Treatment of PERItoneal disease in Stomach Cancer with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy: PERISCOPE I initial results.

BACKGROUND: The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored. METHODS: Patients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ). RESULTS: Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3). CONCLUSION: Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.

ANTECEDENTES: El papel de la cirugía citorreductora (cytoreductive surgery, CRS) combinado con la quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en el cáncer gástrico no está definido. Este estudio fase I-II no aleatorizado de escalado de dosis fue diseñado para evaluar la seguridad y la viabilidad de HIPEC, después de la quimioterapia sistémica, en pacientes con cáncer gástrico con diseminación peritoneal limitada. Además, se exploró la máxima dosis tolerada (maximum tolerated dose, MTD) de docetaxel intraperitoneal normotérmico en combinación con una dosis fija de oxaliplatino intraperitoneal. MÉTODOS: Se incluyeron pacientes con adenocarcinoma gástrico cT3-cT4a resecable con metástasis peritoneales limitadas y/o citología peritoneal positiva. Se utilizó una técnica HIPEC abierta con 460 mg/m2 de oxaliplatino hipertérmico (30 minutos) seguido de docetaxel normotérmico (90 minutos) en dosis crecientes (0, 50, 75 mg/m2 ). RESULTADOS: Entre 2014 y 2017, se incluyeron 37 pacientes. De los 25 pacientes que completaron la totalidad del protocolo del estudio, 4 pacientes fueron tratados en el nivel de dosis 1 (0 mg/m2 de docetaxel), 6 pacientes en el nivel de dosis 2 (50 mg/m2 ) y 4 pacientes en el nivel de dosis 3 (75 mg/m2 ). En el nivel de dosis 3, se produjeron dos casos de toxicidad limitante de dosis (dose-limiting toxicities, DLTs), ambas asociadas con un íleo postoperatorio. Posteriormente, otros 11 pacientes fueron tratados con el nivel de dosis 2, y no se produjeron más DLTs. La MTD de docetaxel intraperitoneal fue de 50 mg/m2 . Se registraron efectos adversos graves en 17 de 25 pacientes. La tasa de reoperación fue del 16% (n = 4) y la mortalidad relacionada con el tratamiento fue del 8% (n = 2; ambos en el nivel de dosis 3).

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Using textbook outcome as a measure of quality of care in oesophagogastric cancer surgery.

BACKGROUND: Textbook outcome is a multidimensional measure representing an ideal course after oesophagogastric cancer surgery. It comprises ten perioperative quality-of-care parameters and has been developed recently using population-based data. Its association with long-term outcome is unknown. The objectives of this study were to validate the clinical relevance of textbook outcome at a hospital level, and to assess its relation with long-term survival after treatment for oesophagogastric cancer. METHODS: All patients with oesophageal or gastric cancer scheduled for surgery with curative intent between January 2009 and June 2015 were selected from an institutional database. A Cox model was used to study the association between textbook outcome and survival. RESULTS: A textbook outcome was achieved in 58 of 144 patients (40·3 per cent) with oesophageal cancer and in 48 of 105 (45·7 per cent) with gastric cancer. Factors associated with not achieving a textbook outcome were failure to achieve a lymph node yield of at least 15 (after oesophagectomy) and postoperative complications of grade II or more. After oesophagectomy, median overall survival was longer for patients with a textbook outcome than for patients without (median not reached versus 33 months; P = 0·012). After gastrectomy, median survival was 54 versus 33 months respectively (P = 0·018). In multivariable analysis, textbook outcome was associated with overall survival after oesophagectomy (hazard ratio 2·38, 95 per cent c.i. 1·29 to 4·42) and gastrectomy (hazard ratio 2·58, 1·25 to 5·32). CONCLUSION: Textbook outcome is a clinically relevant measure in patients undergoing oesophagogastric cancer surgery as it can identify underperforming parameters in a hospital setting. Overall survival in patients with a textbook outcome is better than in patients without a textbook outcome.

Association between hospital volume and quality of gastric cancer surgery in the CRITICS trial.

BACKGROUND: Studies investigating the association between hospital volume and quality of gastric cancer surgery are lacking. In the present study, the effect of hospital volume on quality of gastric cancer surgery was evaluated by analysing data from the CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. METHODS: Patients who underwent gastrectomy with curative intent in the Netherlands were selected from the CRITICS trial database. Annual hospital volume of participating centres was derived from the Netherlands Cancer Registry. Hospital volume was categorized into very low (1-10 gastrectomies per year per institution), low (11-20), medium (21-30) and high (31 or more), and linked to the CRITICS database. Quality of surgery was analysed by surgicopathological compliance (removal of at least 15 lymph nodes), surgical compliance (removal of indicated lymph node stations) and the Maruyama Index. Postoperative morbidity and mortality were also compared between hospital categories. RESULTS: Between 2007 and 2015, 788 patients were included in the CRITICS study, of whom 494 were analysed. Surgicopathological compliance was higher (86·7 versus 50·4 per cent; P < 0·001), surgical compliance was greater (52·9 versus 19·8 per cent; P < 0·001) and median Maruyama Index was lower (0 versus 6; P = 0·006) in high-volume hospitals compared with very low-volume hospitals. There was no statistically significant difference in postoperative complications or mortality between the hospital volume categories. CONCLUSION: Surgery performed in high-volume hospitals was associated with better surgical quality than surgery carried out in lower-volume hospitals.

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

Biobanking of fresh-frozen endoscopic biopsy specimens from esophageal adenocarcinoma.

The process of preparing endoscopic esophageal adenocarcinoma samples for next-generation DNA/RNA sequencing is poorly described. Therefore, we assessed the feasibility and pitfalls of preparing esophageal adenocarcinoma endoscopic biopsies toward DNA/RNA samples suitable for next-generation sequencing. In this prospective study, four tumor biopsy samples were collected from consecutive esophageal cancer patients during esophagogastroduodenoscopy and fresh-frozen in liquid nitrogen. DNA and RNA were isolated from samples with a tumor percentage of at least 50%. For next-generation sequencing, double-stranded DNA (dsDNA) is required and high-quality RNA preferred. The quantity dsDNA and RNA quantity and quality were assessed with the Nanodrop 2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) and Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). Biopsy samples of 69 consecutive patients with esophageal adenocarcinoma were included. In five patients (7%), the tumor percentage was less than 50% in all four biopsies. Using a protocol allowing simultaneous DNA and RNA isolation, the median dsDNA yield was 2.4 µg (range 0.1-12.0 µg) and the median RNA yield was 0.5 µg (range 0.01-2.05 µg). The median RNA integrity number of samples that were fresh-frozen within 30 minutes after sampling was 6.7 (range 4.2-8.9) compared with 2.5 (1.8-4.5) for samples that were fresh-frozen after 2 hours. The results from this study show that obtaining dsDNA and RNA for next-generation sequencing from endoscopic esophageal adenocarcinoma samples is feasible. Tumor percentage and dsDNA/RNA yield and quality emphasize the need for sampling multiple biopsies and minimizing the delay before fresh-freezing.

Serum human epididymal protein 4 (HE4) as biomarker for the differentiation between epithelial ovarian cancer and ovarian metastases of gastrointestinal origin.

OBJECTIVE: About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of human epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated. METHODS: HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology. RESULTS: Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p<0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p<0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases. CONCLUSION: HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin.

Perioperative systemic chemotherapy in peritoneal carcinomatosis of lymph node positive colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC. PATIENTS AND METHODS: A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence. RESULTS: Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns. CONCLUSIONS: In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.

A prospective pilot study to assess neoadjuvant chemotherapy for unresectable peritoneal carcinomatosis from colorectal cancer.

AIM: Twelve to 13% of patients with colorectal cancer (CRC) develop peritoneal carcinomatosis (PC), the majority of whom present with unresectable disease. This study aimed to document the actual response rate to and response characteristics of preoperative modern systemic chemotherapy in this patient group. METHOD: Patients underwent a positron emission tomography (PET)/CT scan, laparoscopy and peritoneal biopsy to document unresectable PC. After four courses of preoperative chemotherapy (capecitabine/oxaliplatin ± bevacizumab), the extent of PC was re-evaluated by PET/CT(or CT), laparoscopy and peritoneal biopsy (if considered safe). RESULTS: Ten patients (seven men, three women) with good performance status of median age 60.3 (45.6-72.8) years were studied. The first laparoscopy documented unresectable PC. One patient was excluded because of systemic metastases on PET/CT. Nine proceeded to follow the trial protocol. Of these, one developed early progressive disease, two had macroscopically stable disease and five had progressive disease at second laparoscopy. One patient developed a small bowel perforation at first laparoscopy and received palliative chemotherapy outside the protocol, after which progressive disease was found at an explorative laparotomy. Thus, 7 (78%) patients with unresectable PC from CRC developed progressive disease under neoadjuvant chemotherapy and 2 (22%) patients remained stable. No clear macroscopic response to chemotherapy could be demonstrated. CONCLUSION: Unresectable PC from CRC does not respond well to systemic chemotherapy.

Smoking and older age associated with mumps in an outbreak in a group of highly-vaccinated individuals attending a youth club party, the Netherlands, 2012.

We describe a mumps outbreak in a highly-vaccinated population attending a party at a youth club. In a retrospective cohort study with 60 of approximately 100 participants responding, vaccination status was verified for 58/59 respondents, of whom 54 were vaccinated twice and four once. The attack rate was 22% (13 cases, all vaccinated), with smoking at the party (risk ratio (RR) 3.1; 95% confidence interval (CI): 1.6­6.0, p=0.001) and age ≥21 years (RR 4.7; 95% CI: 2.1­10.2, p<0.0001) as risk factors for disease in the binominal regression analysis. Mild upper respiratory illness was also highly prevalent in those who did not meet the mumps case definition (n=46) after the party, suggesting that mumps virus infection may cause mild disease in vaccinated individuals. Our investigation adds toevidence that crowded social events and smoking may facilitate spread of mumps virus among vaccinated populations, with waning immunity playing a role. The suggestion that mumps virus infection in vaccinated individuals may manifest as mild upper respiratory illness could have implications for transmission and warrants further investigation.

Hepatitis C virus prevalence in The Netherlands: migrants account for most infections.

A population-based anti-hepatitis C virus (HCV) prevalence is important for surveillance purposes and it provides insight into the burden of disease. The outcomes of recent studies in the general Dutch population as well as recent HCV data from specific risk groups including migrants, men who have sex with men (MSM) and injecting drug users (IDUs), were implemented in a modified version of the Workbook Method (a spreadsheet originally designed for HIV estimations), to estimate Dutch HCV seroprevalence. The estimated national seroprevalence of HCV was 0·22% (min 0·07%, max 0·37%), corresponding to 28 100 (min n = 9600, max n = 48 000) HCV-infected individuals in The Netherlands. Of these, first-generation migrants from HCV-endemic countries (HCV prevalence ≥2%) accounted for the largest HCV-infected group, followed by IDUs and HIV-positive MSM.

Comparison of the hepatitis B virus core, surface and polymerase gene substitution rates in chronically infected patients.

For phylogenetic comparison of hepatitis B virus (HBV) isolates, often a region of the HBV surface gene is analysed. Because the surface gene completely overlaps the polymerase gene, its evolution is constrained, and it may not be the best choice for genetic comparison of HBV isolates. Analysing serial sample pairs of 33 chronically HBV-infected, untreated patients, with a cumulative follow-up of 184 years, the synonymous and nonsynonymous substitution rates of a part of the overlapping HBV surface and polymerase genes were compared to those of a nonoverlapping part of the HBV core gene. The substitution rate of the HBV core gene was higher (8.15 × 10(-4) vs 4.57 × 10(-4) substitutions/site/year) than that of the surface gene. The difference was mainly due to a significantly lower synonymous substitution rate in the surface gene, with dN/dS ratios of 0.412 in the core gene and 0.986 in the surface gene. Contrary to the core gene, the number of substitutions in the surface gene was higher in low viraemic hosts, who control HBV infection by suppressing replication. The number of substitutions in the core gene correlated more strongly with the duration of follow-up. The overlapping HBV surface and polymerase genes experience strong negative selection, which limits the number of substitutions. Because the HBV core gene reflects the duration of infection more accurately, it is more suitable for the analysis of short-term viral evolution and of hepatitis B transmission chains.

Prevalence of hepatitis B virus infection in The Netherlands in 1996 and 2007.

We aimed to assess differences in the prevalence of hepatitis B virus (HBV) infection in The Netherlands between 1996 and 2007, and to identify risk factors for HBV infection in 2007. Representative samples of the Dutch population in 1996 and 2007 were tested for antibodies to hepatitis B core antigen (anti-HBc), hepatitis B surface antigen (HBsAg) and HBV-DNA. In 2007, the weighted anti-HBc prevalence was 3·5% (95% CI 2·2-5·5) and the HBsAg prevalence was 0·2% (95% CI 0·1-0·4). In indigenous Dutch participants, the anti-HBc prevalence was lower in 2007 than in 1996 (P=0·06). First-generation migrants (FGMs) had a 13-fold greater risk of being HBsAg- and/or HBV-DNA-positive than indigenous Dutch participants. In indigenous Dutch participants, risk factors for anti-HBc positivity were older age and having received a blood product before 1990. In FGMs, being of Asian origin was a risk factor. In second-generation migrants, having a foreign-born partner and injecting drug use were risk factors. FGMs are the main target group for secondary HBV prevention in The Netherlands.

EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.

This consensus report of the EGILS (European Gastro-Intestinal Lymphoma Study) group includes recommendations on the management of gastric extranodal marginal zone B-cell lymphoma of MALT. They are based on data from the literature and on intensive discussions and votings of the experts during their annual meetings.

Comparison of the Beacon and Quark indirect calorimetry devices to measure resting energy expenditure in ventilated ICU patients.

INTRODUCTION: Critically ill patients in the Intensive Care Unit (ICU) should receive nutritional support matched to their metabolic needs as both under- and overfeeding energy has been shown to increase mortality. Critical illness can significantly affect metabolism. Consequently, resting energy expenditure (REE) can vary markedly during critical illness. Therefore, indirect calorimetry to estimate REE is recommended to determine energy requirements in individual ICU patients and to guide optimal nutritional support. Currently, the Quark metabolic monitor is considered the gold standard in our ICU, but novel mechanical support devices are also equipped with indirect calorimetry functionalities. This study aimed to evaluate the performance of a currently unevaluated device. METHODS: A cross-sectional analysis in mechanically ventilated patients was conducted in a mixed medical-surgical ICU. The primary outcome was a numerical and visual comparison of the performance of the Beacon indirect calorimeter to calculate REE compared to the Quark device using Bland Altman plots. Performance was evaluated using bias, precision, accuracy, and reliability. Secondary analysis included a comparison with REE estimated by predictive equations. RESULTS: Seventy-one measurements were obtained in 27 mechanically ventilated subjects. An underestimation by the Beacon device in calculated REE of -96.2 kcal/day (4.5%) was found. There was a bias towards higher VCO2 and lower VO2 values with Beacon as compared to Quark. The reliability of the Beacon was good, with an absolute intraclass correlation coefficient of 0.897 (95%CI 0.751-0.955; p = 0.000). There was a poor correlation (<0.40) between the separate indirect calorimetry devices and most predictive equations. Only the Faisy predictive equations had good reliability (ICC 0.687, p = 0.002). CONCLUSIONS: Beacon indirect calorimetry accurately determined REE in mechanically ventilated critically ill patients compared to the gold standard in our ICU (Quark indirect calorimeter), although confidence intervals were wide. There was low bias and good reliability. On the other hand, predictive equations performed poorly compared to both devices, underestimating the true metabolic needs of mechanically ventilated ICU patients.

HBsAg-negative mono-infection with hepatitis B virus genotype G.

Infection with a genotype G strain of hepatitis B virus (HBV-G) often occurs as a co-infection with HBV genotype A. In mono-infection with HBV-G, the production of hepatitis B surface antigen (HBsAg), HBe antigen and anti-HBe seems diminished, hampering the serological diagnosis of HBV-G mono-infection. To corroborate this notion, we studied in detail a series of samples of a blood donor with transient HBV-G infection. In this donor, during the temporary presence of HBV DNA and the seroconversion to HBcore antibodies (anti-HBc), no HBsAg or hepatitis B e antigen was detected. During follow-up, no anti-HBe appeared. Multiple resistance mutations to lamivudine were present, demonstrating primary infection with a resistant HBV strain. Cloning and sequencing indicated that no other HBV genotype but genotype G was present. Like other HBV-G isolates, the DNA sequence of the HBsAg a-determinant showed no mutations that could explain the failure to detect HBsAg. Our findings demonstrate that HBV genotype G mono-infection occurs and that routine serology is unsuitable for its detection.

Changing risk profile of hepatitis A in The Netherlands: a comparison of seroprevalence in 1995-1996 and 2006-2007.

The prevalence of antibodies to hepatitis A virus (HAV) was assessed in a nationwide sample (n=6229) in The Netherlands in 2006-2007, and compared to the seroprevalence in a similar study in 1995-1996 (n=7376). The overall seroprevalence increased from 34% in 1995-1996 to 39% in 2006-2007, mainly due to vaccination of travellers and an increased immigrant population. Risk factors remain travelling to, and originating from, endemic regions, and vaccination is targeted currently at these risk groups. Our results show a trend of increasing age of the susceptible population. These people would also benefit from HAV vaccination because they are likely to develop clinically serious symptoms after infection, and are increasingly at risk of exposure through imported viruses through foods or travellers. The cost-effectiveness of adding elderly people born after the Second World War as a target group for prophylactic vaccination to reduce morbidity and mortality after HAV infection should be assessed.

Mumps epidemic in orthodox religious low-vaccination communities in the Netherlands and Canada, 2007 to 2009.

We assessed the epidemiological characteristics of a mumps virus epidemic (genotype D) that occurred in the Netherlands between August 2007 and May 2009 and its association with a subsequent mumps outbreak in Canada. In the Netherlands, five data sources were used: notifications (only mandatory since the end of 2008) (56 cases), laboratory confirmation data (177 cases), a sentinel general practitioner (GP) database (275 cases), hospitalisation data (29 cases) and weekly virological reports (96 cases). The median age of cases in the notification, laboratory and GP databases ranged from 13 to 15 years. The proportion of cases that were unvaccinated ranged from 65% to 85% in the notification, laboratory and GP databases. Having orthodox Protestant beliefs was the main reason for not being vaccinated. In Canada, a mumps virus strain indistinguishable from the Dutch epidemic strain was detected between February and October 2008 in an orthodox Protestant community with historical and family links to the affected community in the Netherlands, suggesting that spread to Canada had occurred. Prevention and control of vaccine-preventable diseases among population subgroups with low vaccination coverage remains a priority.

Systemic exposure of oxaliplatin and docetaxel in gastric cancer patients with peritonitis carcinomatosis treated with intraperitoneal hyperthermic chemotherapy.

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.