Intestinal barrier function in morbid obesity: results of a prospective study on the effect of sleeve gastrectomy.

BACKGROUND: Obesity has been associated with impaired intestinal barrier function. It is not known whether bariatric surgery leads to changes in intestinal barrier function. We hypothesized that obesity is associated with disturbances in gastrointestinal barrier function, and that after bariatric surgery barrier function will improve. METHODS: Prospective single center study in which we assessed segmental gut permeability by urinary recovery of a multisugar drink in 27 morbidly obese (BMI 43.3 ± 1.1 kg/m2) and 27 age and gender matched lean subjects (BMI 22.9 ± 0.43 kg/m2). Fecal calprotectin, SCFAs, plasma cytokines, and hsCRP were assessed as inflammatory and metabolic markers. Comparisons: (a) morbidly obese subjects vs. controls and (b) 2 and 6 months postsleeve vs. presleeve gastrectomy (n = 14). In another group of 10 morbidly obese and 11 matched lean subjects colonic and ileal biopsies were obtained in order to measure gene transcription of tight junction proteins. RESULTS: Gastroduodenal permeability (urinary sucrose recovery) was significantly increased in obese vs. lean controls (p < 0.05). Small intestinal and colonic permeability (urinary recovery of lactulose/L-rhamnose and sucralose/erythritol, respectively) in obese subjects were not significantly different from controls. Morbidly obese subjects had a proinflammatory systemic and intestinal profile compared with lean subjects. After sleeve gastrectomy BMI decreased significantly (p < 0.001). Postsleeve gastroduodenal permeability normalized to values that do not differ from lean controls. CONCLUSIONS: Gastroduodenal permeability, but not small intestinal or colonic permeability, is significantly increased in morbidly obese patients. After sleeve gastrectomy, gastroduodenal permeability normalized to values in the range of lean controls. Thus, the proximal gastrointestinal barrier is compromised in morbid obesity and is associated with a proinflammatory intestinal and systemic profile.

Palliative chemotherapy for patients with synchronous metastases of small-bowel adenocarcinoma: A reflection of daily practice.

Background: As small-bowel adenocarcinoma (SBA) is scarce, no standard systemic regimen in metastatic disease has been defined. Objective: To obtain insights into the use and effects of palliative chemotherapy in patients with metastatic SBA in a population-based setting. Methods: Data from the Netherlands Cancer Registry of patients with metastatic SBA between 2007 and 2016 were used (n = 522). For patients treated with palliative chemotherapy, differences in treatment regimens and survival were evaluated. Results: Palliative chemotherapy was received by 38% of patients (n = 199). First-line combination chemotherapy was administered to 80% of patients, mainly CAPOX/FOLFOX. Single-agent chemotherapy mostly consisted of capecitabine. Second-line treatment, mostly irinotecan-based (58%), was prescribed to 27% of patients. Age 70 years or older was an adverse predictive factor for receiving first-line combination chemotherapy (odds ratio (OR) 0.2, 95% confidence interval (CI) 0.08-0.62) and second-line therapy (OR 0.3, 95% CI 0.10-0.72). Median overall survival with palliative chemotherapy was 9.3 months, compared with 3.0 months without. In subanalyses, patients who received only first-line treatment had a median overall survival of 5.6 and 7.0 months after single-agent and combination chemotherapy, respectively. Conclusion: A minority of patients were treated with palliative chemotherapy. First-line treatment consisted predominantly of oxaliplatin-based combination chemotherapy, whereas second-line treatment was mainly irinotecan-based. Population-based median overall survival for selected patients treated with chemotherapy amounted to nine months.

Addition of Bevacizumab to First-Line Palliative Chemotherapy in Patients with Metastatic Small Bowel Adenocarcinoma: A Population-Based Study.

BACKGROUND: Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce. OBJECTIVE: The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA. PATIENTS AND METHODS: Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated. RESULTS: In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3 months, compared to 9.1 months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5 months with and 6.4 months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59). CONCLUSIONS: Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Phase II study of docetaxel, cisplatin and capecitabine as preoperative chemotherapy in resectable gastric cancer.

AIM: To investigate the feasibility of preoperative docetaxel, cisplatin and capecitabine (DCC) in patients with resectable gastric cancer. METHODS: Patients with resectable gastric cancer fulfilling the inclusion criteria, were treated with 4 cycles of docetaxel (60 mg/m2), cisplatin (60 mg/m2) and capecitabine (1.875 mg/m2 orally on day 1-14, two daily doses) repeated every three weeks, followed by surgery. Primary end point was the feasibility and toxicity/safety profile of DCC, secondary endpoints were pathological complete resection rate and pathological complete response (pCR) rate. RESULTS: All of the patients (51) were assessable for the feasibility and safety of the regimen. The entire preoperative regimen was completed by 68.6% of the patients. Grade III/IV febrile neutropenia occurred in 10% of all courses. Three patients died due to treatment related toxicity (5.9%), one of them (also) because of refusing further treatment for toxicity. Of the 45 patients who were evaluable for secondary endpoints, four developed metastatic disease and 76.5% received a curative resection. In 3 patients a pCR was seen (5.9%), two patients underwent a R1 resection (3.9%). CONCLUSION: Four courses of DCC as a preoperative regimen for patients with primarily resectable gastric cancer is highly demanding. The high occurrence of febrile neutropenia is of concern. To decrease the occurrence of febrile neutropenia the prophylactic use of granulocyte colony-stimulating factor (G-CSF) should be explored. A curative resection rate of 76.5% is acceptable. The use of DCC without G-CSF support as preoperative regimen in resectable gastric cancer is debatable.

Trends in incidence, treatment and survival of small bowel adenocarcinomas between 1999 and 2013: a population-based study in The Netherlands.

BACKGROUND: We conducted a population-based study to establish the incidence, treatment and overall survival over time of patients with small bowel adenocarcinoma. MATERIAL AND METHODS: All patients diagnosed with small bowel adenocarcinoma in the Netherlands between 1999 and 2013 were included (n = 1775). Age-standardized incidence rates were calculated per 100 000 person-years using the European standardized population rate. The influence of patient and tumor characteristics on the administration of chemotherapy was analyzed by means of a multivariable logistic regression analysis. The Cochran-Armitage trend test was conducted to evaluate trends in treatment and survival and the Cox proportional hazards model was used to identify prognostic factors of overall survival. RESULTS: The incidence of small bowel adenocarcinomas increased, mainly due to an almost twofold increase of duodenal adenocarcinomas. Patients with locoregional duodenal tumors were less likely to undergo surgery (58%), towards 95% of the locoregional jejunal and ileal tumors (p < 0.0001). The use of chemotherapy doubled for adjuvant (7-15%) and palliative chemotherapy (19-37%). Median overall survival of patients with locoregional disease increased from 19 to 34 months (p = 0.0006), whereas median overall survival of patients with metastatic disease remained 4-5 months. Favorable prognostic factors for prolonged survival in locoregional disease, identified by multivariable survival analysis, included age <60 years, tumor stage I or II, diagnosis in 2009-2013, surgical treatment and chemotherapy. Favorable prognostic factors for prolonged survival in metastatic disease were age <50 years, jejunal tumors, surgical treatment and chemotherapy. CONCLUSION: Small bowel adenocarcinomas are rare tumors with an increasing incidence. The administration of adjuvant and palliative chemotherapy doubled, but median overall survival only increased for patients with locoregional disease. Given the rarity and dismal prognosis, it is important to develop international studies to determine the optimal treatment for these patients.

Does long-term survival exist in pancreatic adenocarcinoma?

BACKGROUND: We conducted a population-based study to investigate long-term survival in patients diagnosed with a (suspected) pancreatic adenocarcinoma. METHODS: All patients diagnosed with a pancreatic adenocarcinoma or with a pathologically unverified tumour of the pancreas between 1993 and 2008 in the South of the Netherlands were selected from the Netherlands Cancer Registry (NCR). Medical charts of patients who were alive five years or longer since diagnosis were reviewed. RESULTS: A total of 2 564 patients were included, of whom 1 365 had a pancreatic adenocarcinoma and 1 199 had a pathologically unverified pancreatic tumour. Five-year survival of patients with pathologically verified adenocarcinomas was 1.7% (24 of 1 365 patients). Twenty-one-one of these 24 long-term survivors were among the 207 cases that underwent surgical resection as initial treatment; five-year survival after resection thus being 10.1%. Half of the long-term survivors who underwent surgical resection still eventually died of recurrent disease. Five-year survival among patients with clinically suspected but microscopically unverified pancreatic tumours was 1.3% (16 of 1 199 patients). In 15 of these 16 long-term survivors the initial clinical diagnosis was revised: 14 had benign disease and one a premalignant tumour. CONCLUSIONS: Long-term survival among patients with pancreatic adenocarcinoma is extremely rare. As long-term survival in clinically suspected but pathologically unverified cancer is very unlikely, repeated fine needle aspiration or, preferably, histological biopsy is recommended in order to establish an alternative diagnosis in patients who survive longer than expected (more than 6-12 months).

The relevance of pathological verification in suspected pancreatic cancer.

OBJECTIVES: This population-based study assessed which factors were associated with pathological verification of pancreatic cancer. METHODS: All patients diagnosed with a malignancy of the pancreas between 1993 and 2010 in the South of the Netherlands (N=3321) were included. RESULTS: Pancreatic cancer was pathologically verified in 59% of patients. The proportion of verification increased over time from 56% in 1993-1996 to 69% in 2009-2010 (p<0.0001). High rates of verification were found among young patients (<50 years vs. 60-69 yrs: adjusted odds ratio (ORadj) 3.2 (95% CI: 1.9-5.4)), patients with a high socioeconomic status (high vs. low: ORadj 1.3 (95% CI: 1.1-1.7)), patients with metastatic disease (metastatic vs locoregional: ORadj 3.2 (95% CI: 2.7-3.8)) and patients treated with chemotherapy (yes vs. no: ORadj 2.4 (95% CI: 1.8-3.2)). The most favorable prognosis was found in patients with verified locoregional disease (median overall survival (mOS) 7.6 months, 95% CI: 7.1-8.6). Patients with unverified metastatic disease carried the worst prognosis (mOS 1.7 months, 95% CI: 1.4-2.0). CONCLUSION: Verification by pathology remains preferable and desirable whenever possible. However, the median survival rate exhibited by patients without verification suggests that the vast majority of patients suffered from true invasive pancreatic cancer. This may justify treatment decisions even in the absence of pathologic verification in selected patients.

Ten weeks to live: a population-based study on treatment and survival of patients with metastatic pancreatic cancer in the south of the Netherlands.

BACKGROUND: A large proportion of patients with pancreatic cancer presents with metastatic disease. We conducted a population-based study to evaluate trends in treatment and survival of patients with metastatic pancreatic cancer. METHODS: We included all patients diagnosed with pancreatic cancer between 1993 and 2010 in the South of the Netherlands (N=3099). Multivariable logistic regression analysis was conducted to evaluate trends in treatment with chemotherapy. Crude overall survival according to period of diagnosis was analyzed, and independent risk factors for death were identified. RESULTS: Forty-eight percent of the patients (N=1494) were diagnosed with metastatic disease. The percentage of patients being diagnosed with metastatic disease increased during the study period from 35% in 1993-1996 to 59% in 2009-2010 (p<0.0001). Overall, 18% of these patients received chemotherapy. The prescription of palliative chemotherapy almost tripled from 10% to 27% (p<0.0001). Treatment largely depended on age, ranging from 38% among patients aged <50 years [compared to 60-69 years: adjusted odds ratio (ORadj) 2.5 (95% CI 1.4-4.2)] to 1% among patients aged ≥80 years [compared to 60-69 years: ORadj 0.04 (95% CI 0.0-0.2)]. Patients were more likely to receive chemotherapy if they had a high socioeconomic status [ORadj 2.0 (95% CI 1.3-3.1)], and if diagnosis was pathologically verified [no verification vs. verification: ORadj 0.3 (95% CI 0.2-0.5)]. The administration of chemotherapy varied widely between 10 hospitals (5-34%, p<0.0001). The median overall survival of patients with metastatic pancreatic cancer remained 9-11 weeks. CONCLUSION: A growing proportion of pancreatic cancer patients presented with metastatic disease. Usage of palliative chemotherapy increased over time, but median survival remained 9-11 weeks. In the near future, it should be evaluated if the recently introduced regimens have an impact on population-based survival.