanas entre el final de la nCRT y la TME aumenta las tasas de pCR y la reducción del estadio tumoral, así como mejora la RFS sin comprometer la morbilidad quirúrgica.

A systematic review of the role of re-laparoscopy in the management of complications following laparoscopic colorectal surgery.

The benefits of laparoscopic versus open surgery for patients with both benign and malignant colorectal disease have been well established. Re-laparoscopy in patients who develop complications following laparoscopic colorectal surgery has recently been reported by some groups and the aim of this systematic review was to summarise this literature. A literature search of PubMed, Medline and EMBASE identified a total of 11 studies that reported laparoscopic re-intervention for complications in 187 patients following laparoscopic colorectal surgery. The majority of these patients required re-intervention in the immediate postoperative period (i.e. less than seven days). Anastomotic leakage was the commonest complication requiring re-laparoscopy reported (n = 139). Other complications included postoperative hernia (n = 12), bleeding (n = 9), adhesions (n = 7), small bowel obstruction (n = 4), colonic ischaemia (n = 4), bowel and ureteric injury (n = 3 respectively) and colocutaneous fistula (n = 1). Ninety-seven percent of patients (n = 182) who underwent re-laparoscopy had their complications successfully managed by re-laparoscopy, maintaining the benefits of the laparoscopic approach and avoiding a laparotomy. We conclude that re-laparoscopy for managing complications following laparoscopic colorectal surgery appears to be safe and effective in highly selected patients.

Collating evidence to support the validation of a simulated laparotomy incision and closure-training model.

BACKGROUND: It is essential to evaluate the functionality of surgical simulation models, in order to determine whether they perform as intended. In this study, we assessed the use of a simulated laparotomy incision and closure-training model by collating validity evidence to determine its utility as well as pre and post-test interval data. METHOD: This was a quantitative study design, informed by Messick's unified validity framework. In total, 93 participants (surgical trainees â€‹= â€‹80, experts â€‹= â€‹13) participated in this study. Evaluation of content validity and the models' relationships with other variables was conducted, along with a pre and post-test confidence assessment. RESULTS: The model was deemed realistic and useful as a teaching tool, providing strong content validity evidence. In assessment of relationships with other variables, the expert group out-performed the novice group conclusively. Pre and post-test evaluation reported a statistically significant increase in confidence levels. CONCLUSION: We present strong validity evidence of a novel laparotomy incision and closure simulation-training model.

Randomized clinical trial of the benefit of laparoscopy with closure of loop ileostomy.

BACKGROUND: The aim was to compare reversal and laparoscopy with standard reversal of loop ileostomy in terms of hospital stay and morbidity in a randomized study. METHODS: Patients having reversal of a loop ileostomy were randomized to either standard reversal of ileostomy or reversal and laparoscopy. Strict discharge criteria were applied: toleration of two meals without nausea and vomiting, passing a bowel motion, and attaining adequate pain control with oral analgesia. Morbidity and cost were also compared between the two groups. RESULTS: A total of 74 patients (reversal and laparoscopy 40, standard reversal 34) with a median age of 61 years underwent loop ileostomy reversal; there were 45 men (61 per cent). Ileostomy was most commonly carried out after laparoscopic low anterior resection (36 patients). Median length of stay, based on discharge criteria, was significantly shorter in the reversal and laparoscopy group than in the standard group: 4 (interquartile range 3-4) versus 5 (4-6) days (P = 0·003). The overall morbidity rate was also lower in patients who had ileostomy reversal and laparoscopy: 10 versus 32 per cent (P = 0·023). The median cost per patient was lower in the reversal and laparoscopy group: €3450 (interquartile range 2766-3450) versus €4527 (3843-7263) (P = 0·015). There was no statistically significant difference in American Society of Anesthesiologists fitness grade or time to reversal between the two groups. CONCLUSION: Reversal of loop ileostomy with laparoscopy was associated with a shorter hospital stay, lower morbidity and reduced cost compared with the standard technique. REGISTRATION NUMBER: ISRCTN46101203 (http://www.controlled-trials.com).

Re-laparoscopy in the diagnosis and treatment of postoperative complications following laparoscopic colorectal surgery.

BACKGROUND: Laparoscopic colorectal surgery has increasingly become the standard of care in the management of both benign and malignant colorectal disease. We herein describe our experience with laparoscopy in the management of complications following laparoscopic colorectal surgery. METHODS: Between November 2010 and July 2012, data were prospectively collected for all patients requiring surgical intervention for colorectal cancer. This was performed by a full-time colorectal cancer data manager. RESULTS: A total of 203 patients had surgery for colorectal cancer during this period, 154 (75.9%) of which were performed laparoscopically and 49 (24.1%) performed by open surgery. Ten patients (4.9%) underwent surgery for complications of which 7 were following laparoscopic surgery. Two of these 7 patients had an exploratory laparotomy due to abdominal distension and haemodynamic instability. Laparoscopic surgical intervention was successful in diagnosing and treating the remaining 5 patients. Three of these patients developed small bowel obstruction which was managed by re-laparoscopy while in 2 patients there was a significant suspicion of an anastomotic leakage despite appropriate diagnostic imaging which was out ruled at laparoscopy. CONCLUSIONS: Laparoscopy can frequently be used to diagnose and treat complications following laparoscopic colorectal surgery. This is another benefit associated with laparoscopic colorectal surgery which is rarely described and allows the benefits associated with the laparoscopic approach to be maintained.

A systematic review of the anal fistula plug for patients with Crohn's and non-Crohn's related fistula-in-ano.

BACKGROUND: The management of fistula-in-ano is a balance between fistula cure and preservation of continence. OBJECTIVE: The aim of this study is to summarize the anal fistula plug literature for Crohn's and non-Crohn's fistula-in-ano in a homogenous patient population. DATA SOURCES: PubMed, MEDLINE, Embase, and Cochrane medical databases were searched from 1995 to 2011. Abstracts from The American Society of Colon and Rectal Surgeons, The Society for Surgery of the Alimentary Tract, The European Society of Coloproctology, and the Association of Coloproctology of Great Britain and Ireland meetings between 2007 and 2010 were also evaluated. STUDY SELECTION: Studies were included if results for patients with and without Crohn's disease could be differentiated. Patients with rectovaginal, anovaginal, rectourethral, or ileal-pouch vaginal fistulas were excluded as were studies where the mean or median follow-up was less than 3 months. Two researchers independently selected studies matching the inclusion criteria. INTERVENTION: Anal fistula plug insertion was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the overall fistula closure rates and length of follow-up. RESULTS: Seventy-six articles or abstracts were identified from the title as being of relevance. Twenty studies (2 abstracts, 18 articles) were finally included. Study sample size ranged from 4 to 60 patients; 530 patients were included in all studies (488 non-Crohn's and 42 Crohn's patients). The plug extrusion rate was 8.7% (46 patients). The proportion of patients achieving fistula closure varied widely between studies for non-Crohn's, ranging from 0.2 (95% CI 0.04-0.48) to 0.86 (95% CI 0.64-0.97). The pooled proportion of patients achieving fistula closure in patients with non-Crohn's fistula-in-ano was 0.54 (95% CI 0.50-0.59). The proportion achieving closure in patients with Crohn's disease was similar (0.55, 95% CI 0.39-0.70). LIMITATIONS: This study was limited by the variability of operative technique and perioperative care between studies. CONCLUSIONS: Fistula closure is achieved by using the anal fistula plug in approximately 54% of patients without Crohn's disease. The anal fistula plug has not been adequately evaluated in the Crohn's population.

Laparoscopic surgery for complicated diverticular disease: a single-centre experience.

AIM: The role of laparoscopic surgery in the management of patients with diverticular disease is still not universally accepted. The aim of our study was to evaluate the results of laparoscopic surgery for diverticular disease in a centre with a specialist interest in minimally invasive surgery. METHOD: All diverticular resections carried out between 2006 and 2010 were reviewed. Data recorded included baseline demographics, indication for surgery, operative details, length of hospital stay and complications. Complicated diverticular disease was defined as diverticulitis with associated abscess, phlegmon, fistula, stricture, obstruction, bleeding or perforation. RESULTS: One hundred and two patients (58 men) who had surgery for diverticular disease were identified (median age 59 years, range 49-70 years). Sixty-four patients (64%) had surgery for complicated diverticular disease. The indications were recurrent acute diverticulitis (37%), colovesical fistula (21%), stricture formation (17%) and colonic perforation (16%). Sixty-nine cases (88%) were completed by elective laparoscopy. Postoperative mortality was 0%. For elective cases there was no difference in morbidity rates between patients with complicated and uncomplicated diverticular disease. The overall anastomotic leakage rate was 1% and the wound infection rate 7%. There was a nonsignificant trend to higher conversion to open surgery in the elective group in complicated (11.4%) compared with uncomplicated patients (5.2%) (P=0.67). Electively, the rate of stoma formation was higher in the complicated (31.6%) than the uncomplicated group (5.2%) (P<0.02). CONCLUSION: Laparoscopic surgery for both complicated and uncomplicated diverticular disease is associated with low rates of postoperative morbidity and relatively low conversion rates. Laparoscopic surgery is now the standard of care for complicated and uncomplicated diverticular disease in our institution.

The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage--an observational study.

BACKGROUND: Fibrinogen replacement is critical in major obstetric haemorrhage (MOH). Purified, pasteurised fibrinogen concentrate appears to have benefit over cryoprecipitate in ease of administration and safety but is unlicensed in pregnancy. In July 2009, the Irish Blood Transfusion Service replaced cryoprecipitate with fibrinogen. OBJECTIVES: To examine the impact of this externally imposed change on blood product use and clinical outcomes in MOH. METHODS: Women with MOH requiring fibrinogen between 1 January 2009 and 30 June 2011 were identified from an MOH database. Aetiology of MOH, medical treatments, blood product use and clinical outcomes were compared between the cryoprecipitate and fibrinogen groups. RESULTS: Of 21 614 deliveries, 77 cases of MOH were identified. Of the 77 cases, 34 (44%) received cryoprecipitate (n = 14) or fibrinogen concentrate (n = 20). The mean (± SEM) dose utilised was 2.21 ± 0.35 pools of cryoprecipitate and 4 ± 0.8 g of fibrinogen. There was a stronger correlation between the increase in fibrinogen level and dose of fibrinogen (Pearson co-efficient 0.5; P = 0.03) than dose of cryoprecipitate (Pearson co-efficient 0.32; P = 0.3). Mean (± SEM) estimated blood loss (EBL), red cell concentrate (RCC) and Octaplas transfused were greater (but not significantly) in the cryoprecipitate group compared with the fibrinogen group; EBL = 5.2 ± 1.1 vs 3.3 ± 0.5 L (P = 0.1); RCC = 7.2 ± 1.2 vs 5.9 ± 1.0 U (P = 0.4); Octaplas = 4.1 ± 0.7 vs 3.2 ± 0.7 U (P = 0.36), respectively. Haemostasis was secured, and there were no adverse reactions or thrombotic complications. CONCLUSION: Purified virally inactivated fibrinogen concentrate is as efficacious as cryoprecipitate in correcting hypofibrinogenaemia in MOH.

Long-term outcome of colectomy and ileorectal anastomosis for Crohn's colitis.

BACKGROUND: Ileorectal anastomosis is an important surgical option for patients with Crohn's colitis with relative rectal sparing. OBJECTIVE: This study aimed to audit outcomes of ileorectal anastomosis for Crohn's and factors associated with proctectomy and reoperation. DESIGN: This retrospective study involved a chart review and contacting patients. SETTINGS: Patients with Crohn's colitis who had an ileorectal anastomosis were identified from the Mount Sinai Hospital Inflammatory Bowel Disease Database. PATIENTS: Demographics, operative and perioperative outcomes, and reoperative data were collected. MAIN OUTCOME MEASURES: Five- and 10-year Kaplan-Meier survival estimates and 95% confidence intervals were calculated for survival from proctectomy and Crohn's-related revisional surgery. Cox proportional hazards models were used to model the hazards of proctectomy and Crohn's-related revision on the clinical characteristics of patients. RESULTS: Eighty-one patients had an ileorectal anastomosis for Crohn's disease from 1982 to 2010. The most common indications for surgery were failed medical management (60/81, 74.1%) and a stricture causing obstruction (14/81, 17.3%). Seventy-seven percent (n = 62) had a 1-stage procedure, whereas 23% (n = 19) had a 2-stage procedure (colectomy followed by ileorectal anastomosis). The overall anastomotic leak rate was 7.4% (n = 6). Fifty-six patients had a functioning ileorectal anastomosis at the time of follow-up. At 5 and 10 years, 87% (95% CI: 75.5-93.3) and 72.2% (95% CI: 55.8-83.4) of individuals had a functioning ileorectal anastomosis. Eighteen patients required proctectomy for poor symptom control, whereas 11 patients required a small-bowel resection plus redo-ileorectal anastomosis. The mean time to proctectomy from the original ileorectal anastomosis was 88.3 months (SD = 62.1). Smoking was associated with both proctectomy (HR 3.93 (95% CI: 1.46-10.55)) and reoperative surgery (HR 2.12 (95% CI: 0.96-4.72)). LIMITATIONS: : This study was retrospective. CONCLUSIONS: Ileorectal anastomosis is an appropriate operation for selected patients with Crohn's colitis with sparing of the rectum. However, patients must be counseled that the reoperation rate and/or proctectomy rate is approximately 30%.

Hereditary mixed polyposis syndrome due to a BMPR1A mutation.

The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)-beta signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF-beta pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.

Monitoring of lineage-specific chimaerism allows early prediction of response following donor lymphocyte infusions for relapsed chronic myeloid leukaemia.

Donor lymphocyte infusions (DLI) have been shown to enhance the graft-versus-leukaemia (GVL) effect and induce haematological and molecular remission in patients with relapsed CML following allogeneic bone marrow transplantation (BMT). The potent donor cell-mediated cytolysis following DLI may lead to a short period of aplasia before the re-establishment of donor haematopoiesis. The absence of detectable donor cells in patients prior to DLI infusion may result in permanent aplasia in certain patients. We report on four patients who relapsed 1, 3, 6.5 and 7 years post-BMT for chronic phase CML and were treated with DLI from their original BMT donor. Polymorphic short tandem repeats (STRs) were used to assess haematological chimaerism both prior to and following DLI. At the time of relapse, STR-PCR indicated the presence of donor cells in all four patients, at levels ranging from 1-40%. A clinical and molecular response was seen in 4/4 patients following a short period of cytopenia and all patients remain in clinical remission with a follow-up of 2 months-3 years post-DLI. STR-PCR indicated that a response was occurring during the period of pancytopenia when metaphase analysis was unsuccessful. Lineage-specific analysis of the cellular response to DLI was monitored using STR-PCR of peripheral blood (PB) and bone marrow (BM) lymphocyte-enriched fractions and CD2-positive and -negative T cell fractions. In one patient BM and PB CD34-positive and -negative fractions were also assessed. A change in the ratio of donor:recipient cells in the PB lymphocyte fraction was the earliest molecular indication of an anti-leukaemic response. Subsequent conversion to donor chimaerism occurred in the other lineages and the granulocyte fraction was the last lineage to convert. In conclusion, lineage-specific STR-PCR permits detailed monitoring of subtle changes in donor/recipient cell dynamics in specific lineages following DLI during the crucial pancytopenic phase and may be a useful predictor of haematological response to DLI therapy.

Retinal microvascular changes following bone marrow transplantation: the role of cyclosporine.

Three patients complained of deteriorating vision 16, 20 and 29 weeks following bone marrow transplantation (BMT) while receiving cyclosporine (CsA). Opthalmic examination revealed a marked microvascular retinopathy with multiple cotton-wool spots, macular stars and retinal oedema. These appearances could not be accounted for by the mild to moderate hypertension in two cases, the third patient being normotensive. Two of the patients had received total body irradiation (TBI) and cyclophosphamide (CY) as conditioning therapy for BMT as well as previous cranial irradiation for acute lymphoblastic leukaemia; one case with chronic myeloid leukaemia was conditioned with busulphan and CY. Withdrawal of CsA in two patients and reduction of dose in the third led to complete resolution of retinopathy and restoration of visual function. Previous reports have documented ischaemic fundus lesion in BMT recipients treated with CsA and TBI. Our findings suggest that CsA in association with busulphan can produce a similar retinopathy.

Bench and bedside? Surgeons' views on the role of research in surgical training.

AIMS: Internationally, surgical training is facing the challenge of balancing research and clinical experience in the context of reduced working hours. This study aimed to investigate trainees and trainers' views on surgeons participating in full-time research during surgical training. METHODS: An anonymous voluntary survey was conducted of surgical trainers and trainees in two training systems. To examine surgeons' views across two different training schemes, surgeons were surveyed in Ireland (Royal College of Surgeons in Ireland) and in a Canadian centre (University of Toronto) between January 2009 and September 2010 (n = 397 respondents). RESULTS: The majority of respondents felt that time spent in research by trainees was important for surgery as a specialty, while 65 % felt that research was important for surgical trainees (trainers 79 %, trainees 60 %, p = 0.001). A higher proportion of Canadian surgeons reported that they enjoyed their time spent in research, compared to Irish surgeons (84 vs. 66 %, p = 0.05). Financial worries and loss of clinical time were common demotivating factors. Full-time research was more popular than part-time options to obtain a post-graduate degree. CONCLUSIONS: Most agree that research remains an important component of surgical training. However, there are significant differences in opinion among surgeons in different countries on the precise role and structure of research in surgical training.

Impact of a new electronic handover system in surgery.

Accurate handover of clinical information is imperative to ensure continuity of patient care, patient safety and reduction in clinical errors. Verbal and paper-based handovers are common practice in many institutions but the potential for clinical errors and inefficiency is significant. We have recently introduced an electronic templated signout to improve clarity of transfer of patient details post-surgical take. The aim of this study was to prospectively audit the introduction of this new electronic handover in our hospital with particular emphasis regarding efficacy and efficiency. The primary surrogate chosen to assess efficacy and efficiency was length of stay for those patients admitted through the emergency department. To do this we compared two separate, two-week periods before and after the introduction of this new electronic signout format. Users were not informed of the study. Information recorded on the signout included details of the emergency admissions, consults received on call and any issues with regard to inpatients. ASA grade, time to first intervention and admission diagnosis were also recorded. Our results show that introduction of this electronic signout significantly reduced median length of stay from five to four days (P=0.047). No significant difference in ASA grades, time to first intervention or overall admission diagnosis was obtained between the two time periods. In conclusion, this is the first study to show that the introduction of electronic signout post-call was associated with a significant reduction in patient length of stay and provided better continuity of care than the previously used paper-based handover.

Sacral nerve stimulation for faecal incontinence.

BACKGROUND: Faecal incontinence resulting from obstetric injury is a socially disabling condition with a significant impact on quality of life. Sacral nerve stimulation (SNS) is a relatively new treatment modality, which offers patients a potential for improved continence. METHODS: We reviewed our initial experience of SNS in 14 patients (mean age 54 years, range 30-72) with faecal incontinence from January 2006 to June 2007. Background demographics, past medical and obstetric history, anal manometry, endoanal ultrasound and pudendal nerve studies were recorded on all patients. All patients who had permanent SNS implants inserted had pre and post operative questionnaires consisting of the Wexner Continence Score and the Rockwood and SF-36 Quality of Life Indices. RESULTS: Out of 14 patients, 13 had incontinence related to obstetric injuries while one was related to a cauda equina syndrome. All patients had a test procedure consisting of placement of temporary electrodes and a 2-week trial of external SNS. Ten patients noted a significant improvement in their continence and these 10 patients subsequently had a permanent SNS device implanted with an overall significant improvement in continence (P < 0.001) and quality of life (P < 0.01). There were no immediate postoperative complications and one late failure consisting of a lead fracture, which was replaced successfully. Four (29%) patients did not have a significant benefit from temporary SNS and two of these patients subsequently had a colostomy. CONCLUSIONS: SNS offers improvement in continence and quality of life in patients with faecal incontinence whose only other option might otherwise be a permanent colostomy.

Activated nuclear factor-kappa B and cytokine profiles in the esophagus parallel tumor regression following neoadjuvant chemoradiotherapy.

Esophageal adenocarcinoma is increasing in incidence; it relates to chronic gastroesophageal reflux, it is difficult to cure, and treatment modalities increasingly use chemotherapy and radiation therapy prior to resectional surgery. Nuclear factor-kappa B (NF-kappaB) is a pleiotropic transcription factor that regulates several genes for cytokines and enzymes involved in inflammation and immunity, and we have previously described sequential expression of NF-kappaB from the normal esophagus through Barrett's metaplasia to adenocarcinoma. The aim of this exploratory study was to assess the NF-kappaB status and cytokine profiles pre- and post-chemoradiotherapy for esophageal adenocarcinoma. Fresh biopsy specimens obtained from 20 patients with esophageal adenocarcinoma and normal adjacent squamous epithelium were obtained pre-, during and post-chemoradiotherapy, and NF-kappaB expression was analyzed by electrophoretic mobility shift assay. The cytokine protein content of interleukin-1 beta (IL-1beta) and interleukin-8 (IL-8) of tissue homogenates was measured using the ELISA technique. NF-kappaB was constitutively activated in tumor tissues from esophageal adenocarcinoma but was not detected in adjacent normal esophageal mucosa. Elevated levels of IL-1beta and IL-8 were significantly (P < 0.05) higher in tumor tissues compared to control tissues. Patients with a major or complete pathological response (responders) were associated with absence of activated NF-kappaB from nuclear extracts after treatment. Moreover, IL-1beta and IL-8 levels were significantly (P < 0.05) down-regulated in tumor tissues from patients who demonstrated a complete pathological response. No differences in NF-kappaB, IL-1beta and IL-8 levels were detected pre- and post-treatment in patients who did not have a major or complete pathological response (non-responders). The study suggests that monitoring of molecular and cytokine patterns in patients undergoing this neoadjuvant regimen may help subselect the cohort that derives most benefit from the multimodal approach.