Gastric banding interferes with esophageal motility and gastroesophageal reflux.

BACKGROUND: Gastroesophageal reflux and progressive esophageal dilatation can develop after gastric banding (GB). HYPOTHESIS: Gastric banding may interfere with esophageal motility, enhance reflux, or promote esophageal dilatation. DESIGN: Before-after trial in patients undergoing GB. SETTING: University teaching hospital. PATIENTS AND METHODS: Between January 1999 and August 2002, 43 patients undergoing laparoscopic GB for morbid obesity underwent upper gastrointestinal endoscopy, 24-hour pH monitoring, and stationary esophageal manometry before GB and between 6 and 18 months postoperatively. MAIN OUTCOME MEASURES: Reflux symptoms, endoscopic esophagitis, pressures measured at manometry, esophageal acid exposure. RESULTS: There was no difference in the prevalence of reflux symptoms or esophagitis before and after GB. The lower esophageal sphincter was unaffected by surgery, but contractions in the lower esophagus weakened after GB, in correlation with preoperative values. There was a trend toward more postoperative nonspecific motility disorders. Esophageal acid exposure tended to decrease after GB, with fewer reflux episodes. A few patients developed massive postoperative reflux. There was no clear correlation between preoperative testing and postoperative esophageal acid exposure, although patients with abnormal preoperative acid exposure tended to maintain high values after GB. CONCLUSIONS: Postoperative esophageal dysmotility and gastroesophageal reflux are not uncommon after GB. Preoperative testing should be done routinely. Low amplitude of contraction in the lower esophagus and increased esophageal acid exposure should be regarded as contraindications to GB. Patients with such findings should be offered an alternative procedure, such as Roux-en-Y gastric bypass.

Bone metabolism and risk of secondary hyperparathyroidism 12 months after gastric banding in obese pre-menopausal women.

OBJECTIVE: To evaluate, during the first postoperative year in obese pre-menopausal women, the effects of laparoscopic gastric banding on calcium and vitamin D metabolism, the potential modifications of bone mineral content and bone mineral density, and the risk of development of secondary hyperparathyroidism. SUBJECTS: Thirty-one obese pre-menopausal women aged between 25 and 52 y with a mean body mass index (BMI) of 43.6 kg/m(2), scheduled for gastric banding were included. Patients with renal, hepatic, metabolic and bone disease were excluded. METHODS: Body composition and bone mineral density (BMD) were measured at baseline, 6 and 12 months after gastric banding using dual-energy X-ray absorptiometry. Serum calcium, phosphate, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bilirubin, urea, creatinine, uric acid, proteins, parathormone, vitamin D(3), IGF-1, IGF-BP3 and telopeptide, as well as urinary telopeptide, were measured at baseline and 1, 3, 6, 9 and 12 months after surgery. RESULTS: After 1 y vitamin D3 remained stable and PTH decreased by 12%, but the difference was not significant. Serum telopeptide C increased significantly by 100% (P<0.001). There was an initial drop of the IGF-BP3 during the first 6 months (P<0.05), but the reduction was no longer significant after 1 y. The BMD of cortical bone (femoral neck) decreased significantly and showed a trend of a positive correlation with the increase of telopeptides (P<0.06). The BMD of trabecular bone, at the lumbar spine, increased proportionally to the reduction of hip circumference and of body fat. CONCLUSION: There is no evidence of secondary hyperparathyroidism 1 y after gastric banding. Nevertheless biochemical bone markers show a negative remodelling balance, characterized by an increase of bone resorption. The serum telopeptide seems to be a reliable parameter, not affected by weight loss, to follow up bone turnover after gastroplasty.

Sorafenib fourth-line treatment in imatinib-, sunitinib-, and nilotinib-resistant metastatic GIST : a retrospective analysis : 10564

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors usually caused by mutations in the KIT or PDGFRA gene. Advanced disease generally cannot be cured by surgery nor by tyrosine kinase inhibitors (TKI), but TKIs have considerably improved outcome for patients (pts) with advanced GIST. Patients failing TKI treatment with imatinib (IM), sunitinib (SU) or nilotinib (NI) have a poor prognosis. Sorafenib is a multi kinase inhibitor that blocks not only receptor tyrosine kinases such as KIT, VEGFR and PDGFR but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway. Recently, clinical activity of sorafenib in third-line treatment in patients with GIST after IM and SU failure has been shown (Wiebe et al. ASCO 2008, #10502). Methods: We report herein preliminary data of 32 pts treated with sorafenib in nine European centers. Centers were selected based on their previous and known experience in GIST and reported all pts treated. Pts received sorafenib after failure of IM, SU and NI in fourth-line treatment. Baseline characteristics and treatment details have been retrieved via questionary. Results: Median age at sorafenib treatment start was 62 years (range 33-81 y), and the majority of pts were male (63 %). Primary tumor site was gastric or small intestine in 25% and 41% of pts, respectively. All pts had failed IM, SU, NI. 19 % of pts achieved partial remission and 44% disease stabilization. Approximately half of the pts had an improvement of symptoms and/or performance. Half of the pts were on treatment longer than 4 months (actuarial data) and 41% of pts continue to receive sorafenib. Median progression-free survival is 20 weeks and median overall survival 42 weeks (Kaplan-Meier), at a median follow-up of 22 weeks (range 3-54). Conclusions: This is the largest series assessing efficacy of sorafenib fourth-line treatment for IM, SU and NI refractory GIST reported yet. Sorafenib displays significant clinical activity in this heavily pretreated group of patients.

Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype.

Gastric cancer incidence and mortality decreased substantially over the last decades in most countries worldwide, with differences in the trends and distribution of the main topographies across regions. To monitor recent mortality trends (1980-2011) and to compute short-term predictions (2015) of gastric cancer mortality in selected countries worldwide, we analysed mortality data provided by the World Health Organization. We also analysed incidence of cardia and non-cardia cancers using data from Cancer Incidence in Five Continents (2003-2007). The joinpoint regression over the most recent calendar periods gave estimated annual percent changes (EAPC) around -3% for the European Union (EU) and major European countries, as well as in Japan and Korea, and around -2% in North America and major Latin American countries. In the United States of America (USA), EU and other major countries worldwide, the EAPC, however, were lower than in previous years. The predictions for 2015 show that a levelling off of rates is expected in the USA and a few other countries. The relative contribution of cardia and non-cardia gastric cancers to the overall number of cases varies widely, with a generally higher proportion of cardia cancers in countries with lower gastric cancer incidence and mortality rates (e.g. the USA, Canada and Denmark). Despite the favourable mortality trends worldwide, in some countries the declines are becoming less marked. There still is the need to control Helicobacter pylori infection and other risk factors, as well as to improve diagnosis and management, to further reduce the burden of gastric cancer.

Impact of preoperative embolization of the left gastric artery on the rate of anastomotic leakage after esophageal resection

Objective: Impaired blood flow of the gastric tube represents a major cause of anastomotic leakage after esophageal resection. In order to improve local vascularisation, preoperative embolization (PE) of the left gastric artery has recently been proposed. The aimof this study was to assess our initial experience of this novel approach with a particular focus on anastomotic leakage.Methods: A consecutive series of 102 patients (81 male, 21 female, median age 64 years) underwent resection (82 Ivor-Lewis procedures, 9 transhiatal resections, 11 triple incisions) for esophageal malignancies at our institution from 2000 to 2009. Since 2004, PE was used selectively in 19 patients 21 days prior to elective esophagectomy. Selection criteria were normal gastric vascular anatomy, no pre-existing vascular disease, i.e. atheromatosis of the celiac trunk or superior mesenteric artery, and resectability of the tumor. PE was performed under local anesthesia on a dedicated system in a standard fashion. Following percutaneous transfemoral visceral angiography to identify gastric vascular anatomy, embolization was performed either with 5-F or with coaxial 3-F catheters and fibered metal coils. We analyzed retrospectively patient's data, operative data, and outcome from a prospective database.Results: The overall anastomotic leakage rate was 18・6% (19/102 patients); cervical anastomosis had a leak rate of 25% compared to intrathoracic anastomosis leak rate of 18・2%. While 17 of 83 patients without PE developed anastomotic leakage (20・5%), there were only 2 of 19 patients after PE revealing an anastomotic leakage (10・5%). Otherwise, patients with PE had no more other complications. There was only one PE-related complication (i.e. partial splenic necrosis).Mean hospital stay was 25 days versus 27 days for patients with PE and without PE, respectively. The mortality rate was 7・8% (8/102 patients), whereby four deaths were related to anastomotic leakage (1 and 3 patients with PE and without PE, respectively).Conclusion: PE is an interesting novel approach to improve gastric blood flow in order to minimize anastomotic leakage. Its application is safe and technically easy. Our preliminary experience revealed a decrease of the anastomotic leakage rate of almost 50%.

MR features of gastrointestinal stromal tumors.

We report on two patients presenting with gastrointestinal stromal tumors (GIST). The important tumor size and the marked tissular hypersignal seen on T2-weighted magnetic resonance images (MRI) should be considered as magnetic resonance (MR) features strongly indicating diagnosis of GIST.

The roles of granulocyte-macrophage colony-stimulating factor and interleukin 3 in stromal cell-mediated hemopoiesis in vivo.

Adherent cells from murine long-term marrow cultures (LTMC) were examined for presence of mRNA for granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (Il-3). Six hours after medium replacement, GM-CSF mRNA was detected but was no longer detectable 24 h after feeding; Il-3 mRNA was not detected at any time. Neutralizing antibodies against these factors had no effect on hemopoiesis. Exogenous Il-3 increased cell production, notably mature erythroid progenitors, whereas GM-CSF had little long-term effect even at high concentrations. Furthermore, GM-CSF appeared to be specifically removed from the medium, whereas virtually all of the Il-3 could be recovered under identical incubation conditions. These results show that Il-3 is not required for maintaining long-term hemopoiesis in vitro, whereas the precise role of GM-CSF in this system remains unclear.

Time-related improvement of survival in resectable gastric cancer: the role of Japanese-style gastrectomy with D2 lymphadenectomy and adjuvant chemotherapy

Background: We investigated the change of prognosis in resected gastric cancer (RGC) patients and the role of radical surgery and adjuvant chemotherapy. Methods: We retrospectively analyze the outcome of 426 consecutive patients from 1975 to 2002, divided into 2 time-periods (TP) cohort: Before 1990 (TP1, n = 207) and 1990 or after (TP2; n= 219). Partial gastrectomy and D1-lymphadenetomy was predominant in TP1 and total gastrectomy with D2-lymphadenectomy it was in TP2. Adjuvant chemotherapy consisted of mitomycin C (MMC), 10¿20 mg/m2 iv 4 courses or MMC plus Tegafur 500 mg/m2 for 6 months. Results: Positive nodes were similar in TP2/TP1 patients with 56%/59% respectively. Total gastrectomy was done in 56%/45% of TP2/TP1 respectively. Two-drug adjuvant chemotherapy was administered in 65%/18% of TP2/TP1 respectively. Survival at 5 years was 66% for TP2 versus 42%for TP1 patients (p < 0.0001). Survival by stages II, IIIA y IIIB for TP2 versus TP1 patients was 70 vs. 51% (p = 0.0132); 57 vs. 22% (p = 0.0008) y 30 vs. 15% (p = 0.2315) respectively. Multivariate analysis showed that age, stage of disease and period of treatment were independent variables. Conclusion: The global prognosis and that of some stages have improved in recent years with case RGC patients treated with surgery and adjuvant chemotherapy.

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model.

Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.

Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib.

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

Cardiac and pericardial fistulae associated with esophageal or gastric neoplasms: a literature review

Pericardial and cardiac fistulae secondary to esophageal or gastric tumors are considered exceptional. They have never been the object of a literature review. We reviewed the medical literature between 1881 and 2001, searching for all published cases of pericardial or cardiac fistulae developed from esophageal and gastric tumors or favored by the applied therapy to these tumors. The cases of metastasization, tumor spread, and neoplasic pericardial effusion without fistula were excluded. Fifty patients were identified, with one original case. More than half the cases (56%) occurred in the last 25 years. Substernal pain is the main symptom. The majority of patients present at least one condition favoring fistula formation. The auscultation of a water-wheel murmur may suggest a pneumopericardium and therefore a pericardial fistula, as does a purulent pericarditis. Arrhythmias, signs of ischemia, and hematemesis point toward a ventricular fistula. Neurological and hemostasis disorders may be suspect of an atrial lesion. Diagnosis should be made by the association of a scanner and a transit. Prognosis is bad: 76% of the patients die in the first month. Pericardial or cardiac fistulae are part of the differential diagnosis of thoracic pain in patients with esophageal or gastric tumors and in patients who were treated for these pathologies. The diagnosis must be as quick as possible. An operation (patients with a good prognosis) or the placement of a stent (patients with a bad prognosis) is the only chance of survival

Listeria brain abscess, Pneumocystis pneumonia and Kaposi's sarcoma after temozolomide.

BACKGROUND: A 55-year-old man with glioblastoma multiforme was treated with continuous, dose-dense temozolomide. This therapy was curtailed after three cycles because of nausea, asthenia, and neuropsychological deterioration. During a subsequent course of radiotherapy, the patient developed fever, headaches, and cutaneous lesions. INVESTIGATIONS: Physical examination, cerebral MRI, brain biopsy, skin biopsy, immunohistochemistry, bronchoscopy with bronchoalveolar lavage, and laboratory tests. DIAGNOSIS: Severe temozolomide-induced immunosuppression, exacerbated by corticosteroids, with profound T-cell lymphocytopenia and simultaneous opportunistic infections with Pneumocystis jiroveci pneumonia, brain abscess with Listeria monocytogenes, and cutaneous Kaposi's sarcoma. MANAGEMENT: Discontinuation of temozolomide, discontinuation of radiotherapy, antibiotic treatment with amoxicillin and gentamicin, and administration of atovaquone and pentamidine.