Barrett's esophagus (BE) is a precursor lesion of esophageal adenocarcinoma. Besides gastroesophageal reflux, possible risk factors for BE include overweight, cigarette smoking, and alcohol ...consumption. Our objective was to study these associations by using prospective data.
The prospective Netherlands Cohort Study, initiated in 1986, consists of 120,852 men and women, aged 55 to 69 years at baseline. At baseline, all subjects completed a questionnaire on dietary habits and lifestyle. After 16.3 years of follow-up, 370 BE cases with specialized intestinal metaplasia and 3,866 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR) and 95% CIs.
Body mass index (BMI) at baseline was associated with risk of BE in women multivariable adjusted RR per 1 kg/m(2), 1.07 (1.03-1.11) but not in men RR per 1 kg/m(2), 0.99 (0.93-1.05). The association in women was not specifically due to abdominal overweight. Former cigarette smokers were at increased risk of BE (RR = 1.33, 95% CI: 1.00-1.77), but current smokers were not. Smoking duration showed a positive association with BE risk (P(trend) = 0.03). For alcohol consumption, the RR per 10 g ethanol/d was 0.95 (0.87-1.03).
Increased BMI was a risk factor for BE in women but not in men. Several aspects of cigarette smoking were positively associated with BE risk. Alcohol consumption was not associated with an increased risk of BE.
Future research should focus on risk factors both for development and for progression of BE to esophageal adenocarcinoma.
There are few epidemiological data on the dietary risk factors of Barrett's oesophagus, a precursor of oesophageal adenocarcinoma. The present study investigated the association between vegetable, ...fruit and nitrate intake and Barrett's oesophagus risk in a large prospective cohort. The Netherlands Cohort Study recruited 120 852 individuals aged 55–69 years in 1986. Vegetable and fruit intake was assessed using a 150-item FFQ, and nitrate intake from dietary sources and drinking water was determined. After 16·3 years of follow-up, 433 cases (241 men and 192 women) of Barrett's oesophagus with specialised intestinal metaplasia and 3717 subcohort members were analysed in a case–cohort design using Cox proportional hazards models while adjusting for potential confounders. Men exhibited a lower risk of Barrett's oesophagus in the highest v. the lowest quintile of total (multivariable-adjusted hazard ratio (HR): 0·66, 95 % CI 0·43, 1·01), raw (HR 0·63, 95 % CI 0·40, 0·99), raw leafy (HR 0·55, 95 % CI 0·36, 0·86) and Brassica (HR 0·64, 95 % CI 0·41, 1·00) vegetable intake. No association was found for other vegetable groups and fruits. No significant associations were found between vegetable and fruit intake and Barrett's oesophagus risk among women. Total nitrate intake was inversely associated with Barrett's disease risk in men (HR 0·50, 95 % CI 0·25, 0·99) and positively associated with it in women (HR 3·77, 95 % CI 1·68, 8·45) (P for interaction = 0·04). These results suggest that vegetable intake may contribute to the prevention of Barrett's oesophagus. The possible differential effect in men and women should be evaluated further.
Background & Aims Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma, but it is not clear how it affects risk for other cancers or overall mortality. We analyzed data from a ...population-based cohort of subjects with BE. Methods The Netherlands Cohort Study was initiated in 1986 and included 120,852 participants (55–69 years old at baseline). Until December 2002, 626 incident cases of BE (excluding nonintestinal metaplasia) were identified by record linkage with the nationwide Pathology Registry. This cohort was followed for a median period of 5.7 years; data on cancer and mortality were obtained from record linkage to the Netherlands Cancer Registry and Statistics Netherlands. The expected number of cases was calculated using national cancer incidence and mortality data. Results In the BE cohort, 13 individuals developed esophageal cancer and 5 developed gastric cancer. The ratio of observed:expected (O:E) incidence of esophageal and gastric cancer was 10.0 (95% confidence interval CI, 5.3–17.1) and 1.8 (95% CI, 0.6–4.2), respectively. Total cancer incidence (excluding esophageal and gastric cancer) increased in the BE cohort, although not by a statistically significant amount (O:E, 1.3; 95% CI, 1.0–1.6). Of cancer subtypes, incidences of small intestinal and pancreatic cancer increased in subjects with BE, but not by a statistically significant amount, after exclusion of data from the first 6 months of follow-up. During the follow-up period, 225 individuals with BE died. Mortality from all causes (excluding esophageal and gastric cancer) was not increased among subjects with BE (O:E, 1.0; 95% CI, 0.9–1.2), nor was mortality from specific causes of death. Conclusions The incidence of esophageal cancer was increased in a population-based cohort of subjects with BE. However, when esophageal and gastric cancers were excluded, total cancer incidence and overall mortality were not increased among subjects with BE.
Increasing meat intake and its possible role in the development of esophageal adenocarcinoma raises the question whether meat consumption is associated with the premalignant lesion, Barrett's ...esophagus.
Associations between the risk of Barrett's esophagus and meat consumption, intake of N-nitrosodimethylamine, nitrite, and heme iron were examined in the Netherlands Cohort Study among 120,852 subjects aged 55 to 69 years in 1986. Exposure was measured on the basis of a 150-item food frequency questionnaire. After 16.3 years of follow-up, 447 Barrett's esophagus cases with specialized intestinal metaplasia and 3,919 subcohort members were analyzed in a case-cohort design.
There was no association of any of the examined exposures with Barrett's risk in men or women. Results were similar in age-adjusted and fully adjusted models and in models excluding the first two years of follow-up.
Our results do not support a role of meat consumption and N-nitrosation related factors in the development of Barrett's esophagus.
The possible causal association between red meat intake and esophageal adenocarcinoma is unlikely to be mediated by mechanisms through the development of Barrett's esophagus.
Objective To investigate the association between selenium and the risk of Barrett's esophagus (BE), the precursor lesion of esophageal adenocarcinoma. Methods Data from the prospective Netherlands ...Cohort Study were used. This cohort study was initiated in 1986, when 120,852 subjects aged 55-69 years completed a questionnaire on dietary habits and lifestyle, and provided toenail clippings for the determination of baseline selenium status. After 16.3 years of follow-up, 253 BE cases (identified through linkage with the nationwide Dutch pathology registry) and 2,039 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR). Results The multivariable-adjusted RR for the highest versus the lowest quartile of toenail selenium was 1.06 (95% CI 0.71-1.57). No dose-response trend was seen (p trend = 0.99). No association was found in subgroups defined by sex, smoking status, body mass index (BMI), or intake of antioxidants. For BE cases that later progressed to high-grade dysplasia or adenocarcinoma, the RR for a selenium level above the median vs. below the median was 0.64 (95% CI 0.24-1.76). Conclusions In this large prospective cohort study, we found no evidence of an association between selenium and risk of BE.
Abstract
Context. Bortezomib is a proteasome inhibitor with excellent antimyeloma activity. The most frequent toxic side effects are gastrointestinal, neuropathy and thrombocytopenia. The liver was ...not considered an important target organ for toxicity until one case of bortezomib-induced severe hepatitis was reported in a patient with multiple myeloma. Case report. We describe a patient developing acute cholestatic and parenchymal hepatitis complicated by fatal liver failure after bortezomib therapy for multiple myeloma. Discussion: The importance of being aware of this potential fatal complication is emphasized considering that this drug is increasingly prescribed and in order to discontinue this drug if liver adverse reaction is suspected.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated ...factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40 −/− mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8 + T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII + cells exhibited a similar phenotype in DIO as CD40 −/− mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII + cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII + cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII + cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Patients who receive chemoradiotherapy or bioradiotherapy (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates interfering with oral ...intake, causing tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds 4 weeks. We aimed to develop and externally validate a prediction model to identify patients who need TF ≥ 4 weeks and would benefit from prophylactic gastrostomy insertion.
A retrospective multicenter cohort study was performed in four tertiary head and neck cancer centers in the Netherlands. The prediction model was developed using data from University Medical Center Utrecht and the Netherlands Cancer Institute and externally validated using data from Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF dependency ≥4 weeks initiated during CRT/BRT or within 30 days after CRT/BRT completion. Potential predictors were extracted from electronic health records and radiotherapy dose–volume parameters were calculated.
The developmental and validation cohort included 409 and 334 patients respectively. Multivariable analysis showed predictive value for pretreatment weight change, texture modified diet at baseline, ECOG performance status, tumor site, N classification, mean radiation dose to the contralateral parotid gland and oral cavity. The area under the receiver operating characteristics curve for this model was 0.73 and after external validation 0.62. Positive and negative predictive value for a risk of 90% or higher for TF dependency ≥4 weeks were 81.8% and 42.3% respectively.
We developed and externally validated a prediction model to estimate TF-dependency ≥4 weeks in LAHNSCC patients treated with CRT/BRT. This model can be used to guide personalized decision-making on prophylactic gastrostomy insertion in clinical practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinical, histologic, cytogenetic, and molecular genetic data of 31 patients with extranodal, nodal, and splenic marginal zone B-cell lymphoma (MZBCL) are presented. Despite these variable clinical ...manifestations, a similar spectrum of morphologic features as well as distinctive immunophenotypic findings were noted. In all cases, a monotypic B-cell proliferation consistently negative for CD5, CD10, and CD23 was found expanding the marginal zone of the B follicle with and without colonization of the follicle centers. Clonal chromosomal abnormalities were detected in 23 of the 31 patients. Recurrent aberrations included whole or partial trisomy 3 (18 cases), trisomy 18 (9 cases), and structural rearrangements of chromosome 1 with breakpoints in 1q21 (9 cases) or 1p34 (6 cases), all of which were seen in extranodal, nodal, as well as splenic MZBCL. Abnormalities of the additional chromosome 3, such as +del(3)(p13),+i(3)(q10), or structural changes involving the distal part of the long arm, were evident in 9 of the 18 cases. All recurrent abnormalities were found in MZBCL more frequently than in other histologic entities of B-cell non-Hodgkin's lymphoma (B-NHL). None of the known lymphoma-associated chromosomal changes or rearrangements of the BCL1, BCL2, BCL3, BCL6, and CMYC genes were detected. We conclude that MZBCL represent a distinct entity of B- NHL with characteristic morphologic and immunophenotypic features and particular chromosomal abnormalities, and that a close histogenetic relationship between extranodal, nodal, and splenic MZBCL is likely, although the clinical presentation may vary.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
A considerable number of patients develop sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy for colorectal liver metastases (CLMs). SOS is associated with adverse ...outcomes after major hepatectomy. Hyaluronic acid (HA) is a marker of hepatic sinusoidal endothelial cell function and may serve as an accurate marker of SOS. This study aimed to assess the value of systemic HA levels and fractional extraction (FE) of HA by the splanchnic area and liver as markers of SOS after oxaliplatin-based chemotherapy for CLMs.
Methods
Forty patients were studied. The presence of SOS was assessed histopathologically. Blood samples from the radial artery and portal and hepatic veins were collected. HA levels were determined by ELISA and the FE of HA was estimated.
Results
SOS was present in 23 patients, 11 of whom demonstrated moderate or severe SOS. Preoperative HA levels were significantly higher in patients with moderate or severe SOS (group B,
n
= 11) compared to patients with no or mild SOS (group A,
n
= 29) (51.6 ± 10.2 ng/mL vs. 32.1 ± 3.5 ng/mL,
p
= 0.030). A cutoff HA level of 44.1 ng/mL yielded a sensitivity of 67 % and specificity of 83 % for detection of SOS. The positive predictive value was 50 % and the negative predictive value 91 %. Both groups exhibited a similar FE of HA by the splanchnic area (−7.9 ± 8.5 % in Group A vs. 7.3 ± 3.6 % in Group B,
p
= 0.422) and liver (−10.7 ± 6.2 % in Group A vs. 4.6 ± 2.3 % in Group B,
p
= 0.265).
Conclusions
Systemic HA levels can be used to detect patients at risk of SOS after oxaliplatin-based chemotherapy for CLMs. Additional investigations into the presence of SOS are indicated in patients with elevated HA levels.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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