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Biomedical subjects

J V Reynolds

Publications and source records attributed to J V Reynolds.

At least 19 recordsLinked to original sources
PubMed2006

(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.

Adult↗
PubMed2006

Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone.

BACKGROUND: Health-related quality of life (HRQL) outcomes are important in assessing new approaches to the treatment of cancer. Neoadjuvant therapy is being used increasingly before surgery in patients with localized oesophageal cancer. This prospective non-randomized study evaluated HRQL in patients treated by preoperative chemotherapy and radiation therapy followed by surgery (multimodal therapy) or by surgery alone. METHODS: Data from European Organization for Research and Treatment of Cancer quality of life questionnaires QLQ-30 and QLQ-OES24 were collected prospectively. Questionnaires were completed at diagnosis, after chemoradiotherapy where applicable, and at 3, 6 and 12 months after surgery. RESULTS: The study included 202 consecutive patients with oesophageal cancer considered suitable for curative (R0) resection at the time of staging. Eighty-seven patients received chemotherapy combined with external-beam radiotherapy before surgery. At baseline, 75 (86 percent) of 87 patients in the multimodal group completed questionnaires, compared with 72 (62.6 percent) of 115 in the surgery-alone group. There were no significant differences in baseline global HRQL scores between groups. Preoperative chemoradiotherapy significantly reduced physical (P=0.004) and role (P=0.007) functioning before surgery, despite a significant (P=0.043) improvement in the dysphagia score. Oesophageal resection had a negative impact on global, functional and symptom HRQL scores at 3 months in both groups. Most variables had recovered by 6 months in the two groups, but at 12 months physical and role functioning remained impaired in the surgery-alone group, and social functioning and financial worries in the multimodal group. CONCLUSION: Although the multimodal regimen had a negative impact on HRQL before surgery, postoperative quality of life in patients who had multimodal therapy was similar to that in those who had surgery alone.

Adult↗
PubMed2006

Clinicopathologic factors predicting complete pathological response to neoadjuvant chemoradiotherapy in esophageal cancer.

Multimodal therapy comprising neoadjuvant chemotherapy and radiation therapy prior to radical resection is increasingly utilized in gastroesophageal cancer. The achievement of a complete pathological response (pCR) or a major response is associated with an improved survival. However, up to 70% of patients show an incomplete or no response to the neoadjuvant regimen, and the identification of factors which predict a response would be of considerable clinical benefit. A retrospective analysis of a prospectively updated esophageal cancer database was performed. The predictive values of the following clinicopathological factors were investigated: age, sex, tobacco, alcohol, weight, clinical history, tumor type, site, length, width, morphology and differentiation. Statistical analysis was performed using Chi-square test with Pearson's test or Kruskal-Wallis test. One hundred and seventy-six patients were identified who had undergone neo-adjuvant chemoradiotherapy at St James's Hospital Dublin, between January 1990 and June 2003. A complete pathological response was seen in 40 cases (23%). There was a significant (P < 0.05) relationship between response to chemoradiotherapy and pretreatment tumor length. The median tumor length in the pCR group was 2 cm (1-5 cm) compared with 3 cm (2-7 cm) in non-responders (P < 0.05). Body weight, sex, tobacco or alcohol usage, tumor site, or differentiation were not predictive of response, although a trend (P = 0.08) was observed for squamous cell cancer compared with adenocarcinoma. Smaller tumor length was predictive of a greater response to chemotherapy and radiation therapy. This may reflect different tumor biology, perhaps with acquired resistance to treatment-induced apoptosis in the larger tumors. A simpler explanation is that the existing dose and treatment schedule for combination chemoradiotherapy is suboptimal in patients with larger tumors.

Adenocarcinoma↗
PubMed2006

Laryngopharyngeal reflux in patients with symptoms of gastroesophageal reflux disease.

Laryngopharyngeal reflux (LPR) has been extensively studied in patients with laryngeal signs and symptoms, gastroesophageal reflux being identified in approximately 50%. Few studies have investigated the incidence and significance of LPR in GERD patients. Two-hundred and seventy-six consecutive patients referred with symptoms of gastroesophageal reflux had dual probe 24 h pH, esophageal manometry, GERD and ENT questionnaires. LPR was defined as at least three pharyngeal reflux events less than pH 5.0 with corresponding esophageal reflux, but excluding meal periods. Fourty-two percent of patients were positive for LPR on 24 h pH monitoring and 91.3% corresponded with an abnormal esophageal acid score. Distal esophageal acid exposure was significantly greater (P < 0.001) in patients with LPR but symptoms of GERD and regurgitation scores showed no significant differences between patients with positive and negative LPR on 24 h pH. There was no significant difference between the incidence of LPR in patients with or without laryngeal symptoms. There is a high incidence of LPR in patients with GERD but its significance for laryngeal symptoms is tenuous. Fixed distance dual probe pH monitoring allows documentation of conventional esophageal reflux and LPR.

Adolescent↗
PubMed2005

Pathological and molecular predictors of the response of rectal cancer to neoadjuvant radiochemotherapy.

AIMS: The prediction of sensitivity and resistance to neoadjuvant therapy has great potential value for many tumour sites. A neoadjuvant regimen is increasingly the gold standard in rectal cancer management and the aim of this review was to highlight predictive markers currently assessed and evaluate their clinical utility. METHODS: A systematic search of Medline was conducted using the following keywords 'colorectal', 'neoadjuvant', 'molecular', 'predict' and 'radiotherapy'. Original manuscripts from all relevant listings were sourced. These were hand searched for further articles of relevance. RESULTS: Conventional indices including tumour stage and grade were unable to predict histological response. Immunohistochemical assessment of P53 gene, Bcl 2, Bax and microsatellite instability are of no predictive value. Studies utilising molecular response predictors from archival pre-treatment tumour tissues have identified several promising predictive markers including p21, spontaneous apoptosis and direct sequencing of the p53 gene. Global gene expression from fresh pre-treatment tissue using cDNA microarray has only recently been assessed but identified expression differences between 54 genes and was able to predict response with 78% sensitivity and 86% specificity. CONCLUSIONS: Currently there are no clinically useful predictors of response based on standard pathological assessment and immunocytochemistry. Direct gene sequencing of p53, studies of apoptosis and global gene sequencing may hold promise.

Biomarkers, Tumor↗
PubMed2005

Major upper gastrointestinal surgery is associated with an antigen-dependent proinflammatory T cell response.

BACKGROUND: T cells play a central role in the immune response to injury. Oesophageal and pancreatic resections are associated with significant risk of systemic inflammatory response syndrome and sepsis. This study involved a detailed analysis of T cell function in a consecutive cohort of patients undergoing such surgery. METHODS: Twenty-five patients undergoing major oncological upper gastrointestinal surgery were investigated for T cell expression of Fas and the activation markers CD69 and CD25, as well as interleukin (IL) 2, IL-10 and interferon (IFN) gamma responses to stimulation with staphylococcal enterotoxin B (SEB). T cell activation in healthy volunteer peripheral blood mononuclear cells was studied in co-culture with patients' serum, either alone or with cytotoxic T lymphocyte-associated antigen (CTLA) 4, an inhibitor of antigen presentation. RESULTS: T cells expressed significantly raised levels of CD69 and CD25 after surgery, but no change in Fas expression was evident. There was a significant increase in the production of IL-2 after surgery without a concomitant increase in IFN-gamma or IL-10 in response to SEB. Postoperative serum activated healthy volunteer T cells, a response that was inhibited (P = 0.053) by co-incubation with CTLA-4. CONCLUSION: Major surgery results in pan-T cell activation via a serum-mediated antigenic mechanism that is independent of Fas expression. Postoperative T cells are primed for an augmented proinflammatory response to superantigen, sustained for at least 1 week, implicating the adaptive immune system in the development of the postoperative systemic immunoinflammatory state.

Adult↗
PubMed2005

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.

Adenocarcinoma↗
PubMed2005

Effect of physical exercise on esophageal motility in patients with esophageal disease.

The most common type of esophageal dysfunction associated with chest pain is gastroesophageal reflux, which may be induced by exercise. The effect of exercise on esophageal function has mainly been investigated in normal subjects or trained athletes. Few studies have investigated exercise and esophageal motility disorders. One hundred and thirty-five patients underwent ambulatory esophageal manometry and pH monitoring, before, during and immediately after moderate exercise. Patients were divided into four groups: Normal, nutcracker, diffuse spasm and gastroesophageal reflux disease (GERD). Ambulatory manometry and pH were monitored while exercising on a treadmill during which standardized boluses of water were administered. Nutcracker and diffuse spasm patients demonstrated a significant fall in esophageal wave amplitude during exercise compared to controls, which returned rapidly to pre exercise values after resting. There was no evidence of acid reflux in the non-reflux groups during exercise. Reflux was noted in 13 patients with GERD during exercise, none of whom had evidence of reflux at the onset of exercise. When these patients were classified by reflux type, the majority, 11 patients, were found to come from the combined or supine reflux group. Esophageal amplitude in nutcracker esophagus does not increase during moderate exercise. Moderate exercise provokes reflux in GERD patients with combined or supine reflux.

Esophageal Motility Disorders↗
PubMed2005

Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.

BACKGROUND: The incidence of esophageal adenocarcinoma has increased significantly in the western world over the last 20 yr. Most cases arise in a background of chronic gastroesophageal reflux, and specialized intestinal metaplasia in Barrett's esophagus is frequently an antecedent phenotype or evident in association with adenocarcinoma. The molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood. AIMS: To examine the expression of the proinflammatory cytokines IL-8 and IL-1beta along the esophagitis, metaplasia, dysplasia, and adenocarcinoma pathway, and to correlate this with histological changes and expression of the transcription factor NF-kappaB. PATIENTS AND METHODS: Fresh biopsy specimens were collected from patients with reflux esophagitis (n=15), Barrett's esophagus (n=35), Barrett's adjacent to adenocarcinoma (n=8), and esophageal adenocarcinoma (n=35). IL-8 and IL-1beta expression were measured using enzyme-linked immunosorbent assay. NF-kappaB expression was measured by electrophoretic mobility shift assay. RESULTS: Elevated expression of NF-kappaB was found in 2 (13%) out of 15 patients with reflux esophagitis, 21 (60%) out of 35 patients with Barrett's esophagus, and 28 (80%) out of 35 patients with esophageal adenocarcinoma. All 5 patients with Barrett's esophagus and high-grade dysplasia showed elevated expression of NF-kappaB. IL-8 and IL-1beta were significantly increased in esophagitis, Barrett's, and adenocarcinoma compared with squamous epithelium, and in adenocarcinoma compared with all other groups. There was a stepwise increase in the expression of IL-8, IL-1beta, and NF-kappaB from normal through Barrett's epithelium to adenocarcinoma in eight cases of esophageal adenocarcinoma. The levels of both IL-8 and IL-1beta in adenocarcinoma patients correlated with stage of disease. Patients with adenocarcinoma who were NF-kappaB positive had significantly higher levels of both IL-8 (p=0.04) and IL-1beta (p=0.03) compared to adenocarcinoma patients who were NF-kappaB negative. CONCLUSIONS: The proinflammatory cytokines IL-8 and IL-1beta are elevated in esophagitis and Barrett's epithelium, and markedly elevated in adenocarcinoma. NF-kappaB activation is infrequent in esophagitis, but is increased in Barrett's epithelium and adenocarcinoma. The association of NF-kappaB activation with cytokine upregulation was only evident in patients with adenocarcinoma. These patterns may play an important role in Barrett's inflammation and tumourigenesis, and inhibition of the NF-kappaB/proinflammatory cytokine pathway may be an important target for future chemoprevention strategies.

Adenocarcinoma↗
PubMed2005

Stab to second intercostal space: a bubbling extrapleural wound.

A 37 year old man was found collapsed at the roadside and taken to the emergency department. Communication was difficult, as the patient could not speak English. There was a wound in the left second intercostal space on the midclavicular line, which was bleeding and was bubbling air. A drain was inserted, bleeding controlled, and his wounds sutured. Chest x ray later confirmed satisfactory placement of the drain. The following day, swelling and discharge indicated oesophageal damage, which was later confirmed by gastrografin swallow. With conservative management in hospital for 2 weeks, he made a full recovery and was discharged.

Adult↗
PubMed2005

Vitamin C enhances chemosensitization of esophageal cancer cells in vitro.

Chemotherapy is increasingly utilised in multimodal protocols to try and improve outcomes. Cisplatin and 5-fluorouracil (5-Fu) are the mainstay of chemotherapeutic regimens, and an understanding of sensitivity and resistance of esophageal cancer to these agents is of considerable clinical importance. Antioxidants may modulate the response to chemotherapy, and in this study we examined the effect of vitamin C on 5-Fu and cisplatin cytotoxicity and related pathways in the esophageal cancer cell lines OE33 and SKGT-4. The antiproliferative effect of antitumor agents was measured by the MTT assay, and the transcription factors NF-kappaB and AP-1 pathways were assessed by electrophoretic mobility gel shift assay. 5-Fu and cisplatin demonstrated marked morphological changes and decreased cell proliferation. A combination of vitamin C with 5-Fu or cisplatin exerted a significantly enhanced cytotoxic effect compared to both drugs individually. Treatment of esophageal cancer cells with 5-Fu and cisplatin induced NF-kappaB and AP-1 activation. Pretreatment with vitamin C inhibited 5-Fu or cisplatin induced NF-kappaB nuclear translocation and DNA binding activity, but vitamin C had no effect on IkappaB-alpha protein levels. Vitamin C also inhibited 5-Fu- and cisplatin-induced AP-1 activation. Our data demonstrate that vitamin C enhances the antitumor activity of 5-Fu and cisplatin, in part by inhibiting translocation of NF-kappaB and AP-1, and sensitizes cancer cells to drug-induced cell death. The data suggest that vitamin C supplementation may improve the efficacy of chemotherapy for esophageal cancer.

Antimetabolites, Antineoplastic↗
PubMed2004

Margin involvement and outcome in oesophageal carcinoma: a 10-year experience in a specialist unit.

AIMS: Positive microscopic margins after major cancer surgery adversely affect prognosis. We questioned whether the benefit of a multimodal approach in oesophageal carcinoma is due to reduced resection margin involvement and whether multimodal therapy alters the disease course when margins are involved. METHODS: Pathology specimens of 212 patients, treated with either multimodal therapy or surgery alone, were re-reviewed to assess margin involvement by tumour. Margin status was compared with recurrence and survival data. RESULTS: Margin involvement was decreased with multimodal therapy (16 of 103 patients) vs surgery (33 of 109 patients), associated with reduced tumour recurrence and a significant survival advantage. However, even with involved margins, multimodal therapy had lower recurrence vs surgery and a small survival benefit. CONCLUSIONS: Multimodal therapy significantly reduces margin involvement. The benefit of multimodal therapy remains highly significant for patients with clear margins. This study confirms for oesophageal carcinoma the value of an aggressive surgical approach in achieving negative resection margins.

Adenocarcinoma↗
PubMed2004

Gastric myoelectrical activity post-chemoradiotherapy and esophagectomy: a prospective study using subscapular surface recording.

The aims of this study were to prospectively evaluate gastric function in esophageal cancer patients after chemoradiotherapy and following surgery, using cutaneous electrogastrography (EGG). Twenty-three patients with esophageal adenocarcinoma were recruited to the study. A subset of patients (n = 11) underwent neoadjuvant chemoradiotherapy and were also studied at 14 days after treatment. All patients underwent EGG studies prior to and following surgery, at 3 months postoperatively. Ten of these patients were also studied at medians of 6 months and 12 months after surgery. Twenty normal volunteers were used as controls. Post-operative EGG studies were monitored with a modified technique; the electrodes being placed in the subscapular region in the area of the transposed stomach. Following neoadjuvant treatment there was a significant increase in abnormal gastric myoelectrical activity involving changes in tachygastrias and decreased motility as measured by power ratio. Post-operatively there was a significant increase in bradygastria which persisted at 6 months but not at 12 months. There was a corresponding decrease in normogastria which persisted at 6 months and to a lesser extent at 12 months. Dominant frequency remained significantly depressed at 3, 6 and 12 months. Gastric myoelectrical activity is normal in untreated esophageal cancer. Neoadjuvant chemoradiotherapy causes a disruption to normal myoelectrical activity involving reduced motility and tachygastrias. Surgery causes a depression in dominant frequency with a reduced incidence of normogastria at 3 months and 6 months but with a tendency towards normality at 12 months.

Adenocarcinoma↗
PubMed2004

Factors influencing the development of Barrett's epithelium in the esophageal remnant postesophagectomy.

BACKGROUND: Barrett's esophagus results from chronic reflux of both acid and bile. Reflux of gastric and duodenal contents is facilitated through the denervated stomach following esophagectomy, but the development of Barrett's changes in this model and the relationship to gastric and esophageal physiology is poorly understood. AIMS: To document the development of new Barrett's changes, i.e., columnar metaplasia or specialized intestinal metaplasia (SIM) above the anastomosis, and relate this to the recovery of gastric acid production, acid and bile reflux, manometry, and symptoms. PATIENTS AND METHODS: Forty-eight patients at a median follow-up of 26 months (range = 12-67) postesophagectomy underwent endoscopy with biopsies taken 1-2 cm above the anastomosis. The indication for esophagectomy had been adenocarcinoma (n = 27), high-grade dysplasia (n = 2), and squamous cell cancer (n = 19). Physiology studies were performed in 27 patients and included manometry (n = 25), intraluminal gastric pH (n = 24), as well as simultaneous 24-hour esophageal pH (n = 27) and bile monitoring (n = 20). RESULTS: Duodenogastric reflux increased over time, with differences between patients greater than and less than 3 years postesophagectomy for acid (p = 0.04) and bile (p = 0.02). Twenty-four patients (50%) developed columnar metaplasia and of these 13 had SIM. The prevalence of columnar metaplasia did not relate to the magnitude of acid or bile reflux, to preoperative neoadjuvant therapies, or to the original tumor histology. The duration of reflux was most significant, with increasing prevalence over time, with SIM in 13 patients at a median of 61 months postesophagectomy compared with 20 months in the 35 patients who were SIM-negative (p < 0.006). Supine reflux correlated with symptoms. CONCLUSIONS: The development of Barrett's epithelium is frequent after esophagectomy, is time-related, reflecting chronic acid and bile exposure, and is not specific for adenocarcinoma or the presence of previous Barrett's epithelium. This model may represent a useful in vivo model of the pathogenesis of Barrett's metaplasia and tumorigenesis.

Adenocarcinoma↗
PubMed2003

Serum antigen(s) drive the proinflammatory T cell response in acute pancreatitis.

BACKGROUND: Immune cells and cytokines are central to the systemic inflammatory response syndrome and multiple organ failure associated with acute pancreatitis. The specific role of T cells in this response is unclear, and this study focused on evaluating T cell activation and its regulation in patients with acute pancreatitis. METHODS: Peripheral blood samples of 14 patients with acute pancreatitis were obtained within 24 h of the onset of pain, within 48 h and at 1 week. T cell expression of surface markers CD69, CD62L and CD25 was measured. The production of interleukin (IL) 10 and IL-2 in vitro in response to the superantigen Staphylococcus enterotoxin B (SEB) was assessed. Serum samples from these patients were co-cultured with peripheral blood mononuclear cells from volunteers in the presence or absence of cytotoxic T lymphocyte-associated antigen (CTLA) 4 immunoglobulin, a specific inhibitor of antigen-dependent T cell activation. RESULTS: Expression of CD69 was significantly increased in CD3(+) and CD4(+) populations at 48 h and 1 week, and on CD8(+) cells at 1 week. There was a significant increase in the production of SEB-induced IL-2 compared with findings in controls, but no significant IL-10 response. Serum from patients with pancreatitis activated normal T cells. This response was abolished completely by CTLA-4. CONCLUSION: Acute pancreatitis results in the systemic activation of T cells. These cells are primed for a proinflammatory response to antigen stimulation and can be inhibited by antigen-specific T cell blockade. These data indicate that the immunoinflammatory response in acute pancreatitis is fueled by one or more serum antigens and offer prospects for further understanding of the aetiogenesis of pancreatitis.

Acute Disease↗
PubMed2003

Gastrointestinal stromal tumours.

BACKGROUND: Gastrointestinal stromal tumours (GISTs), previously classified as benign or malignant smooth muscle tumours, are the most common mesenchymal tumours of the gastrointestinal tract. GISTs express a growth factor receptor with tyrosine kinase activity, termed KIT. Mutations of KIT are common in malignant GISTs and lead to constitutional activation of tyrosine kinase function, which causes cellular proliferation and resistance to apoptosis. GISTs are notoriously unresponsive to chemotherapy and, until the recent introduction of the KIT inhibitor imatinib, there has been no effective therapy for advanced, metastatic disease. METHODS: A Medline literature search was preformed to locate all articles relating to gastrointestinal tumours, GISTs, KIT and imatinib. RESULTS AND CONCLUSIONS: The 5-year survival rate after complete resection of GISTs is approximately 50 per cent. The median duration of survival for patients with a metastatic GIST is approximately 20 months, and 9-12 months for patients with local recurrence. Phase II trials have investigated the effect of imatinib on irresectable or metastatic GISTs. In these trials more than 50 per cent of patients responded to imatinib within a few months and approximately 12 per cent had disease progression. Uptake of [(18)F]fluoro-2-deoxy-D-glucose demonstrated by positron emission tomography has been found to be reduced after starting imatinib. The potential for cure and the optimal length of treatment is currently unknown. Imatinib is the first effective systemic therapy for metastatic and locally irresectable GISTs. Large multi-institutional clinical trials to investigate the efficacy of imatinib as adjuvant or neoadjuvant therapy for GISTs are now required.

Antineoplastic Agents↗
PubMed2003

Loss of Bcl-2 expression in Barrett's dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation.

Esophageal adenocarcinoma arising on a background of Barrett's esophagus is increasing in incidence. A molecular understanding of both the progression of Barrett's esophagus and the factors determining the response of adenocarcinoma to neoadjuvant therapy is required, and this study focused on the role of proteins regulated by the bcl-2 family of genes, which are important regulators of programmed cell death (apoptosis). In total, 48 patients (36 men, 12 women) with Barrett's adenocarcinoma were studied. All patients received preoperative chemoradiotherapy followed by surgery. Bcl-2, bax and bcl-x protein expression were detected by standard avidin-biotin peroxidase method. Bcl-2, bax and bcl-x expression were detected in 84%, 80%, and 76%, respectively, of normal squamous mucosa. An increasing degree of dysplasia in Barrett's mucosa both before and after chemoradiotherapy was significantly associated with a reduction of bcl-2 expression (P = 0.03 and 0.009, respectively). Bcl-2 expression was significantly associated with tumor differentiation (P = 0.03) and a trend towards earlier T stage (P = 0.08), but not with nodal status. Pre-therapeutic bcl-2, bax and bcl-x protein expression (27%, 75%, and 87.5%, respectively) were not associated with tumor response or resistance to therapy. Bcl-2-positive patients had a significantly improved survival compared with bcl-2-negative tumors. A significant reduction of bcl-2 expression is associated with the progression of Barrett's mucosa to adenocarcinoma. Bcl-2 expression was associated with improved survival. Preoperative chemoradiotherapy induces expression of bax and bcl-x protein. The pretreatment expression of bcl-2 and related proteins did not predict response or resistance to neoadjuvant chemoradiotherapy, suggesting that regulators of apoptosis alone do not determine the response of Barrett's adenocarcinoma to neoadjuvant therapy.

Adenocarcinoma↗