Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial.

BACKGROUND: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. METHODS: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. DISCUSSION: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. TRIAL REGISTRATION: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

Hepatitis B virus quasispecies evolution after liver transplantation in patients under long-term lamivudine prophylaxis with or without hepatitis B immune globulin.

AIMS: To investigate an optimal long-term prophylactic strategy for prevention of hepatitis B virus (HBV) recurrence after liver transplantation, we conducted a randomized study of 29 transplant recipients receiving a short course of hepatitis B immune globulin (HBIg) + lamivudine (LAM), followed by randomization to long-term prophylaxis with LAM with or without HBIg. METHODS: The efficacy and safety, and impact on survival and HBV recurrence of these 2 prophylactic regimens were compared over a mean period of 10 years. In patients with viral recurrence, the HBV quasispecies in the surface/polymerase region were studied by ultra-deep pyrosequencing (UDPS). RESULTS: The 10-year survival rate was 76% and was not affected by the type of prophylaxis. Four patients had hepatitis B surface antigen (HBsAg) recurrence within the first 48 months after orthotopic liver transplantation (OLT). HBsAg-positive and -negative patients showed similar mean survival times, with no differences between the 2 regimens. Low HBV DNA levels were transiently detected in 32% of HBsAg-negative patients. UDPS showed major changes after OLT in the HBV quasispecies of patients with viral recurrence, which may be explained by a "bottleneck" effect of OLT together with prophylactic therapy. CONCLUSION: Long-term survival after OLT in end-stage chronic hepatitis B patients was good with both prophylactic strategies. However, low, transient HBV DNA levels were detected even in the absence of HBsAg, showing the importance of continuing HBV prophylaxis.

Development and evaluation of a baseline-event-anticipation score for hepatitis delta.

Hepatitis delta is considered the most severe form of viral hepatitis, but variables associated with disease progression are poorly defined. This study aimed to identify risk factors associated with worse clinical outcome in patients with hepatitis delta and to develop a clinical score to determine their risk of experiencing liver-related morbidity or mortality. We followed 75 HBsAg-anti-HDV-positive patients with hepatitis delta for up to 16 years (median 5 years). The baseline-event-anticipation score (BEA score) was developed based on variables associated with the development of liver-related clinical complications. Age, region of origin, presence of cirrhosis, albumin, INR, hyperbilirubinemia and thrombocytopenia were all associated with the development of an event in the training cohort. The BEA score included age, sex, region of origin, bilirubin, platelets and INR. Points were allocated according to hazard ratios, and three risk groups were defined: BEA-A mild risk, BEA-B moderate risk and BEA-C high risk. Hazard ratios of BEA-B and BEA-C patients for liver-related clinical endpoints were 9.01 and 25.27 vs BEA-A with an area under curve of the receiving operating characteristic curve of 0.88. The accuracy of the BEA score was confirmed in two independent validation cohorts followed in Barcelona (n = 77) and Düsseldorf (n = 62). Delta hepatitis is associated with a very severe long-term outcome. The BEA score is easy to apply and predicts with a very high accuracy the development of liver-related complications in patients with hepatitis delta.

HIV, HEV and cirrhosis: evidence of a possible link from eastern Spain.

OBJECTIVES: The aim of the study was to assess the seroprevalence of hepatitis E virus (HEV) infection in an HIV-infected population, as determined by HEV immunoglobulin G (IgG) antibodies (anti-HEV). METHODS: The design of the study was cross-sectional. Serum anti-HEV IgG was determined by enzyme immunoassay in 238 HIV-infected patients consecutively attending our out-patient clinic between April and May 2011. In HEV-seropositive patients, HEV RNA was analysed by nested reverse transcriptase-polymerase chain reaction (RT-PCR). Associations between anti-HEV and liver cirrhosis, route of HIV infection, hepatitis B virus (HBV) and hepatitis C virus (HCV) serological markers, age, sex and alanine aminotransferase (ALT) levels were examined by univariate and multivariate analysis. RESULTS: One hundred and forty patients (59%) had chronic liver disease (99% were HBV- and/or HCV-coinfected). Liver cirrhosis was detected in 44 individuals (19%). Two hundred and twelve patients (89%) were on antiretroviral treatment; the median CD4 T-cell count was 483 cells/µL [interquartile range (IQR) 313-662 cells/µL] and the HIV viral load was <25 HIV-1 RNA copies/mL. Overall, 22 patients (9%) were anti-HEV positive. Liver cirrhosis was the only factor independently associated with the presence of anti-HEV, which was documented in 23% of patients with cirrhosis and 6% of patients without cirrhosis (P=0.002; odds ratio 5.77). HEV RNA was detected in three seropositive patients (14%), two of whom had liver cirrhosis. CONCLUSIONS: Our findings show a high prevalence of anti-HEV in HIV-infected patients, strongly associated with liver cirrhosis. Chronic HEV infection was detected in a significant number of HEV-seropositive patients. Further research is needed to ascertain whether cirrhosis is a predisposing factor for HEV infection and to assess the role of chronic HEV infection in the pathogeneses of cirrhosis in this population.

IL28B genetic variation and hepatitis C virus-specific CD4(+) T-cell responses in anti-HCV-positive blood donors.

Epidemiological, viral and host factors are associated with the outcome of hepatitis C virus (HCV) infection, and strong host immune responses against HCV favour viral clearance. Recently, genome-wide association studies have shown a strong correlation between single-nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene and spontaneous or treatment-induced HCV clearance. We have investigated whether protective IL28B genetic variants are associated with HCV-specific T-cell responses among Spanish blood donors. The rs12979860 IL28B haplotype was determined in 69 anti-HCV-positive blood donors (21 HCV RNA negative and 48 HCV RNA positive) and 30 seronegative donors. In all cases, HCV-specific CD4(+) T-cell responses to HCV recombinant proteins (core, NS3 and NS3 helicase) were assessed by ex vivo interferon-γ ELISpot assay. The rs12979860-CC genotype was highly overrepresented in donors with spontaneous HCV clearance when compared to those with chronic infection (76.2%vs 29.2%, P < 0.001; odds ratio, 7.77; 95% confidence interval, 2.4-25.3, P < 0.001). HCV-specific CD4(+) T-cell responses were detected in 16 (76.2%) spontaneous resolvers especially towards nonstructural proteins, but with no correlation with IL28B genotype. Chronic individuals had a significantly lower overall T-cell response again irrespective of IL28B genotype. When spontaneous resolvers and chronic individuals were stratified according to their IL28B genotype, significantly stronger T-cell responses were only observed among those with non-CC haplotypes. Although the protective rs12979860 IL28B CC genotype is associated with spontaneous HCV clearance, stronger CD4(+) T-cell responses towards NS3 were only evident among those with non-CC haplotypes.

Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study.

Long-term changes in the frequency and outcome of hepatitis delta virus (HDV) infection have seldom been analysed. This retrospective, longitudinal study includes 398 consecutive hepatitis B surface antigen (HBsAg)-positive patients with anti-HDV antibodies who attended our institution between 1983 and 2008. At enrolment, 182 patients had acute and 216 chronic hepatitis. Patients were grouped into two periods. Those who attended between 1983 and 1995 and those between 1996 and 2008. The former group was significantly younger, mainly intravenous drugs users, and had a greater incidence of acute HDV and HIV and HCV coinfection. Patients with acute HBV/HDV coinfection cleared both infections in 90% of cases, while all patients with HDV superinfection evolved to chronic disease. One hundred and fifty-eight patients with chronic HDV were followed for a median period of 158months. Seventy-two per cent of the patients remained stable, 18% had hepatic decompensation, 3% developed hepatocellular carcinoma, and 8% cleared HBsAg. Liver-related death was observed in 13% of patients and mainly occurred in patients from the first period (P=0.012). These results indicate an outbreak of HDV at the end of the 1980s and the beginning of the 1990s, with a large number of acute HDV cases affecting predominately young, male intravenous drug users. Currently, patients with chronic HDV disease are older, and factors associated with worse prognosis include the presence of cirrhosis and age at the time of diagnosis.

Advances in adjuvant therapy of biliary tract cancer: an overview of current clinical evidence based on phase II and III trials.

Patients with biliary tract cancer (BTC) have a high recurrence rate after complete surgical resection. To reduce the risk of recurrence and to improve survival, several chemotherapeutic agents that have shown to be active in locally advanced and metastatic BTC have been investigated in the adjuvant setting in prospective clinical trials. Based on the results of the BILCAP phase III trial, capecitabine was adapted as the standard of care by the ASCO clinical practice guideline. Ongoing randomized controlled trials mainly compare capecitabine with gemcitabine-based chemotherapy or chemoradiotherapy. This review provides an update of adjuvant therapy in BTC based on published data of phase II and III trials and ongoing randomized controlled trials (RCTs).

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): a multicenter stepped-wedge cluster randomized controlled trial.

BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.

Subclinical inflammation in renal transplant recipients: impact of cyclosporine microemulsion versus tacrolimus.

BACKGROUND: Renal insufficiency and renal transplant (RT) provoke a microinflammatory state that leads to increased atherosclerosis. It is not fully known whether calcineurin inhibitors (CNIs) play a role in the inflammation observed in these patients or whether any differences exist between CNIs. OBJECTIVES: The study aimed to establish differences in the inflammatory state of two groups treated with cyclosporine microemulsion (CyA) or tacrolimus (TC). PATIENTS AND METHODS: This prospective study included 81 RT patients divided into two groups according to the CNI: CyA group, n = 35 versus TC group, n = 46. The markers of inflammation (MIF) were determined preRT and at 3 and 12 months' postRT: C-reactive protein (CRP), serum amyloid protein A (SAA), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and pregnancy-associated plasma protein A (PAPP-A). Samples were collected in stable patients in the absence of rejection, active infection, or inflammatory processes. RESULTS: No significant differences existed between the markers of inflammation in the two treatment groups prior to transplantation. At 3 months' posttransplant, patients treated with CyA showed significantly higher levels of IL-6 (P = .05), SAA (P = .03), and sIL-2R (P = .008) compared with patients treated with TC. These differences were maintained for IL-6 (P = .03) and sIL-2R (P = .027) at 12 months' posttransplant. A multivariate analysis at 3 months showed that only age [OR 10.1; CI (95% 2.6-38.4); P = .001], SAA [OR 4.8; IC (95% 1.4-16.5); P = .015], and sIL-2R [OR 4.9; IC (95% 1.5-16.2); P = .009] were independent predictors of the CNI used. At 12 months, age [OR 3.7; IC (95% 0.9-14.2] and sIL-2R [OR 6.04; IC (95% 1.5-23); P = .006] continued to be independent predictors. CONCLUSIONS: Patients treated with CyA displayed significantly higher levels of inflammatory markers (IL-6, SAA, sIL-2R) at 3 and 12 months' posttransplantation, independent of age, gender, time on dialysis, diabetes mellitus (preRT and de novo postRT), and renal function measured by serum creatinine.

Serum hepatitis B core-related antigen is more accurate than hepatitis B surface antigen to identify inactive carriers, regardless of hepatitis B virus genotype.

OBJECTIVES: To investigate whether hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels are useful to identify inactive carriers among HBeAg-negative patients infected by different hepatitis B virus (HBV) genotypes. METHODS: In all, 202 consecutive HBeAg-negative patients with chronic hepatitis B, 135 inactive carriers and 67 with HBV activity, were prospectively followed for 1 year. RESULTS: In HBeAg-negative patients, HBsAg levels differed across the different genotypes (p <0.001). The highest levels were observed in genotypes F or H (4.2 ± 0.6 logIU/mL), followed by genotype E (3.4 ± 1.1 logIU/mL), genotype A (3.4 ± 0.8 logIU/mL), and the lowest in genotype D (2.7 ± 1.1 logIU/mL). Variations in HBsAg levels were similar in inactive carriers and patients with HBV activity. HBsAg <3 logIU/mL showed good performance for identifying genotype D inactive carriers: 76% of genotype D inactive carriers met this cut-off versus ≤31% for genotypes A, E, F or H. However, in patients with genotype A, HBsAg levels ≤3.7 logIU/mL better classified inactive carriers. The combination of a single measurement of HBcrAg ≤3 logU/mL plus HBV DNA ≤2000 IU/mL yielded a positive predictive value and diagnostic accuracy >85% in all HBV genotypes, except genotype H or F, with values of 62.5% and 72.7%, respectively, for the two parameters. CONCLUSIONS: HBsAg levels varied across genotypes in HBeAg-negative patients. HBsAg levels <3 logIU/mL were only useful for identifying genotype D inactive carriers. A single HBcrAg measurement ≤3 logU/mL plus HBV DNA ≤2000 IU/mL was highly accurate for identifying inactive carriers, regardless of their HBV genotype.

High HCV subtype heterogeneity in a chronically infected general population revealed by high-resolution hepatitis C virus subtyping.

OBJECTIVES: This study aimed to characterize the chronically infected general hepatitis C virus (HCV) population in Barcelona using a highly sensitive subtyping method that can identify the 67 recognized HCV subtypes and diagnose mixed infection by various genotypes/subtypes in a single individual. The resulting information has implications for selecting optimal direct-acting antiviral (DAA) treatment for each patient and establishing public healthcare policies in our setting. METHODS: Consecutive HCV patients (treatment-naïve or interferon-based failures) attending Vall d'Hebron Hospital outpatient clinics from February 2015 to May 2016 (N=1473) were included in the study. Patient samples were characterized using HCV subtyping by next-generation ultra-deep pyrosequencing. RESULTS: The following genotypes (G) were found: G1 (1126/1473 (76.4%)), G4 (145/1473 (9.8%)), G3 (135/1473 (9.2%)), G2 (51/1473 (3.5%)), and G5 (1/1473 (0.1%)). Twenty-two subtypes were seen: 1b (790/1473 (53.6%)), 1a (332/1473 (22.5%)), 3a (133/1473 (9.0%)), 4d (105/1473 (7.1%)), 4a (29/1473 (2.0%)), and 2c (25/1473 (1.7%)), with 16 low-prevalence subtypes accounting for the remaining 3.0% (44/1473). There was a worrisome 1.0% (15/1473) of mixed infections. G2 (51/1473 (3.5%)) showed a high level of heterogeneity. Analyses by age groups showed a predominance of G1b over G1a (428/506 (84.6%) vs. 24/506 (4.7%)) in patients born before 1950 (N=506/1473), and similar percentages of these subtypes in those born between 1951 and 1975 (N=834/1473) (315/834, 37.8% vs. 266/834, 31.9%) and after 1976 (N=133/1473) (47/133, 35.3% vs. 42/133, 31.6%). CONCLUSIONS: Subtype distribution showed a higher level of heterogeneity than was expected, particularly for G2. Prevalence of mixed infections was around 1%. HCV subtype distribution related to patient age group suggested that patients born from 1936 to 1975 in our setting should undergo screening for the infection. Next-generation sequencing enabled better classification of candidates for DAA-based treatment.

Chemotherapy for metastatic carcinoma of the esophagus and gastro-esophageal junction.

BACKGROUND: More than 50% of patients with esophageal cancer have metastatic disease at presentation. The use of chemotherapy for this patient group is increasing with the intention of local and distant tumor control, improving quality of life and prolongation of survival. OBJECTIVES: To assess the effectiveness of a) chemotherapy versus best supportive care or b) different chemotherapy regimes against each other, in metastatic esophageal carcinoma. SEARCH STRATEGY: Searches were conducted on the Cochrane Central register of Controlled Trials--CENTRAL (which includes the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register) on The Cochrane Library (Issue 1 2004) MEDLINE (1966 to February 2004), EMBASE (1980 to February 2004) and Cancerlit. Reference lists from trials selected by electronic searching were handsearched to identify further relevant trials. Published abstracts from conference proceedings from the United European Gastroenterology Week (published in Gut) and Digestive Disease Week (published in Gastroenterology) were handsearched. The search was updated in February 2005 and February 2006. Members of the Cochrane UGPD Group, and experts in the field were contacted and asked to provide details of outstanding clinical trials and any relevant unpublished materials SELECTION CRITERIA: Randomized controlled trials comparing chemotherapy versus best supportive care, or different chemotherapy regimes against each other in patients with metastatic carcinoma of the esophagus or gastro-esophageal junction. DATA COLLECTION AND ANALYSIS: Two authors (MYVH/EJK) extracted data and assessed trial quality. Study authors were contacted to obtain subgroup results of patients with metastatic esophageal carcinoma. MAIN RESULTS: Only two RCTs with a total of 42 participants compared chemotherapy with best supportive care for metastatic esophageal cancer. No survival benefit was shown for chemotherapy treatment in these RCTs. Five RCTs with a total of 1242 participants compared different chemotherapy regimes. Due to variation in patient population and chemotherapy regimes, it was not possible to perform a formal pooled analysis. There was no consistent benefit of any specific chemotherapy regimen. AUTHORS' CONCLUSIONS: There is a need for well designed, adequately powered, phase III trials comparing chemotherapy versus best supportive care for patients with metastatic esophageal cancer. Chemotherapy agents with promising response rates and tolerable toxicity are cisplatin, 5-fluorouracil (5-FU), paclitaxel and antracyclins. Future trials comparing palliative treatment modalities should assess quality of life with validated quality of life measures.

Self-Assembly and Formation of Chromonic Liquid Crystals from the Dyes Quinaldine Red Acetate and Pyronin Y.

The aqueous self-assembly behavior of the dyes Quinaldine red acetate and Pyronin Y in a wide range of concentrations is reported here for the first time. (1)H NMR spectroscopy, polarized-light optical microscopy, and small and wide X-ray scattering were used to get insight into molecular interactions, phase boundaries and aggregate structure. Quinaldine red acetate and Pyronin Y self-organize into unimolecular stacks driven by attractive aromatic interactions. At high concentrations, spatial correlation among the molecular stacks gives rise to nematic liquid crystals in both systems. Quinaldine red acetate additionally produces a rare chromonic O phase built of columnar aggregates with anisotropic cross-section ordered in a rectangular lattice. The O phase changes into a columnar lamellar structure as a result of a temperature-induced phase transition. Results open the possibility of finding chromonic liquid crystals in other commercially available dyes with a similar molecular structure. This would eventually expand the availability of these unique soft materials and thus introduce new applications for marketed dyes.

[Palliative treatment in patients with oesophagus carcinoma]. / De palliatieve behandeling van patiënten met een oesofaguscarcinoom.

More than 50% of patients with oesophageal carcinoma will undergo palliative treatment because of distant metastases or local tumour ingrowth into surrounding organs. The majority of these patients have symptoms ofdysphagia. If metastases from oesophageal carcinoma are present, the most commonly used treatment modalities for dysphagia in The Netherlands are placement of a self-expanding stent or intraluminal radiotherapy (brachytherapy). If the life expectancy of patients is longer than 3 months, brachytherapy is sometimes combined with external radiotherapy. If patients with metastases are in a good condition, chemotherapy may be considered. If there is local tumour ingrowth but no metastases, chemotherapy in combination with radiation therapy (chemoradiation) is an option. These treatments should preferably make up part of well-designed studies. Quality of life is an important endpoint to consider in the palliative treatment of patients with oesophageal cancer. Well-established standardized and validated questionnaires are available for this purpose.

[Palliative treatment of esophageal cancer with dysphagia: more favourable outcome from single-dose internal brachytherapy than from the placement of a self-expanding stent; a multicenter randomised study]. / Palliatieve behandeling voor slokdarmkanker met passageklachten: gunstiger uitkomsten van eenmalige inwendige brachytherapie dan van plaatsing van een zelfexpanderende stent; multicentrisch, gerandomiseerd onderzoek.

OBJECTIVE: To compare the results of single-dose internal irradiation (brachytherapy) and self-expanding metal stent placement in the palliation of oesophageal obstruction due to cancer of the oesophagus. DESIGN: Randomised trial. METHOD: In the period from December 1999-Jun 2002, 209 patients with dysphagia due to inoperable carcinoma of the oesophagus were randomised to placement of an Ultraflex stent (n = 108) or single-dose (12 Gy) brachytherapy (n = 101). Primary outcome was relief of dysphagia; secondary outcomes were complications, persistent or recurrent dysphagia, health-related quality of life, and costs. Patients were followed up by monthly home visits from a specialised nurse. RESULTS: Dysphagia improved more rapidly after stent placement than after brachytherapy, but long-term relief of dysphagia was better after brachytherapy. Stent placement resulted in more complications than did brachytherapy (36/108 (33%) versus 21/101 (21%); p = 0.02), due mainly to an increased incidence of late haemorrhage in the stent group (14 versus 5; p = 0.05). The groups did not differ with regard to the incidence of persistent or recurrent dysphagia or median survival (p > 0.20). In the long term, quality-of-life scores were higher in the brachytherapy group. Total medical costs were also similar for both treatments: Euro 8,215 for stent placement and Euro 8,135 for brachytherapy. CONCLUSION: Brachytherapy provided better long-term relief of dysphagia than did stent placement and also produced fewer complications. Brachytherapy is therefore recommended as the preferred treatment for the palliation of dysphagia due to oesophageal cancer.

Effects of radiotherapy on mandibular reconstruction plates.

The radiation dose in the vicinity of metal mandibular implants was measured using lithium fluoride (TLD-100) thermoluminescent dosimeters. Dosimeters were positioned in contact with Vitallium and stainless steel (AO) reconstruction plates. Simple transmission was measured with a solid state detector removed from the implant at a depth of 2.5 cm in a polystyrene phantom. The measurements were made for a 6 mV photon beam from a linear accelerator. At points in front of, but in contact with the metal implants, the dose was greater by 23 percent for Vitallium and 17 percent for stainless steel than that with no implant. At contact behind the implant, the dose was reduced considerably: 14 percent for Vitallium and 13 percent for stainless steel. At remote points behind the implant, the dose was reduced due to attenuation.

Iron deficiency and risk factors for lower iron stores in 6-24-month-old New Zealanders.

OBJECTIVES: To determine the prevalence of biochemical iron deficiency and identify factors associated with ferritin levels among 6-24-month-old urban South Island New Zealand children. DESIGN: Cross-sectional survey conducted from May 1998 to March 1999. SETTING: The cities of Christchurch, Dunedin and Invercargill. SUBJECTS: A total of 323 randomly selected 6-24-month-old children participated (response rate 61%) of which 263 provided a blood sample. METHODS: A complete blood cell count, zinc protoporphyrin, serum ferritin and C-reactive protein were measured on nonfasting venipuncture blood samples, 3-day weighed food records and general questionnaire data were collected. RESULTS: Among children with C-reactive protein<10 mg/l (n=231), 4.3% had iron deficiency anaemia, 5.6% had iron deficiency without anaemia, and 18.6% had depleted iron stores, when a ferritin cutoff of < or =12 g/l was used. Age (negative), sex (girls>boys), ethnicity (Caucasian>non-Caucasian), weight-for-age percentiles (negative) and birth weight (positive) were associated with ferritin after adjusting for infection and socioeconomic status. When current consumption of iron fortified formula and >500 ml of cows' milk per day were included, these were associated with a 22% increase and 25% decrease in ferritin, respectively (R2=0.28). CONCLUSIONS: The presence of suboptimal iron status (29%) among young New Zealand children is cause for concern, even though severe iron deficiency is rare, because children with marginal iron status are at risk of developing severe iron deficiency if exposed to a physiological challenge.