First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II).

INTRODUCTION: Despite its increasing use, first-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX), hereinafter referred to as first-line bidirectional therapy, has never been prospectively investigated in patients with colorectal peritoneal metastases (CPM). As a first step to address this evidence gap, the present study aims to assess the safety, feasibility, antitumour activity, patient-reported outcomes, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM. METHODS AND ANALYSIS: In this single-arm, phase II study in two Dutch tertiary referral centres, 20 patients are enrolled. Key eligibility criteria are a good performance status, pathologically proven isolated unresectable CPM, no previous palliative systemic therapy for colorectal cancer, no (neo)adjuvant systemic therapy ≤6 months prior to enrolment and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Patients receive three cycles of bidirectional therapy. Each cycle consists of 6 weeks first-line palliative systemic therapy at the medical oncologists' decision (CAPOX-bevacizumab, FOLFOX-bevacizumab, FOLFIRI-bevacizumab or FOLFOXIRI-bevacizumab) followed by ePIPAC-OX (92 mg/m2) with an intraoperative bolus of intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Study treatment ends after the third ePIPAC-OX. The primary outcome is the number of patients with-and procedures leading to-grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0) up to 4 weeks after the last procedure. Key secondary outcomes include the number of bidirectional cycles in each patient, treatment-related characteristics, grade ≤2 adverse events, tumour response (histopathological, cytological, radiological, biochemical, macroscopic and ascites), patient-reported outcomes, systemic pharmacokinetics of oxaliplatin, costs, progression-free survival and overall survival. ETHICS AND DISSEMINATION: This study is approved by the Dutch competent authority, a medical ethics committee and the institutional review boards of both study centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NL8303.

Pressurized Intraperitoneal Aerosol Chemotherapy (Oxaliplatin) for Unresectable Colorectal Peritoneal Metastases: A Multicenter, Single-Arm, Phase II Trial (CRC-PIPAC).

BACKGROUND: Despite its increasing use, pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) has never been prospectively investigated as a palliative monotherapy for colorectal peritoneal metastases in clinical trials. This trial aimed to assess the safety (primary aim) and antitumor activity (key secondary aim) of PIPAC-OX monotherapy in patients with unresectable colorectal peritoneal metastases. METHODS: In this two-center, single-arm, phase II trial, patients with isolated unresectable colorectal peritoneal metastases in any line of palliative treatment underwent 6-weekly PIPAC-OX (92 mg/m2). Key outcomes were major treatment-related adverse events (primary outcome), minor treatment-related adverse events, hospital stay, tumor response (radiological, biochemical, pathological, ascites), progression-free survival, and overall survival. RESULTS: Twenty enrolled patients underwent 59 (median 3, range 1-6) PIPAC-OX procedures. Major treatment-related adverse events occurred in 3 of 20 (15%) patients after 5 of 59 (8%) procedures (abdominal pain, intraperitoneal hemorrhage, iatrogenic pneumothorax, transient liver toxicity), including one possibly treatment-related death (sepsis of unknown origin). Minor treatment-related adverse events occurred in all patients after 57 of 59 (97%) procedures, the most common being abdominal pain (all patients after 88% of procedures) and nausea (65% of patients after 39% of procedures). Median hospital stay was 1 day (range 0-3). Response rates were 0% (radiological), 50% (biochemical), 56% (pathological), and 56% (ascites). Median progression-free and overall survival were 3.5 months (interquartile range [IQR] 2.5-5.7) and 8.0 months (IQR 6.3-12.6), respectively. CONCLUSIONS: In patients with unresectable colorectal peritoneal metastases undergoing PIPAC-OX monotherapy, some major adverse events occurred and minor adverse events were common. The clinical relevance of observed biochemical, pathological, and ascites responses remains to be determined, especially since radiological response was absent.

Vegetable, fruit and nitrate intake in relation to the risk of Barrett's oesophagus in a large Dutch cohort.

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.

Meat consumption and the risk of Barrett's esophagus in a large Dutch cohort.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results do not support a role of meat consumption and N-nitrosation related factors in the development of Barrett's esophagus. IMPACT: 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.

Modified UroVysion scoring criteria increase the urothelial carcinoma detection rate in cases of equivocal urinary cytology.

AIMS: UroVysion(®) is a four-target fluorescence in situ hybridization technique for the detection of urothelial carcinoma (UC) in urinary cytology. The aim of this retrospective study was to investigate the UC detection rate of a modified UroVysion test in patients with equivocal urinary cytology. The modification comprised the addition of a cytological prescreening technique and different evaluation criteria. METHODS AND RESULTS: Thin-layer slides were prepared from the residual urine samples of 82 patients with equivocal urinary cytology, prestained and prescreened to confirm the presence of atypical urothelial cells. The same slides were used for the UroVysion test, and scored according to different evaluation criteria. The results were compared with the outcomes of cystoscopic and histological findings. UroVysion detected 68% of the UCs when the manufacturer's evaluation criteria were applied. In cases of altered evaluation criteria, the sensitivity increased to 81% when at least one copy number change of a probe target was considered to be a positive test result. The specificity only decreased from 84% to 82%. CONCLUSIONS: Our data suggest that the sensitivity of the UroVysion test can be increased by the addition of a cytological pre-screening technique prior to the UroVysion test and a modification of the UroVysion evaluation criteria.

Total cancer incidence and overall mortality are not increased among patients with Barrett's esophagus.

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.

A prospective cohort study on overweight, smoking, alcohol consumption, and risk of Barrett's esophagus.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. IMPACT: Future research should focus on risk factors both for development and for progression of BE to esophageal adenocarcinoma.

Toenail selenium status and the risk of Barrett's esophagus: the Netherlands Cohort Study.

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.

Pentalogy of Cantrell: two patients and a review to determine prognostic factors for optimal approach.

Two patients with incomplete pentalogy of Cantrell are described. The first was a girl with a large omphalocele with evisceration of the heart, liver and intestines with an intact sternum. Echocardiography showed profound intracardiac defects. The girl died 33 h after birth. The second patient was a female fetus with ectopia cordis (EC) without intracardiac anomalies; a large omphalocele with evisceration of the heart, stomach, spleen and liver; a hypoplastic sternum and rib cage; and a scoliosis. The pregnancy was terminated. A review of patients described in the literature is presented with the intention of finding prognostic factors for an optimal approach to patients with the pentalogy of Cantrell. In conclusion the prognosis seems to be poorer in patients with the complete form of pentalogy of Cantrell, EC, and patients with associated anomalies. Intracardial defects do not seem to be a prognostic factor.