Impact of sex on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC). Subgroup analysis of the PanaMa-study (AIO-KRK-0212).

BACKGROUND: Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest. METHODS: PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy. RESULTS: In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis. CONCLUSIONS: In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.

Efficacy, safety and quality-of-life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial.

INTRODUCTION: Trifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted. METHODS: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). A validated questionnaire, EORTC QLQ-C30, was employed to assess HRQoL. Secondary endpoints included OS, PFS and safety. RESULTS: Of 194 eligible patients, 185 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. On the other hand, treatment with FTD/TPI was associated with maintained HRQoL. Median OS was 6.9 months [95% confidence interval (CI) 6.1-8.2 months] and median PFS was 2.5 months (95% CI 2.1-2.9 months). The most frequent treatment-emergent adverse events were neutropenia (27.6%) and anaemia (22.7%). Febrile neutropenia occurred in 1.1%. CONCLUSIONS: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression but also with maintained HRQoL.

Anticoagulation treatment of cancer patients with deep or superficial leg vein thrombosis - a retrospective observational study of German statutory health insurance claims data (the CERTIFICAT initiative).

Background: Thrombosis is a common complication of cancer with a negative impact on quality of life and overall prognosis. Guidelines recommend low-molecular-weight heparin (LMWH) as initial and prolonged anticoagulation treatment. Little is known about current treatment patterns of these patients in ambulatory care. Patients and methods: The current retrospective observational study interrogates a large German statutory health insurance claims database in order to understand which kind of data can be extracted and analysed. An age- and sex-adjusted sample of about 4.1 million insured people from 2011 to 2016 could be used. Cancer patients with incident deep and superficial leg vein thrombosis were identified. Patients with preexisting cancer were allocated to a normal risk group; those who suffered from simultaneously diagnosed cancer and thrombosis were classified as high-risk group. Results: We identified 322,600 patients with inpatient or outpatient documented cancer diagnosis in at least two different quarters within one year. 87,755 patients were identified with an incident deep or superficial vein thrombosis. 8,201 patients suffered from both cancer and incident thrombosis. 56.9% of the patients received an anticoagulation regimen with predominant LMWH prescription, 24.2% vitamin K antagonists, 17.2% direct oral anticoagulants; in 1.7% of patients, no predominant anticoagulant drug/regime could be identified. On average, patients were prescribed anticoagulants for 4.5 months. An estimate of clinically relevant gastrointestinal bleeding could be derived (1.8% of patients). Conclusions: The dataset allows assigning detailed information of anticoagulant prescriptions in ambulatory care to well-defined groups of cancer patients. A first analysis suggests that in Germany current medical care of patients with cancer-related deep or superficial vein thrombosis does not entirely comply with guideline recommendations regarding type and duration of anticoagulation.

Modifications to a Vitis Shoot Tip Cryopreservation Procedure: Effect of Shoot Tip Size and Use of Cryoplates.

BACKGROUND: Cryopreservation has been considered a preferred method for the long-term storage of plant germplasm, especially to efficiently conserve and maintain the genetic integrity of genebank materials. Droplet-vitrification (DV) procedures have been developed to cryopreserve Vitis shoot tips from in vitro-grown plants. OBJECTIVE: This research focused on optimizing shoot tip sizes for DV and the feasibility of using cryo-plates for Vitis cryopreservation. MATERIALS AND METHODS: Uniform shoot tips were obtained from nodal sections cultured from in vitro-grown stock plants of Vitis aestivalis and Vitis jacquemontii (PI 135726). Shoot tips were precultured for 3 days on medium containing 0.3 M sucrose, salicylic acid, glutathione (reduced form), and ascorbic acid. They were cryopreserved using either DV on aluminum foil strips or by placement in calcium alginate gel in the wells of aluminium cryo-plates (V cryo-plate method). Shoot tips were then treated with loading solution followed by PVS2 treatment prior to liquid nitrogen (LN) exposure. Shoot tips were warmed in unloading solution and placed on recovery medium. The effect of extraction or non-extraction of the cryopreserved shoot tips from alginate beads was also tested. RESULTS: The highest regrowth levels of cryopreserved shoot tips were obtained using 1 mm shoot tips and a PVS2 exposure for 90 min at 0°C with the DV method on aluminum foil strips or by using 30 min of PVS2 at 22°C using V cryo-plates. CONCLUSION: Shoot tip size is an important factor in the cryopreservability of Vitis shoot tips; 1 mm shoot tips were the most successful for the DV cryopreservation method that was tested. In addition, the V cryo-plate cryopreservation technique described herein can be easily executed and results in high regrowth levels (≥70%) with quality plants obtained from cryo-exposed shoot tips, making it a practical and promising Vitis cryopreservation methodology.

FKBP51 inhibits GSK3ß and augments the effects of distinct psychotropic medications.

Psychotropic medications target glycogen synthase kinase 3ß (GSK3ß), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3ß at serine 9 (pGSK3ß(S9)). FKBP51 associates with GSK3ß mainly through its FK1 domain; furthermore, it also changes GSK3ß's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3ß on the downstream targets Tau, ß-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3ß(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3ß pathway activity and by pGSK3ß(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3ß activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3ß pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.

A New Stratified Sampling Procedure which Decreases Error Estimation of Varroa Mite Number on Sticky Boards.

A new procedure of stratified sampling is proposed in order to establish an accurate estimation of Varroa destructor populations on sticky bottom boards of the hive. It is based on the spatial sampling theory that recommends using regular grid stratification in the case of spatially structured process. The distribution of varroa mites on sticky board being observed as spatially structured, we designed a sampling scheme based on a regular grid with circles centered on each grid element. This new procedure is then compared with a former method using partially random sampling. Relative error improvements are exposed on the basis of a large sample of simulated sticky boards (n=20,000) which provides a complete range of spatial structures, from a random structure to a highly frame driven structure. The improvement of varroa mite number estimation is then measured by the percentage of counts with an error greater than a given level.

Deciphering the spatio-temporal expression and stress regulation of Fam107B, the paralog of the resilience-promoting protein DRR1 in the mouse brain.

Understanding the molecular mechanisms that promote stress resilience might open up new therapeutic avenues to prevent stress-related disorders. We recently characterized a stress and glucocorticoid-regulated gene, down-regulated in renal cell carcinoma - DRR1 (Fam107A). DRR1 is expressed in the mouse brain; it is up-regulated by stress and glucocorticoids and modulates neuronal actin dynamics. In the adult mouse, DRR1 was shown to facilitate specific behaviors which might be protective against some of the deleterious consequences of stress exposure: in the hippocampal CA3 region, DRR1 improved cognitive performance whereas in the septum, it specifically increased social behavior. Therefore DRR1 was suggested as a candidate protein promoting stress-resilience. Fam107B (family with sequence similarity 107, member B) is the unique paralog of DRR1, and both share high sequence similarities, predicted glucocorticoid response elements, heat-shock induction and tumor suppressor properties. So far, the role of Fam107B in the central nervous system was not studied. The aim of the present investigation, therefore, was to analyze whether Fam107B and DRR1 display comparable mRNA expression patterns in the brain and whether both are modulated by stress and glucocorticoids. Spatio-temporal mapping of Fam107B mRNA expression in the embryonic and adult mouse brain, by means of in situ hybridization, showed that Fam107B was expressed during embryogenesis and in the adulthood, with particularly high and specific expression in the forming telencephalon suggestive of an involvement in corticogenesis. In the adult mouse, expression was restricted to neurogenic niches, like the dentate gyrus. In contrast to DRR1, Fam107B mRNA expression failed to be modulated by glucocorticoids and social stress in the adult mouse. In summary, Fam107B and DRR1 show different spatio-temporal expression patterns in the central nervous system, suggesting at least partially different functional roles in the brain, and where the glucocorticoid receptor (GR)-induced regulation appears to be a unique property of DRR1.

MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma.

With ∼30 000 deaths annually in the United States, prostate cancer (PCa) is a major oncologic disease. Here we show that the microRNAs miR-130a, miR-203 and miR-205 jointly interfere with the two major oncogenic pathways in prostate carcinoma and are downregulated in cancer tissue. Using transcriptomics we show that the microRNAs repress several gene products known to be overexpressed in this cancer. Argonaute 2 (AGO2) co-immunoprecipitation, reporter assays and western blot analysis demonstrate that the microRNAs directly target several components of the mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signaling pathways, among those several AR coregulators and HRAS (Harvey rat sarcoma viral oncogene homolog), and repress signaling activity. Both pathways are central for the development of the primary tumor and in particular the progression to its incurable castration-resistant form. Reconstitution of the microRNAs in LNCaP PCa cells induce morphological changes, which resemble the effect of androgen deprivation, and jointly impair tumor cell growth by induction of apoptosis and cell cycle arrest. We therefore propose that these microRNAs jointly act as tumor suppressors in prostate carcinoma and might interfere with progression to castration resistance.

Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO){dagger}.

BACKGROUND: This prospective multicentre phase II trial assessed the feasibility and efficacy of perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in patients with gastro-oesophageal adenocarcinoma. METHODS: Patients with curatively resectable adenocarcinoma of the stomach, the gastro-oesophageal junction or the lower third of the oesophagus were enrolled. Patients received docetaxel 75 mg/m(2) plus cisplatin 60 mg/m(2) (day 1), followed by oral capecitabine 1875 mg/m(2) divided into two doses (days 1-14) every 3 weeks. There were three cycles preoperatively and three cycles postoperatively. The primary end point was the R0 resection rate. RESULTS: Fifty-one patients were recruited and assessed for feasibility and efficacy. 94.1% of patients received all three planned cycles preoperatively, and 52.9% received three cycles postoperatively. The R0 resection rate was 90.2%. 13.7% of patients showed complete pathological remission (pCR). Toxicity was acceptably tolerable. Without prophylactic granulocyte colony-stimulating factor administration, neutropenic fever developed in 21.5% of patients preoperatively (grade 3 or 4) and in 11.1% of patients postoperatively. CONCLUSIONS: DCX is a safe and feasible perioperative regimen in the treatment of gastro-oesophageal adenocarcinoma with a high percentage of cycles delivered pre- and postoperatively, compared with standard practice. The high efficacy in terms of R0 resection rate and pCR is very promising.

Docetaxel and capecitabine for advanced gastric cancer: investigating dose-dependent efficacy in two patient cohorts.

BACKGROUND: No comparisons of different doses of docetaxel-capecitabine in patients with advanced gastric cancer have been performed. METHODS: Patients with previously untreated metastatic/locally advanced gastro-oesophageal or gastric adenocarcinoma were enrolled in a prospective multicentre phase II trial. Two sequential cohorts received docetaxel 75 mg m(-2) (day 1) plus capecitabine 1000 mg m(-2) twice daily (days 1-14) (cohort I) or docetaxel 60 mg m(-2) (day 1) plus capecitabine 800 mg m(-2) twice daily (days 1-14) (cohort II) every 3 weeks. The primary end point was confirmed overall response rate. RESULTS: In all, 91 patients were enrolled (cohort I, n=40; cohort II, n=51) and 87 were evaluable for efficacy (n=38, 49, respectively). Overall response rate was 50.0% in cohort I and 23.5% in cohort II (exploratory analysis, P=0.014). Median times to tumour progression and overall survival were 5.6 and 10.1 months in cohort I and 3.7 and 7.2 months in cohort II, respectively. Dose reductions for docetaxel and capecitabine were required in 50.0% and 57.5% of patients in cohort I and 11.8% and 15.7% in cohort II, respectively. CONCLUSION: Starting treatment with full doses and reducing promptly seems to be the more promisingly effective strategy than starting cautiously with lower doses. Docetaxel/capecitabine 75/2000 mg m(-2) is a manageable, convenient outpatient combination with promising efficacy against advanced gastric cancer.

Protective proteins are differentially expressed in tomato genotypes differing for their tolerance to low-temperature storage.

When stored at low temperature, tomato fruits exhibit chilling injury symptoms, such as rubbery texture and irregular ripening. To identify proteins related to chilling tolerance, we compared two tomato near isogenic lines differing for their texture phenotype at harvest in a fruit-storage trial including two temperatures (4 and 20 degrees C) along several days of conservation. Fruit evolution was followed by assessing fruit color, ethylene emission and texture parameters. The most contrasted samples were submitted to proteomic analysis including two-dimensional electrophoresis and mass spectrometry of protein spots to identify the proteins, whose expression varied according to the genotype or the storage conditions. Unexpectedly, the most firm genotype at harvest was the most sensitive to cold storage. The other genotype exhibited a delay in fruit firmness loss leading to the texture differences observed after 20 days of 4 degrees C storage. The proteome analysis of these contrasted fruits identified 85 proteins whose quantities varied with temperature or genotype. As expected, cold storage decreased the expression of proteins related to maturation process, such as acidic invertase, possibly controlled post-translational regulation of polygalacturonase and up-regulated proteins related to freezing tolerance. However, the study point out proteins involved in the differential resistance to chilling conditions of the two lines. This includes specific isoforms among the large family of small heat shocked proteins, and a set of proteins involved in the defense against of the reticulum endoplasmic stress.

Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells.

Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study.

BACKGROUND: Bevacizumab significantly improves survival when added to chemotherapy for metastatic colorectal cancer (mCRC). The Bevacizumab Expanded Access Trial (BEAT) evaluated the safety and efficacy of bevacizumab plus first-line chemotherapy in a general cohort of patients with mCRC. PATIENTS AND METHODS: Patients with unresectable mCRC received chemotherapy (physician's choice) plus bevacizumab [5 mg/kg every 2 weeks (5-fluorouracil regimens) or 7.5 mg/kg every 3 weeks (capecitabine regimens)]. The primary end point was safety, including prospective data collection in patients receiving unanticipated surgery during the study. Secondary objectives were progression-free survival (PFS) and overall survival (OS). RESULTS: The final analysis comprised 1914 assessable patients (male 58%; median age 59 years). Chemotherapy included 5-fluorouracil/leucovorin (5-FU/LV) + oxaliplatin (29%), irinotecan plus 5-FU/LV (26%), capecitabine plus oxaliplatin (18%) and monotherapy (16%). Serious/grade 3-5 adverse events of interest for bevacizumab included bleeding (3%), gastrointestinal perforation (2%), arterial thromboembolism (1%), hypertension (5.3%), proteinuria (1%) and wound-healing complications (1%). Sixty-day mortality was 3%. Median PFS was 10.8 months [95% confidence interval (CI) 10.4-11.3 months] and median OS reached 22.7 months (95% CI 21.7-23.8 months). CONCLUSIONS: The BEAT study shows that the efficacy and safety profile of bevacizumab in routine clinical practice is consistent with results observed in prospective randomised clinical trials and another large observational study in the United States (BRiTE study).

Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial.

Platinum/taxane combinations are widely used in patients with carcinoma of unknown primary (CUP), yielding response rates of 30% and median overall survival of 9-11 months in selected patients. Yet these combinations have not been subject to a randomised trial to overcome selection bias, a major problem in CUP. We randomised 92 patients to either paclitaxel/carboplatin (arm A) or the non-platinum non-taxane regimen gemcitabine/vinorelbine (arm B). The primary endpoint was rate of practicability as defined: application of >or=2 cycles of therapy (1) with a maximal delay of 1 week (2) and survival of >or=8 months (3). Practicability was shown in 52.4% (95% CI 36-68%) in arm A and in 42.2% (95% CI 28-58%) in arm B, respectively. The median overall survival, 1-year survival -rate and response rate of patients treated in arm A was 11.0 months, 38, and 23.8%, arm B 7.0 months, 29, and 20%. In conclusion, the paclitaxel/carboplatin regimen showed clinically meaningful activity in this randomised trial (Clinical trial registration number 219, 'Deutsches KrebsStudienRegister', German Cancer Society.)

[Influence of prism overcorrection on residual postoperative strabismus]. / Einfluss der Prismenüberkorrektur auf den postoperativen Restschielwinkel.

BACKGROUND: Prism overcorrection is a complementary procedure to reduce the residual postoperative esotropia caused by anomalous retinal correspondence (ARC) after surgery for esotropia. We have investigated the results of this treatment. PATIENTS AND METHODS: For Group 1, the files of 63 patients treated with postoperative prism overcorrection in the Department of Ophthalmology, University of Giessen, were evaluated regarding the pre-and postoperative squint angles (SPCT, simultaneous and APCT, alternate prism and cover test) and the angle of ARC, determined by the red filter test and by the increase of esotropia after neutralisation of the squint angle (APCT). Postoperatively, squint angles had been measured immediately (APCT) after removal of the eye patch and 10 minutes to 2 hours later (SPCT and APCT). Subsequently, prism overcorrection was performed with a Fresnel prism foil (40 PD basis temporally) in front of the fellow eye for a maximum of 3 months. After 3 months, SPCT and APCT were performed. For Group 2, the files of 28 patients with a preoperative angle of ARC of 5 degrees or more, treated in the Department of Ophthalmology, University of Heidelberg, were evaluated. These patients had not been treated with prism overcorrection. The squint angles had been measured (SPCT and APCT) on the preoperative day, on the first postoperative day, a few hours after removing the eye patch, and after three months. RESULTS: For Group 1, at surgery, the patients were 4 to 12 years old (median: 6.2 years). The preoperative squint angle ranged from + 5 degrees to + 27 degrees (median: + 12 degrees) in the SPCT and from + 7 degrees to + 27 degrees (median: + 14 degrees) in the APCT. The angle of ARC was between + 4 degrees and + 15 degrees (median: + 7 degrees). Both combined recess and resect surgery (with or without additional oblique muscle surgery) or bilateral retroequatorial medial rectus myopexy, in part depending on the squint angle pattern with medial rectus recession, were performed. Immediately after removing the patch, the squint angle (APCT) was between - 10 degrees and + 5 degrees (median: + 1 degrees). Ten minutes to 2 hours later, the manifest squint angle ranged from 0 to + 12 degrees (median: + 7 degrees). The angle had decreased significantly to - 6 to + 12 degrees (median: + 5 degrees) after 3 months. For Group 2, the patients' ages were between 5 and 12 years (median: 6.5 years). The squint angles ranged from + 11.5 degrees to + 35 degrees (median: + 20 degrees) in the SPCT and APCT. The angle of ARC was between + 5 degrees and + 17 degrees (median: + 8 degrees). Combined recess and resect surgery or bilateral recession of the medial rectus (with or without oblique muscle surgery both) were performed. The SPCT several hours after removal of the patch showed angles of - 4 degrees to + 14 degrees (median: + 4.25 degrees). Three months later the manifest squint angles ranged from - 5 degrees to + 14 degrees (median: + 3 degrees). DISCUSSION: After prism overcorrection (Group 1), there was a significant reduction of the residual esotropia. Without this additional treatment (Group 2), there was no significant change in the postoperative squint angle. However, neither the positive outcome in Group 1 nor the difference to Group 2 do unequivocally prove that there is a beneficial effect of prism overcorrection, since preoperative conditions were different and the sample size in Group 2 was small, especially after matching for equal preoperative conditions. A spontaneous reduction of the postoperative esotropia cannot be excluded. Further studies are necessary in order to investigate the specific effect of prism overcorrection.

[Efficacy of current adjuvant and neoadjuvant therapeutic concepts in gastric cancer?]. / Welchen Stellenwert hat die neoadjuvante und die adjuvante Therapie im Behandlungskonzept des Magenkarzinoms?

The incidence of gastric cancer in Europe is declining but the prognosis after curatively intended surgery remains dismal. In recent years several studies and meta-analysis concerning the impact of adjuvant postoperative chemotherapy and chemoradiation as well as preoperative chemotherapy were published. This review aims to interpret results and to support decision making in individual patients. Results of trials on adjuvant chemotherapy were inconsistent and the studies were underpowered to detect meaningful but modest advantages. Meta-analyses including more than 3 000 patients revealed a significant survival benefit but no specific chemotherapy protocol can be regarded an optimal regimen. Postoperative adjuvant schedules including cisplatin led to high drop out rates due to toxicity. Applying cisplatin and infusional fluorouracil initially after diagnosis as a so called neoadjuvant therapy is better tolerated. Two trials testing this approach showed a significant survival benefit with preoperative cisplatin and infusional fluorouracil as compared to surgery alone. Postoperative chemoradiation was shown to be effective concerning local regional relapses and survival benefit in a large trial in the US but the majority of patients were treated with less radical lymph node dissection than it is routine in Germany. Enrollment of patients in prospective trials evaluating the impact of adjuvant and neoadjuvant strategies is warranted.

Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial.

BACKGROUND: Cancer patients receiving chemotherapy experience thromboembolic complications associated with the use of long-term indwelling central venous catheters (CVCs). This prospective, double-blind, placebo-controlled, multicenter study evaluated whether prophylactic treatment with a low molecular weight heparin could prevent clinically relevant catheter-related thrombosis. PATIENTS AND METHODS: Patients with cancer undergoing chemotherapy for at least 12 weeks (n=439) were randomly assigned, in a 2:1 ratio, to receive either dalteparin (5000 IU) or placebo, by subcutaneous injection, once daily for 16 weeks. Patients underwent upper extremity evaluation with either venography or ultrasound at the time of a suspected catheter-related complication (CRC) or upon completion of study medication. The primary end point, as determined by a blinded adjudication committee, was the occurrence of a CRC, defined as the first occurrence of any one of the following: clinically relevant catheter-related thrombosis that was symptomatic or that required anticoagulant or fibrinolytic therapy; catheter-related clinically relevant pulmonary embolism; or catheter obstruction requiring catheter removal. RESULTS: There was no significant difference in the frequency of CRCs between the dalteparin arm (3.7%) and the placebo arm (3.4%; P=0.88), corresponding to a relative risk of 1.0883 (95% confidence interval 0.37-3.19). No difference in the time to CRC was observed between the two arms (P=0.83). There was no significant difference between the dalteparin and placebo groups in terms of major bleeding (1 versus 0) or overall safety. CONCLUSIONS: Dalteparin prophylaxis did not reduce the frequency of thromboembolic complications after CVC implantation in cancer patients. Dalteparin was demonstrated to be safe over 16 weeks of treatment in these patients.

Chemotherapy in alveolar soft part sarcomas. What do we know?

Alveolar soft part sarcoma (ASPS) is a rare tumour. Published series about treatment and outcome are scarce. Conclusive data about the response to chemotherapy are not available. The aim of this study was to analyse the efficacy of palliative chemotherapeutic treatment options and the incidence and mode of presentation of brain metastases. We retrospectively analysed our own sarcoma data-base and reviewed the literature. From our registry containing 757 patients, we identified 8 patients with ASPS. From the literature, 47 cases of adult patients and 13 children with sufficient data about chemotherapy were identified. Response to first-line chemotherapy in 68 patients was: complete remission (CR) 4%, partial remission (PR) 3%, stable disease (SD) 41%, progressive disease (PD) 51%. 285 patients with stage IV disease were evaluable for the analysis of metastatic sites. The incidence of brain metastases was 30.5% (87/285). Brain metastases were detected at a median interval of 48 months (range 0-396 months) after the primary diagnosis. Median survival after the diagnosis of brain metastases was 12 months. The median survival for patients with stage IV disease treated by chemotherapy was 36+ months (range 10-132 months) (31 patients evaluable) with a median follow-up of 46 months (range 10-135 months). ASPS shows a high incidence of brain metastases, at least 3 times higher than that of other soft tissue sarcomas. Chemotherapeutic regimens used for the treatment of other soft tissue sarcomas lack efficacy in ASPS. Staging investigations for ASPS should routinely include imaging of the brain. ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. New targets for specific biologically-directed therapies need to be developed.