Purpose To evaluate the safety and tolerability of LiPlaCis a liposomal formulated platinum compound in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous... Show morePurpose To evaluate the safety and tolerability of LiPlaCis a liposomal formulated platinum compound in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous v) LiPlaCis and to assess plasma and urine pharmacokinetics and plasma biomarkers Patients and methods Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3 weeks until RECIST progression or unacceptable toxicity Cohorts of 3-6 patients were treated at each dose level until MTD was reached Results Eighteen patients were enrolled and 64 cycles were delivered At the first dose level 3 patients experienced an infusion reaction Despite prophylactic pre medication and prolongation of the infusion to 2 h in further patients three other patients had mild acute infusion reactions Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients Peak plasma concentrations and AUC were dose proportional The interpatient variability in the clearance of total LiPlaCis derived platinum was 41% Platinum was excreted via the urine mainly during the first 24 h after administration Investigated plasma biomarkers sPLA(2) and SC5b 9 were related to but not predictive for acute infusion reactions Conclusion The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development (C) 2010 Elsevier Ltd All rights reserved Show less
Novelli, M.; Rossi, S.; Rodriguez-Justo, M.; Taniere, P.; Seddon, B.; Toffolatti, L.; ... ; Tos, A.P. dei 2010
Aims: The histopathological diagnosis of gastrointestinal stromal tumours (GIST) is typically made based on a combination of clinical and morphological features supported by immunohistochemistry... Show moreAims: The histopathological diagnosis of gastrointestinal stromal tumours (GIST) is typically made based on a combination of clinical and morphological features supported by immunohistochemistry studies. The aim of this study was to examine the staining quality, sensitivity, specificity and utility of antibodies used commonly in GIST diagnosis. Methods and results: Immunohistochemistry with a panel of antibodies [CD117, DOG1, protein kinase C (PKC)-theta, nestin, CD34, smooth muscle actin (SMA), desmin, S100 and CD171] was performed on whole sections from 187 GIST and 29 gastrointestinal mesenchymal tumours, and on several microarrays including 355 GISTs and 120 soft tissue sarcomas. Results showed that DOG1 and CD117 were the most sensitive and specific antibodies used in GIST diagnosis. PKC-theta and nestin were sensitive, but less specific, also staining other spindle cell tumours commonly considered in the differential diagnosis of GIST. CD34 staining was less sensitive than many of the other antibodies and of limited aid in diagnosis. The smooth muscle markers SMA and desmin, together with the neural marker S100, were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the exclusion/diagnosis of other gastrointestinal mesenchymal tumour types. Conclusions: In the majority of histologically suspected GISTs a combination of CD117 and DOG1 immunostaining is sufficient to confirm the histological diagnosis. Show less
Hamberg, P.; Steeghs, N.; Loos, W.J.; Biessen, D. van de; Hollander, M. den; Tascilar, M.; ... ; Sleijfer, S. 2010
BACKGROUND: This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide. METHODS: Patients with advanced solid tumours,... Show moreBACKGROUND: This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide. METHODS: Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 gm (2) for 3 days or 6 g m(-2) for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed. RESULTS: With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. CONCLUSION: With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored. British Journal of Cancer (2010) 102, 1699-1706. doi:10.1038/sj.bjc.6605696 www.bjcancer.com Published online 18 May 2010 (C) 2010 Cancer Research UK Show less
Loos, W.; Hamberg, P.; Steeghs, N.; Kroep, J.; Tascilar, M.; Verweij, J.; ... ; Sleijfer, S. 2010
Background: Adult patients with advanced soft tissue sarcomas (STS) are generally treated similarly, regardless of great differences between STS subtypes, disease presentation and patients'... Show moreBackground: Adult patients with advanced soft tissue sarcomas (STS) are generally treated similarly, regardless of great differences between STS subtypes, disease presentation and patients' characteristics. As ifosfamide is frequently applied in first line systemic therapy, we aimed to establish prognostic and predictive factors for outcome to ifosfamide-based therapy. Methods: A retrospective, exploratory analysis was performed on data from 1337 advanced STS patients who received first-time ifosfamide-containing chemotherapy. For predictive factor analysis, 660 patients treated with doxorubicin monotherapy served as comparators. Results: Independent favourable prognostic factors for overall survival (OS) were good performance status, female gender, low histological grade, extremity primary tumour site and locally advanced disease; for progression-free survival (PFS), the combination of doxorubicin and ifosfamide, locally advanced disease, and tumour entity with a lower risk to progress for synovial sarcoma patients compared to leiomyosarcoma. For response, independent favourable prognostic factors were doxorubicin combined with ifosfamide, higher histological grade, and histology with synovial sarcoma patients having the highest chance to respond. Predictive factor analysis showed that compared to doxorubicin monotherapy, patients who benefited less from ifosfamide-based therapies were leiomyosarcoma patients in terms of OS, and patients with liposarcoma for response. No predictive factors were found for PFS. Conclusion: In this study, we established an independent set of prognostic and predictive factors for outcome to ifosfamide-based chemotherapy in advanced STS patients. This study provides important information for the interpretation and design of clinical trials for specific STS entities and may contribute to further treatment individualisation of advanced STS patients. (C) 2009 Elsevier Ltd. All rights reserved. Show less
