Current unmet needs in locally advanced (unresectable) or metastatic dedifferentiated liposarcoma, the relevance of progression-free survival as clinical endpoint, and expectations for future clinical trial design: an international Delphi consensus report.

BACKGROUND: Locally advanced (unresectable) or metastatic dedifferentiated liposarcoma (DDLPS) is a common presentation of liposarcoma. Despite established diagnostic and treatment guidelines for DDLPS, critical clinical gaps remain driven by diagnostic challenges, symptom burden and the lack of targeted, safe and effective treatments. The objective of this study was to gather expert opinions from Europe and the United States on the management, unmet needs and expectations for clinical trial design as well as the value of progression-free survival (PFS) in this disease. Other aims included raising awareness and educate key stakeholders across healthcare systems. MATERIALS AND METHODS: An international panel of 12 sarcoma key opinion leaders (KOLs) was recruited. The study consisted of two rounds of surveys with pre-defined statements. Experts scored each statement on a 9-point Likert scale. Consensus agreement was defined as ≥75% of experts scoring a statement with ≥7. Revised statements were discussed in a consensus meeting. RESULTS: Consensus was reached on 43 of 55 pre-defined statements across disease burden, treatment paradigm, unmet needs, value of PFS and its association with overall survival (OS), and cross-over trial design. Twelve statements were deprioritised or merged with other statements. There were no statements where experts disagreed. CONCLUSION: This study constitutes the first international Delphi panel on DDLPS. It aimed to explore KOL perception of the disease burden and unmet need in DDLPS, the value of PFS, and its potential translation to OS benefit, as well as the relevance of a cross-over trial design for DDLPS therapies. Results indicate an alignment across Europe and the United States regarding DDLPS management, unmet needs, and expectations for clinical trials. Raising awareness of critical clinical gaps in relation to DDLPS can contribute to improving patient outcomes and supporting the development of innovative treatments.

Sheared edible oils studied using dissipative particle dynamics and ultra small angle X-ray scattering: TAGwood orientation aggregation and disaggregation.

Previous work on the computer simulation of edible fats and oils showed that triglyceride crystalline nanoplatelets (CNPs) aggregated into cylindrical structures dubbed "TAGwoods". This was experimentally verified using Ultra Small Angle X-ray Scattering experiments. In this paper, the aggregation of these TAGwoods was studied using the fluid simulation technique, Dissipative Particle Dynamics. The intent was to predict the TAGwood aggregation structures which arise via the application of a series of shear rates, [small gamma, Greek, dot above]. The effect of shear on TAGwood orientational order was also investigated. Three aggregation regimes were identified: At shear rates below a certain critical value, 0 < [small gamma, Greek, dot above] < [small gamma, Greek, dot above]t aggregation was enhanced. The value of the critical shear rate depended on the size of the CNPs. With large CNPs possessing a side length of ∼500 nm, the critical shear rate was [small gamma, Greek, dot above]t ≈ 0.6 s-1. However, if the CNPs were smaller with a side length of ∼100 nm, then [small gamma, Greek, dot above]t ≈ 75 s-1. For shear rates above the critical shear rate, [small gamma, Greek, dot above] > [small gamma, Greek, dot above]t aggregation was inhibited. The USAXS data was analyzed using the Unified Fit model and the observations were in accord with the simulation results. Three regimes were identified based on the values of the linear slope P2 of the USAXS data. P2 increased as [small gamma, Greek, dot above] increased, indicating increased aggregation of the TAGwoods as the shear rate was increased. P2 ceased increasing and began to decrease when [small gamma, Greek, dot above] ≈ [small gamma, Greek, dot above]t. With further increases in [small gamma, Greek, dot above], P2 decreased as [small gamma, Greek, dot above] increased further, which is indicative of a decrease in aggregation. The orientational quadrupole order parameter, S = 〈Q33〉 = 1/2〈cos2θ - 1〉, was computed, where θ is the angle between the axis of the TAGwood and the axis of flow, and showed that, for large [small gamma, Greek, dot above], it achieved a near-maximum value. This indicates that at high shear rates, the long axis of the cylindrical TAGwoods aligns in a direction parallel to that of the fluid flow.

Prognostic relevance of the mitotic count and the amount of viable tumour after neoadjuvant chemotherapy for primary, localised, high-grade soft tissue sarcoma.

BACKGROUND: We sought to examine whether mitotic count (MC) and the amount of viable tumour (VT) following neoadjuvant systemic chemotherapy (SC) for primary, localised, high-grade soft tissue sarcoma (STS) correlate with prognosis. METHODS: Retrospective analysis of 57 patients who underwent SC involving a combination of an anthracycline and an alkylating agent, followed by surgical resection between 2001 and 2011. RESULTS: The amount of VT after chemotherapy was significantly associated with disease-specific survival (DSS) and event-free survival (EFS). Patients with <10% VT had a DSS of 94% at 5 years, compared with 61% for patients with ⩾10% VT (P=0.033); EFS was 75%, compared with 48% (P=0.030). Patients with an MC of ⩾20/10 high power fields (HPF) after chemotherapy had a significantly lower DSS (33% vs 84% at 5 years, P<0.001) and EFS (40% vs 63% at 5 years, P=0.019) than patients with an MC of <20/10 HPF. CONCLUSIONS: The MC and the amount of VT after neoadjuvant therapy for primary, localised, high-grade STS appear to correlate with prognosis. If these results are validated prospectively, then they could provide a rational for the design of neoadjuvant treatment modification/escalation studies, analogue to the EURAMOS-1 trial for bone sarcomas.

Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors.

BACKGROUND: Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST. METHODS: Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels. RESULTS: Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6). CONCLUSION: Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

Interactions of protamine with the marine bacterium, Pseudoalteromonas sp. NCIMB 2021.

UNLABELLED: Pseudoalteromonas sp. NCIMB 2021 (NCIMB 2021) was grown in synthetic seawater (SSW) containing pyruvate, in the presence (SSW(++) ) and absence (SSW(-) ) of divalent cations. Cultures contained single cells. Addition of the cationic antibacterial peptide (CAP), protamine, did not inhibit, but rather increased, the growth of NCIMB 2021 in SSW(++) and caused the bacteria to grow in chains. Bacterial growth was assessed using turbidity, cell counts and the sodium salt of resazurin. In SSW(-) , NCIMB 2021 was no longer resistant to protamine. The minimum inhibitory concentration (MIC) was 5 mg ml(-1) . SIGNIFICANCE AND IMPACT OF THE STUDY: Protamine is a cationic antimicrobial peptide (CAP), which is active against a variety of bacteria. This is the first in-depth study of the interaction of protamine with a marine bacterium, Pseudoalteromonas sp. NCIMB 2021. Our results show that protamine is only active in seawater in the absence of divalent cations. In the presence of the divalent cations, Mg(2+) and Ca(2+) , protamine enhances the growth of Pseudoalteromonas sp. NCIMB 2021 and produces chains rather than individual cells. These are important considerations when deciding on applications for protamine and in terms of understanding its mechanism of action.

Differentiation of myxoid liposarcoma by magnetic resonance imaging: a histopathologic correlation.

BACKGROUND: Myxoid liposarcomas represent a heterogeneous group of soft tissue tumors in which prognosis is dependent on differentiation. PURPOSE: To identify magnetic resonance imaging (MRI) criteria to distinguish low-grade from high-grade myxoid liposarcomas. MATERIAL AND METHODS: MR images of 30 histologically proven myxoid liposarcomas were retrospectively reviewed. Tumors were evaluated according to size, localization, tumor border, and structure as well as tumor composition. These imaging criteria were correlated with histopathological findings. RESULTS: Nineteen myxoid liposarcomas were histologically classified as low-grade myxoid liposarcomas, whereas 11 were considered high-grade myxoid liposarcomas. Mean tumor volume of low-grade myxoid liposarcomas (710.1 ± 960.1 ccm) was significantly smaller as compared to high-grade myxoid liposarcomas (2737.0 ± 3423.7 ccm; P = 0.04). In addition to necrotic areas, three tumor components - fatty, myxoid, as well as contrast-enhancing non-fatty, non-myxoid - could be identified. The mean fraction of fatty tumor areas in low-grade myxoid liposarcomas was 10 ± 11% as compared to 6 ± 4% for high-grade myxoid liposarcomas (P = 0.66). Myxoid components accounted for 88 ± 16% in low-grade myxoid liposarcomas, but only for 45 ± 25% in high-grade myxoid liposarcomas (P < 0.0001). The non-fatty, non-myxoid tumor fraction was significantly higher in high-grade myxoid liposarcomas (50 ± 25%) as compared to low-grade myxoid liposarcomas (2 ± 9%; P < 0.0001). A proportion of > 5% of this tumor fraction was found to be a precise unique predictor for high-grade myxoid liposarcomas with a sensitivity of 100% and a specificity of 95%. CONCLUSION: Tumor components with contrast-enhancing non-fatty, non-myxoid imaging features were predominantly found in high-grade myxoid liposarcomas, which may histologically resemble round cell clusters.

Sentinel node biopsy in soft tissue sarcoma subtypes with a high propensity for regional lymphatic spread--results of a large prospective trial.

BACKGROUND: The role of sentinel lymph node biopsy (SLNB) in soft tissue sarcoma patients has yet to be determined. We sought to evaluate the role of SLNB in the treatment of patients with clear cell sarcoma (CCS), synovial sarcoma (SS), epithelioid sarcoma (ES) and rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Sixty-two consecutive patients without history of regional lymphatic spread or evidence of distant metastases underwent SLNB. RESULTS: Positive sentinel nodes were identified in 2 out of 42 patients with SS and in 6 out of 12 patients with CCS. Only two CCS patients had further metastatic nodes in regional dissection. Both of these patients, along with another CCS patient, developed distant metastases and ultimately died of disease. The remaining three CCS patients are disease-free in follow-up. One patient with SS and another with ES developed regional lymph node metastases following a negative SLNB, while a further patient with RMS developed distant metastases followed by a local recurrence with regional metastases shortly after. CONCLUSIONS: SLNB is an important diagnostic tool for patients with CCS, who appear to have a high rate of clinically occult regional lymph node metastases at diagnosis. For SS patients, SLNB appears to be of very little relevance.

Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of sorafenib, starting dose 400mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0-2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too. RESULTS: Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p=0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6-8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0-21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS. CONCLUSION: We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.

Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib.

BACKGROUND: Controversies exist about computed tomography (CT) response evaluation criteria for patients with gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Fifty-one patients with advanced GIST treated second line with sunitinib were evaluated with contrast-enhanced CT every 3 months. Response was rated according to RECIST and Choi criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis. RESULTS: According to RECIST, patients were categorized as complete response (CR; n = 0; 0%), partial remission (PR; n = 1; 2.0%), stable disease (SD; n = 37; 72.5%), and progressive disease (PD; n = 13; 25.5%) at 3 months. When Choi criteria were applied responses were CR (n = 0; 0%), PR (n = 16; 31.4%), SD (n = 21; 41.1%), and PD (n = 14; 27.5%). Despite these discrepancies, patients rated as SD with RECIST and PR as well as SD according to Choi criteria displayed similar PFS (41.3, 40.7, and 41.3 weeks, respectively) and OS (100.4, 91.6, and 108.0 weeks, respectively). Patients with PD had significantly shorter PFS (10.1 weeks for both criteria) and OS (29.1 weeks for RECIST; 28.9 weeks for Choi) regardless of the response classification applied. CONCLUSION: In contrast to absence of progression, discrimination of PR from SD with Choi criteria was of no predictive value.

[Systemic therapy of soft tissue sarcomas]. / Systemische Therapie von Weichgewebssarkomen.

The gold standard for the treatment of primary, resectable, high-grade soft tissue sarcomas is complete surgical removal followed by radiotherapy. In cases where preservation of function is not possible, preoperative treatment options should be considered. Systemic therapy is the treatment of choice for metastatic soft tissue sarcomas. The most active single agents include the anthracyclines doxorubicin and epirubicin, as well as ifosfamide. While combination chemotherapy yields higher response rates, this is at the cost of increased toxicity with no evidence of prolonged overall survival. Current treatment strategies focus on the development of specific treatments for well defined soft tissue sarcoma subtypes. The first and highly successful targeted therapy was seen with the introduction of imatinib in the treatment of gastrointestinal stromal tumors.

Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour.

BACKGROUND: This study assessed the outcomes of patients with a gastrointestinal stromal tumour (GIST) that ruptured before or during resection. METHODS: The records of 23 patients (8 women, 15 men; median age 54 years) with ruptured primary non-metastatic GIST were retrieved from a database of 554 patients. The written surgical and pathology reports were analysed. Review pathology was performed in all 23 cases, and mutational analysis of KIT and platelet-derived growth factor α (PDGFRA) genes was performed in 21 patients. Median follow-up was 52 months. RESULTS: Tumour rupture was spontaneous in 16 patients, following abdominal trauma in two and occurred during resection in five. Primary tumour location was the stomach in six patients, duodenum in one and small bowel in 16. Mean tumour size was 10·2 (range 4-28) cm. According to the Miettinen and Lasota risk classification, the distribution of very low-, low-, intermediate- and high-risk cases was one, two, five and 15 respectively. One patient remained disease-free at 83 months. Fifteen of 16 patients who did not receive adjuvant therapy developed tumour recurrence after a median of 19 months. Median recurrence-free survival in patients with KIT mutations involving codons 557-558 was 11 months. CONCLUSION: Patients with a rupture of GIST into the abdominal cavity have a risk of recurrence of nearly 100 per cent. In patients with deletion mutations involving codons 557-558, recurrence-free survival was less than 1 year. All patient groups are clear candidates for adjuvant drug therapy.

Quantification of local water and biomass in wild type PA01 biofilms by Confocal Raman Microspectroscopy.

Confocal Raman Microspectroscopy (CRM) can be used as a tool for the in situ evaluation of the chemical composition of living, fully submerged, unstained biofilms. In this study the estimation of the local water content in Pseudomonas aeruginosa PA01 biofilms is given as an example. The ratio of the area of the O-H stretching vibration band at 3450 cm(-1), (water), to that of the C-H stretching bands at 2950 cm(-1) (biomass), was used to estimate the relative biofilm water content. The quantification of biofilm water and biomass was based on calibration curves generated from protein solutions. Water/biomass ratios (W:BR) equivalent to that of a 30% (w/v) protein solution were observed within some biofilm colonies.

Phyllosphere microbiology with special reference to diversity and plant genotype.

The phyllosphere represents the habitat provided by the aboveground parts of plants, and on a global scale supports a large and complex microbial community. Microbial interactions in the phyllosphere can affect the fitness of plants in natural communities, the productivity of agricultural crops, and the safety of horticultural produce for human consumption. The structure of phyllosphere communities reflects immigration, survival and growth of microbial colonists, which is influenced by numerous environmental factors in addition to leaf physico-chemical properties. The recent use of culture-independent techniques has demonstrated considerable previously unrecognized diversity in phyllosphere bacterial communities. Furthermore, there is significant recent evidence that plant genotype can play a major role in determining the structure of phyllosphere microbial communities. The main aims of this review are: (i) to discuss the diversity of phyllosphere microbial populations; (ii) to consider the processes by which microbes colonize the phyllosphere; (iii) to address the leaf characteristics and environmental factors that determine the survival and growth of colonists; (iv) to discuss microbial adaptations that allow establishment in the phyllosphere habitat and (v) to evaluate evidence for plant genotypic control of phyllosphere communities. Finally, we suggest approaches and priority areas for future research on phyllosphere microbiology.

Confocal Raman microspectroscopy as a tool for studying the chemical heterogeneities of biofilms in situ.

AIMS: To investigate the use of confocal Raman microspectroscopy (CRM) for the analysis of the structure, composition and development of fully hydrated biofilms. METHODS AND RESULTS: Pseudomonas aeruginosa PAO1 biofilms were cultured in a flow cell in minimal nutrient medium (artificial sea water) and their development was followed for up to 3 weeks. The spectroscopic signature of the biofilm cells and extracellular polymeric substances (EPS) were differentiated and their distribution in biofilm colonies and within water channels was mapped in-plane and -depth. The colonies were initially amorphous, mainly composed of cells with no detectable amount of EPS. They developed rapidly to give round colonies composed of a cellular core enclosed in a sheath of EPS. The EPS continued to increase and spread throughout the biofilm to become the dominating feature of aged colonies. Colonies with a liquid core morphology - characteristic of the seeding dispersal process - were also observed. CONCLUSIONS: This study demonstrated that CRM can be used to monitor the distribution of biofilm components in fully hydrated undisturbed biofilms over time. SIGNIFICANCE AND IMPACT OF THE STUDY: Confocal Raman microspectroscopy facilitates the analysis of hydrated, live bacterial biofilms as a function of space and time, thus making it a suitable technique for investigating the effects of various additives and environmental factors on biofilm growth.

Exatecan in pretreated adult patients with advanced soft tissue sarcoma: results of a phase II--study of the EORTC Soft Tissue and Bone Sarcoma Group.

No standard treatment is established for patients with advanced soft tissue sarcoma after previous chemotherapy with anthracyclines and ifosfamide, given either in combination or sequentially. Exatecan (DX-8951f) is a totally synthetic analogue of the topoisomerase I-inhibitor camptothecin, which was synthesised to impart increased aqueous solubility, greater tumour efficacy, and less toxicity than camptothecin itself, topotecan or irinotecan. Since some activity against soft tissue sarcomas, especially leiomyosarcomas, has been reported for topoisomerase I-inhibitors, a study with a new and more potent agent seemed justified. We report on a prospective multicentre phase II study of Exatecan in adult soft tissue sarcomas failing 1 or 2 lines of chemotherapy in advanced phase, performed within the STBSG of EORTC. Thirty-nine patients (16 leiomyosarcomas and 23 other histologies) were included in two independent strata and received a total of 141 cycles (median 2). Median age was 61 years, range 25-76. Exatecan was given as i.v. infusion over 30 min at a dose of 0.5mg/m2 every day for five consecutive days, repeated every 21 days. Seventy-four percentage of cycles could be given without dose or schedule modification. The main toxicity was haematotoxicity with grade 3/4 neutropenia in 49%, grade 3/4 thrombocytopenia in 23%, and grade 3/4 anaemia in 15% of patients, respectively. Non-haematological toxicity consisted mainly of grade 2/3 dyspnoea in 36% of patients and grade 2/3 fatigue in 28%. One treatment-related toxic death due to septic shock was reported. Best overall response was no change with 60% in the leiomyosarcoma group and 53% in the non-leiomysarcoma group, respectively. The 3 months progression-free survival estimates are 56% for leiomysarcomas and 26% for other histologies, respectively. Using a two-step statistical design, the trial was stopped after the first step in both strata, due to lack of activity. In pretreated soft tissue sarcoma patients, Exatecan is well tolerated but does not achieve any objective responses. However, with respect to progression-free survival, Exatecan did show some activity in leiomyosarcomas.

Identification of quantitative trait loci for resistance to Xanthomonas campestris pv. campestris in Brassica rapa.

Resistance to six known races of black rot in crucifers caused by Xanthomonas campestris pv. campestris (Pammel) Dowson is absent or very rare in Brassica oleracea (C genome). However, race specific and broad-spectrum resistance (to type strains of all six races) does appear to occur frequently in other brassica genomes including B. rapa (A genome). Here, we report the genetics of broad spectrum resistance in the B. rapa Chinese cabbage accession B162, using QTL analysis of resistance to races 1 and 4 of the pathogen. A B. rapa linkage map comprising ten linkage groups (A01-A10) with a total map distance of 664 cM was produced, based on 223 AFLP bands and 23 microsatellites from a F(2) population of 114 plants derived from a cross between the B. rapa susceptible inbred line R-o-18 and B162. Interaction phenotypes of 125 F(2) plants were assessed using two criteria: the percentage of inoculation sites in which symptoms developed, and the severity of symptoms per plant. Resistance to both races was correlated and a cluster of highly significant QTL that explained 24-64% of the phenotypic variance was located on A06. Two additional QTLs for resistance to race 4 were found on A02 and A09. Markers closely linked to these QTL could assist in the transference of the resistance into different B. rapa cultivars or into B. oleracea.

Phase 1 European Organisation for Research and Treatment of Cancer study determining safety of pegylated liposomal doxorubicin (Caelyx) in combination with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue sarcomas.

This phase I study evaluated the toxicity of first-line combined pegylated liposomal doxorubicin (Caelyx) and ifosfamide in patients with advanced and/or metastatic soft tissue sarcomas. Five dose levels (L) were studied: Caelyx 30 mg/m2 (L1-4) or 40 mg/m2 (L5) 1-h infusion d 1 q 3 weeks + ifosfamide and mesna at X g/m2/4 h d 1-3 q 3 weeks at five doses: L1: X = 1.7 g; L2: X = 2 g; L3: X = 2.5 g; L4 and L5: X = 3 g. Cohorts of 3 patients were entered at each level unless a dose-limiting toxicity (DLT) occurred. In case of DLT in 1 of 3 patients a new cohort was added. Toxicity was evaluated by Common Toxicity Criteria (CTC). A total of 28 patients was included: 4 at dose L1, 8 at L2, 3 at L3, 6 at L4, and 7 at L5. Median age was 60 years (range 29-69 years). Male/female ratio was 12/16. Seventy-five percent of patients had a performance status of 1.0 and 36% had leiomyosarcomas. No DLT was observed at dose L1-4. Six patients developed a DLT at dose L5, and thus the recommended dose is level 4 (i.e. Caelyx 30 mg/m2/1 h d 1+ifosfamide at 3 g/m2/4 h d 1-3 q 3 weeks). Few haematological and biochemical events were observed and the principal toxicities were granulocytopaenia and leucopaenia. Five patients discontinued therapy because of toxicity, 4 of them at dose level 5. Non-haematological toxicities > grade 2 were also few. Palmar-plantar erythrodysesthesia (PPE) > grade 1 was not seen. Two patients obtained partial response (PR) and 13 stable disease (SD). Median overall survival (OS) was 333 d and median progression-free survival (PFS) 174 d. In conclusion, this seems to be a feasible combination in patients with advanced soft tissue sarcomas, allowing ifosfamide to be given in a dosage similar to that used when given alone. The recommended dose for future studies is Caelyx 30 mg/m2/1 h d 1+ifosfamide 3 g/m2/4 h d 1-3 q 3 weeks.

Active microrheology of networks composed of semiflexible polymers: theory and comparison with simulations.

Based on the results of our computer simulation [Ter-Oganessian et al., Phys. Rev. E 72, 041510 (2005)], we have developed a theoretical description of the motion of a bead, embedded in a network of semiflexible polymers (filaments) and responding to an applied force. The theory reveals the existence of an osmotic restoring force, generated by the piling up of filaments in front of the moving bead and first deduced through computer simulations. The theory predicts that the bead displacement scales like x approximately t(alpha) with time, where alpha = (1/2) in an intermediate-time regime and alpha = 1 in a long-time regime. It also predicts that the compliance varies with a concentration like c(4/3) in agreement with experiment.

[Gastrointestinal stromal tumors (GIST)]. / Gastrointestinale Stromatumoren (GIST).

The vast majority of mesenchymal tumors originating from the GI tract consists of gastrointestinal stromal tumors (GIST), an entity just recently defined. The incidence is estimated to be around 10 - 20/1000000, the median age at diagnosis has been reported to be 55 to 65 years. GISTs most commonly occur in the stomach or duodenum, followed by the small intestine. About half of the patients present with metastatic disease at first diagnosis, predominantly in the liver or periteneum. GISTs are strongly and uniformly positive for CD117 (c-kit), a type III receptor-tyrosine kinase. Kit mutations, mostly in exon 11, leading to ligand independent constitutive activation are supposed to play a major role in the pathogenesis of GIST. Until recently no active systemic treatment was available for advanced gastrointestinal stromal tumors. Imatinib (STI571 = Glivec) is a rationally designed, orally available phenylaminopyrimidin analogue. The mechanism of action consists of a competitive interaction with the ATP-binding pocket of specific tyrosine kinases. Early results from clinical trials with response rates around 60 % and progression arrest in more than 80 % of patients resulting in fast relief of symptoms, confirm the high activity of this novel treatment. The role of adjuvant treatment after potentially curative resection of GIST is currently evaluated in ongoing clinical trials. Patients with progressive disease while under treatment with Imatinib should be enrolled in studies testing novel treatment strategies as RAD001, PKC412 or SU11 248.

Molecular response of gastrointestinal stromal tumour after treatment with tyrosine kinase inhibitor imatinib mesylate.

Bleeding from the tumour site is not uncommon during the treatment of gastrointestinal stromal tumours with imatinib mesylate. It might represent an early reaction of highly vascularised tumour tissue to receptor blockade. Although often requiring emergency surgery, this is not necessarily a deleterious sign. Slow tumour regression and cystic tissue alteration may follow. Using immunohistochemistry and consecutive resection specimens, it was shown that the number of mitoses decreased significantly and MIB-1 as a marker of cell proliferation could no longer be detected. In the few tumour cells still present, the magnitude of expression of the pathognomonic marker CD117 remained unchanged. Decreases in the size of tumours responding to imatinib mesylate cannot be expected to meet the World Health Organisation or RECIST (response evaluation criteria in solid tumours) criteria. This underlines the necessity of functional imaging by positron emission tomography, contrast enhanced magnetic resonance imaging, or magnetic resonance spectroscopy to assess the response to treatment.