[Therapeutic management of nonvalvular atrial fibrillation]. / Therapeutisches Management des nichtvalvulären Vorhofflimmerns.

Atrial fibrillation (AF) is the most frequent persistent cardiac arrhythmia and is associated with an increased mortality. Therefore, an effective differential treatment of patients is mandatory. After a risk stratification oral anticoagulation (OAC) should be initiated depending on the individual stroke risk of each patient. Alternatively, in the presence of contraindications for OAC and an increased risk for bleeding and/or stroke, the implantation of a left atrial appendage closure device can be considered. Symptomatic patients should undergo a rhythm control strategy if possible. Based on the risk-benefit considerations, catheter ablation (CA) of AF plays an increasingly important role in establishing long-term medicinal rhythm control. A pulmonary vein isolation can lead to freedom from AF for 1 year in 70-80% of patients with paroxysmal AF (and approximately 50% in persistent AF). So far, a survival advantage of CA could only be shown in patients with heart failure, so that in most cases this is only a symptomatic treatment for improvement in the quality of life.

Dynamic prediction of transition to psychosis using joint modelling.

Considerable research has been conducted seeking risk factors and constructing prediction models for transition to psychosis in individuals at ultra-high risk (UHR). Nearly all such research has only employed baseline predictors, i.e. data collected at the baseline time point, even though longitudinal data on relevant measures such as psychopathology have often been collected at various time points. Dynamic prediction, which is the updating of prediction at a post-baseline assessment using baseline and longitudinal data accumulated up to that assessment, has not been utilized in the UHR context. This study explored the use of dynamic prediction and determined if it could enhance the prediction of frank psychosis onset in UHR individuals. An emerging statistical methodology called joint modelling was used to implement the dynamic prediction. Data from the NEURAPRO study (n = 304 UHR individuals), an intervention study with transition to psychosis study as the primary outcome, were used to investigate dynamic predictors. Compared with the conventional approach of using only baseline predictors, dynamic prediction using joint modelling showed significantly better sensitivity, specificity and likelihood ratios. As dynamic prediction can provide an up-to-date prediction for each individual at each new assessment post entry, it can be a useful tool to help clinicians adjust their prognostic judgements based on the unfolding clinical symptomatology of the patients. This study has shown that a dynamic approach to psychosis prediction using joint modelling has the potential to aid clinicians in making decisions about the provision of timely and personalized treatment to patients concerned.

Optimization of Single Voxel MR Spectroscopy Sequence Parameters and Data Analysis Methods for Thermometry in Deep Hyperthermia Treatments.

OBJECTIVE: The difference in the resonance frequency of water and methylene moieties of lipids quantifies in magnetic resonance spectroscopy the absolute temperature using a predefined calibration curve. The purpose of this study was the investigation of peak evaluation methods and the magnetic resonance spectroscopy sequence (point-resolved spectroscopy) parameter optimization that enables thermometry during deep hyperthermia treatments. MATERIALS AND METHODS: Different Lorentz peak-fitting methods and a peak finding method using singular value decomposition of a Hankel matrix were compared. Phantom measurements on organic substances (mayonnaise and pork) were performed inside the hyperthermia 1.5-T magnetic resonance imaging system for the parameter optimization study. Parameter settings such as voxel size, echo time, and flip angle were varied and investigated. RESULTS: Usually all peak analyzing methods were applicable. Lorentz peak-fitting method in MATLAB proved to be the most stable regardless of the number of fitted peaks, yet the slowest method. The examinations yielded an optimal parameter combination of 8 cm3 voxel volume, 55 millisecond echo time, and a 90° excitation pulse flip angle. CONCLUSION: The Lorentz peak-fitting method in MATLAB was the most reliable peak analyzing method. Measurements in homogeneous and heterogeneous phantoms resulted in optimized parameters for the magnetic resonance spectroscopy sequence for thermometry.

Initial results after implementation of a multimodal treatment for peritoneal malignancies.

INTRODUCTION: Peritoneal carcinomatosis represents a clinical condition with a limited perspective concerning long term survival. The combination of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) represents a complex multimodal therapeutic management concept with promising results for prolongation of survival. For the identification of pitfalls during implementation of the HIPEC procedure into clinical practice an observational study was conducted. METHODS: Between 2005 and 2009 data from all patients treated with cytoreductive surgery and HIPEC for peritoneal carcinomatosis was prospectively collected and analysed. RESULTS: During the observational interval a total of 42 patients underwent surgical treatment for peritoneal carcinomatosis. In 34 patients the complete procedure with surgical cytoreduction and HIPEC was performed. Perioperative mortality (6%) and morbidity (35%) was similar to other reported series. Twenty-five patients (76%) survived the 18 months follow-up period after complete procedure. CONCLUSION: The multimodal therapeutic treatment concept of surgical cytoreduction and following HIPEC leads to promising results for patients suffering from peritoneal carcinomatosis. However this treatment concept is afflicted with a relevant risk of postoperative complications.

Preclinical and clinical activity of sunitinib in patients with cisplatin-refractory or multiply relapsed germ cell tumors: a Canadian Urologic Oncology Group/German Testicular Cancer Study Group cooperative study.

BACKGROUND: The objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors (GCT). METHODS: The effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and IC(50) (concentration that causes 50% inhibition of growth) doses were determined. Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design. RESULTS: Sunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines, with IC(50) between 3.0 and 3.8 µM. Patient characteristics were as follows: median of 2 (1-6) cisplatin-containing regimens; high-dose chemotherapy 67%; late relapse 33%; and cisplatin refractory or absolute cisplatin refractory 54%. Toxic effects included fatigue (39%), anorexia (21%), diarrhea (27%), mucositis (45%), nausea (33%), hand-foot syndrome (12%), dyspepsia (27%), and skin rash (18%). No unexpected side-effects were observed. Thirty -two of 33 patients were assessable for response. Three confirmed partial responses (PRs) and one unconfirmed PR were seen for a total response rate of 13%. Median progression-free survival (PFS) was 2 months, with a 6-month PFS rate of 11%. CONCLUSIONS: Sunitinib shows in vitro activity in cisplatin-resistant GCT cell lines. Modest clinical activity in heavily pretreated GCT patients was observed.

[Molecular pathology of sarcomas. Update on the research group "Molecular Diagnosis of Sarcomas"]. / Molekularpathologie von Sarkomen. Erste Ergebnisse des Sarkomforschungsverbundes KoSar.

To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).

[Hyperthermic intraperitoneal chemotherapy in the German DRG system. Analysis of case cost calculations of a maximum care university]. / Hypertherme intraperitoneale Chemotherapie im G-DRG-System. Analyse der Fallkostenkalkulationen eines universitären Maximalversorgers.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) offers patients with peritoneal cancer of various origins the chance of a relevant increase in life expectancy. These cases are very complex from a medical viewpoint and very expensive from an economical aspect. An analysis of case cost calculations was performed to find out whether this procedure can on average be carried out cost-effectively by a maximum care university. MATERIALS AND METHODS: All cases from 2008 in which HIPEC was carried out were analyzed. The types of main diagnosis, secondary diagnoses, procedures, times from incision to suture and hospital stay were analyzed. On the basis of the case costs the proceeds and marginal returns were calculated from the diagnosis-related groups (DRGs) and additional remuneration when applicable. The causes of positive and negative marginal returns were explained using the InEK cost matrix. RESULTS: In 18 patients there were 9 different main diagnoses and 7 different "main procedures" (from a surgical perspective the most resource intensive procedures) and a total of 10 different DRGs were identified in the grouping algorithm. With an average of 2 operations (range 1-7) per patient the summed incision-to-suture time was 423 min (170-962 min). The patients stayed on average 6.4 days (1.3-17.6 days) in intensive care. The average case cost was 21,072€ (range 8,657-55,904€) and the proceeds 20,474€ (6,333-37,497€). Each case had on average a debit balance of 598€ (range from 11,843€ profit balance to 18,407€ debit balance) with an assumed base rate of 2,786€. The causes for positive or negative marginal profits were mostly operating times, incision-to-suture times and duration of intensive care. CONCLUSIONS: The proceeds showed on average a deficit of only 3% compared to the costs. The operating times must be decreased by optimization particularly of the preoperative approach. Interventions should be carried out in one stage only and the intraoperative connecting and waiting times should be reduced in order to reduce the incision-to-suture times.

Volume therapy and cardiocircular function during hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Surgical cytoreduction and simultaneous hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis is afflicted with a high incidence of postoperative complications. The knowledge of intraoperative volume therapy during surgery and chemotherapy is limited. On the other hand, the choice of a 'liberal' or 'restrictive' regimen of fluid administration has a deep impact on the postoperative morbidity. The aim of this observational trial was to report detailed data on volume replacement and cardiocircular function during the HIPEC procedure. METHODS: Eighteen consecutive patients undergoing cytoreductive surgery and HIPEC for peritoneal carcinomatosis were enrolled. The intraoperative volume administration was observed as well as the postoperative morbidity and mortality. Cardiofunctional data were assessed by the invasive transthoracic thermodilution technique. RESULTS: The study showed that large amounts of volume (1,240 ml h(-1); range: 810-1,570 ml h(-1)) are given during the HIPEC procedure to replace fluid loss and maintain a stable circulatory function. Signs of a hyperdynamic status during intraoperative intraperitoneal chemotherapy were not found. CONCLUSIONS: During surgical cytoreduction and simultaneous HIPEC, large amounts of volume were administered. HIPEC in itself did not lead to an increased fluid requirement. Further prospective studies with larger populations are needed to investigate whether goal-oriented therapies and a restricted volume regimen can contribute to decrease the postoperative morbidity.

Human-induced changes in the reproductive traits of Lake Constance common whitefish (Coregonus lavaretus).

Size-selective fishery harvest leads to phenotypic changes in fish reproductive traits. When these changes represent an evolutionary response of a stock, they may have severe consequences for future stock dynamics and yields. In freshwater ecosystems, reproductive traits may also be affected by other human impacts such as changes in system productivity. The present study uses regression analysis to evaluate the impacts of changes in lake trophy and of an intensive size-selective harvest over several decades on the reproductive traits of common whitefish in Lake Constance between 1963 and 1999. Fecundity was strongly linked to lake trophy but was also related to the calendar year, suggesting an evolutionary response to size-selective harvest and to massive stocking of the lake with hatchery-reared larvae. The present study is an example of how fish reproductive traits are influenced by the combined action of various human impacts: changes in system productivity, size-selective harvest and massive stocking.

[Selection criteria for peritonectomy with hyperthermic intraoperative chemotherapy (HIPEC) in peritoneal carcinomatosis]. / Selektion zur Peritonektomie mit hyperthermer intraoperativer Chemotherapie (HIPEC) bei Peritonealkarzinose.

BACKGROUND: Cytoreductive peritonectomy with hyperthermic intraoperative chemotherapy (HIPEC) is an established therapy for patients with gastrointestinal, gynaecological metastasised peritoneal carcinomatosis as well as primary peritoneal carcinomatous tumours. METHODS: On the basis of a literature review and our personal experience, selection criteria for peritonectomy are discussed. RESULTS: Computed tomography (CT) scans and diagnostic laparoscopy are not sufficient for the diagnosis of peritoneal carcinomatosis. The combination of fluorodeoxyglucose positron emission tomography (FDG-PET) and CT seems to be the most reliable diagnostic imaging method. In our institution, all patients undergo PET / CT prior to peritonectomy. CONCLUSION: The PET / CT scan may play an important role in forecasting the operability of patients with peritoneal carcinomatosis.

Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial.

This prospective multicentre phase II study characterises the toxicity and activity of first-line capecitabine and oxaliplatin combination therapy (CAPOX) in advanced biliary system adenocarcinomas. Patients received oxaliplatin (130 mg m(-2), day 1) plus capecitabine (1000 mg m(-2) b.i.d., days 1-14) every 3 weeks. Patients were stratified prospectively into two groups based on location of the primary (gallbladder carcinoma (GBC) or extrahepatic cholangiocarcinoma (ECC) versus intrahepatic mass-forming type cholangiocarcinoma (ICC)). Sixty-five patients were evaluable. The response rate in 47 patients with GBC/ECC was 27% (4% complete responses), and in 23 patients (49%) stable disease (SD) was encountered. In 18 patients with ICC, we observed no objective responses, but 6 patients (33%) had SD. Median survival was 12.8 months (95% CI, 10.0-15.6) for patients with GBC or ECC (GBC: 8.2 months; 95% CI, 4.3-11.7; ECC: 16.8 months; 95% CI, 12.7-20.5), and 5.2 months (95% CI, 0.6-9.8) for ICC patients. In both cohorts, therapy was well tolerated. The most common grade 3-4 toxicity was peripheral sensory neuropathy (11 patients). Our data suggest that the CAPOX regimen is a well-tolerated and active treatment option for advanced ECC and GBC but might produce poorer results for ICC.

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX.

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53-/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.

[Demands of private gastroenterologists for collaborative treatment concepts with clinics. Results of a Germany-wide survey]. / Welche Anforderungen stellen niedergelassene Gastroenterologen an integrierte Versorgungskonzepte mit Kliniken? Ergebnisse einer deutschlandweiten Umfrage.

BACKGROUND: New demands and possibilities of collaboration between hospitals and private practices in Germany have appeared, now that the way has been opened legally. A poll was conducted to analyse the current status of collaboration between outpatient gastroenterologists and hospital surgical departments and to identify possible future collaborations. MATERIALS AND METHODS: One thousand twenty-six private practices specialising in endoscopy were found by contacting the Association of Statutory Health Insurance Physicians and additional internet research. Of these, 50% were randomly selected (513 private practices) and contacted by mail with anonymous questionnaires about cooperation with their clinical partners. Two hundred three (39.6%) practices responded, of which 200 could be analysed. RESULTS: Of all practices reached, 75% considered the cooperation with clinics very valuable or even exceptional. Still, almost half (46%) suggested necessary improvements in these collaborations. Around a third of all contacted colleagues were already involved in projects following integrated care models. In about 80% of all participants, the main interest in integrated models was specified to be common therapy planning. CONCLUSION: The data analysis of this study shows a substantial interest of private-practice gastroenterologists in close collaboration with hospitals. It is now up to the hospitals to open contracts with their medical outpatient partners.

Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO.

BACKGROUND: The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy. PATIENTS AND METHODS: Between December 2000 and October 2003, a total of 86 patients were included in both studies. Patients with completely resected gastric adenocarcinoma including a D1 or D2 lymph node dissection (LND) were eligible. Treatment consisted of two cycles of folinic acid 500 mg/m2, 5-FU 2000 mg/m2 continuous infusion over 24 h once weekly for 6 consecutive weeks, paclitaxel 175 mg/m2 in weeks 1 and 4 and cisplatin 50 mg/m2 in weeks 2 and 5 (FLPP; n=41) or two cycles of the same 5-FU/folinic acid schedule but with cisplatin 50 mg/m2 only in weeks 1, 3 and 5 (FLP; n=45). Radiation with 45 Gy plus concomitantly applied 5-FU 225 mg/m2/24 h was scheduled in between the two cycles. RESULTS: Patients characteristics were: D1/D2 LND FLP group 53%/42%; FLPP group 27%/68%; stage distribution: UICC stages III/IV(M0) FLP group 63% and FLPP group 66%. Median follow-up was 10 months (3-25) for FLP and 18 months (2-51) for FLPP patients. CTC grade 3/4 toxicities during the first cycle/chemoradiation/second cycle of FLP: granulocytopenia 3%/0/27%, anorexia 6%/10%/8%; diarrhea 8%/0/4%, nausea 3%/0/4%; FLPP: granulocytopenia 0/0/37%, anorexia 5%/11%/6%; diarrhea 5%/0/3, nausea 3%/8%/0%; early death in one patient due to Pneumocystis carinii pneumonia. Projected 2-year progression-free survival was 64% (95% CI 56% to 68%) for the FLP and 61% (95% CI 42% to 78%) for the FLPP group. CONCLUSIONS: Both chemoradiation regimens appear feasible with an acceptable toxicity profile indicating that cisplatin can be added to 5-FU/FA and that even a four-drug regimen can be investigated further in prospective clinical trials in completely resected gastric cancer patients. Treatment should be given in experienced centres in order to avoid unnecessary toxicity.

Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study.

The aim of this study was to define the maximum tolerated dose (MTD) of bolus mitomycin C (MMC) in combination with 24 h-continuous infusion of 5-flourouracil (FU) plus folinic acid, and to assess the toxicity and activity in patients with previously treated colorectal and gastric cancer. Escalating doses of MMC starting from 6 mg m(-2) in 2 mg m(-2)-steps to a maximum of 10 mg m(-2) were applied on days 1 and 22, given to fixed doses of 5-FU (2.600 mg m(-2)) as 24 h infusion and folinic acid 500 mg m(-2) prior to 5-FU weekly for 6 weeks. At least three patients were treated at each dose level. A total of 16 patients have been included in the phase I study. At the highest dose level (MMC 10 mg m(-2)), grade III thrombocytopenia, dyspnoea, mucositis and diarrhoea were observed in one patient each (17 %). In the phase II study 45 patients, 33 with colorectal cancer and 12 with gastric cancer, 23 patients after failure of first- and 22 patients after at least second-line or subsequent chemotherapy have been treated. Seven partial responses (PR) were registered (16%), one (3%; CI(95%), 0-16) in colorectal and six (50%; CI(95%), 21-79%) in gastric cancer patients. In all, 17 (38%) achieved disease stabilisation, 15 colorectal (45%, CI(95%), 28-64%) and two gastric cancer patients (17%; CI(95%), 2-48%). The median progression-free survival was 3.1 months (range, 0.9-9.1) in colorectal and 4.6 months (range, 0.7-12.4) in gastric cancer. The median overall survival time was 6.6 months (range, 1.9-15.6) in colorectal and 7.1 months (range, 1.7-20.8) in patients with gastric cancer. This regimen was considered to be safe and well tolerated for pretreated patients with gastrointestinal adenocarcinoma. In gastric cancer,MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen with promising antitumour activity.

Phase II study of weekly paclitaxel plus 24-h continuous infusion 5-fluorouracil, folinic acid and 3-weekly cisplatin for the treatment of patients with advanced gastric cancer.

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2 shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.

Activities of antioxidants are affected by colloidal properties of oil-in-water and water-in-oil emulsions and bulk oils.

The activity of alpha-tocopherol, Trolox, propyl gallate, gallic acid, methyl carnosoate, and carnosic acid was studied in two oil-in-water (o/w) emulsions, in two water-in-oil (w/o) emulsions, and in bulk oil with and without added emulsifiers. All antioxidants had either moderate or higher activity in bulk oil than in the emulsions. In most emulsions, the most polar antioxidants, propyl gallate and gallic acid, exhibited either prooxidant activity or no antioxidant activity. Methyl carnosoate was the most active antioxidant in w/o emulsions but was less active than Trolox in o/w emulsions. alpha-Tocopherol was less active in bulk oil than in emulsions, but its activity in bulk oil was markedly enhanced by the addition of o/w emulsifiers. Partitioning of antioxidants, hydrogen bonding, interphase transport, surface accessibility, and interaction of emulsifier with antioxidants are considered to be important parameters that determine antioxidant activity in lipid-containing systems.

A phase II study of paclitaxel, weekly, 24-hour continous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer.

To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35-74) were enrolled. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2 h infusion. Paclitaxel 175 mg/m2 was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m2 as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1-4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% CI: 35.8-66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1-36+) and 14 months (range 2-36+), respectively. Neutropenia WHO III(o)/IV(o) occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III(o)/IV(o) toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment.

A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors.

This study evaluates the degree of kidney damage during cisplatin/ifosfamide-based combination chemotherapy and its possible prevention by amifostine. Thirty-one patients with solid tumors stratified according to pretreatment were randomized to receive VIP- or TIP-chemotherapy with or without amifostine (910 mg/m2) given as a short infusion prior to cisplatin. Chemotherapy consisted of cisplatin (50 mg/m2), ifosfamide (4 g/m2) and either etoposide (500 mg/m2) (= VIP) or paclitaxel (175 mg/m2) (= TIP) repeated at 3 weekly intervals. For all patients the glomerular filtration rate (GFR) measured by creatinine-clearance, serum creatinine, electrolytes and differential urinary protein/enzyme excretion were determined prior to, during and after each cycle. A total of 62 cycles of chemotherapy were evaluable. In the amifostine-group GFR was fully maintained after application of two cycles of chemotherapy, whereas in the control group a > 30%-reduction of median GFR (108 to 80 ml/min) was observed (p < 0.001). Patients receiving amifostine had a lower degree of high molecular weight proteins excretion indicating less glomerular damage. In both groups significant increases of tubular marker profiles peaking at day 3 after chemotherapy were observed with a nearly complete reversibility of these changes prior to the next chemotherapy cycle. The number of patients with low magnesium serum levels during treatment was 17% after amifostine application versus 69% in control patients. The results seem to indicate that treatment with amifostine can preserve GFR after application of two cisplatin/ifosfamide-based chemotherapy cycles. This may be advantageous if repetitive cycles of chemotherapy or subsequent administration of high dose chemotherapy is planned.