A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens.

Rationale: Advanced synovial sarcomas (SyS) refractory to doxorubicin and ifosfamide are highly resistant to the currently available cytotoxic agents. Based on a report showing a specific overexpression of HER-1 in SyS, we investigated an HER-1 inhibitor, gefitinib, in refractory SyS.

Subjects And Methods: To establish the efficacy and safety of gefitinib in HER-1 - positive SyS refractory to one or two lines of doxorubicin- and ifosfamide-based chemotherapy, a phase II study was conducted from December 2002 to October 2005 by 12 centers of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer.

Vorinostat (Zolinza) is a histone deacetylase inhibitor that has demonstrated activity in patients with advanced solid tumors in phase I trials. A multicenter, open-label phase II trial of oral vorinostat 200, 300 or 400 mg bid for 14 days followed by a 7-day rest until disease progression or intolerable toxicity was conducted. Patients with measurable, relapsed or refractory breast or non-small cell lung cancer who had received > or = 1 prior therapy or colorectal cancer who had received > or = 2 prior therapies were eligible.

An economic evaluation of cetuximab combined with radiotherapy for patients with locally advanced head and neck cancer in Belgium, France, Italy, Switzerland, and the United Kingdom.

Objectives: A phase III randomized trial that compared the combination of cetuximab and radiotherapy to radiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck provided a platform for a comprehensive economic evaluation. The study was conducted to estimate the cost-effectiveness of cetuximab in combination with radiotherapy compared to radiotherapy alone, for the treatment of locally advanced head and neck cancer in patients for whom chemoradiotherapy is inappropriate or intolerable.

Methods: Separate economic analyses were conducted for Belgium, France, Italy, Switzerland, and the United Kingdom.

Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma.

Trabectedin (ET-743; Yondelis) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. A pooled analysis of data from these studies showed that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.

Recurrent low- to intermediate-grade chondrosarcoma of the thumb with lung metastases: an objective response to trofosfamide.

Background: Low- to intermediate-grade chondrosarcoma is usually a slow-growing and highly chemotherapyresistant tumor type.

Case Report: The 76-year-old female patient presented with low- to intermediate-grade chondrosarcoma of the distal phalanx of the right thumb in 1993 and was treated with an excision of the carpometacarpal joint. Approximately 10 years later, the patient presented with recurrent local disease at the trapezoid bone, which was resected.

Imatinib for the treatment of patients with unresectable or metastatic malignant KIT-positive gastrointestinal stromal tumours: an open-label Belgian trial.

Background: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. They are defined immunohistologically as KIT positive tumours. The only effective treatment for malignant GIST was surgery until 2000.

Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.

Background & Aims: Intestinal neurofibromatosis (Online Mendelian inheritance in Man database number 162220) is an alternate form of neurofibromatosis. Patients present with neurofibromas limited to the intestine in the absence of any other typical features of NF1 and NF2. At present, the molecular basis of intestinal neurofibromatosis remains elusive.

Simultaneous determination of AMN107 and Imatinib (Gleevec, Glivec, STI571) in cultured tumour cells using an isocratic high-performance liquid chromatography procedure with UV detection.

A reversed phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for the simultaneous determination of imatinib (Gleevec, Glivec, STI571) and AMN107 in cultured tumour cells, using clozapine as an internal standard. The compounds of interest were extracted by liquid-liquid extraction using TOXI-TUBES((R)) A extraction tubes. Chromatographic separation was performed on a Phenomenex Gemini C18 reversed phase column (150 mm x 2.

Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.

Many clinicians often do not feel comfortable with the Continual Reassessment Method (CRM). This article reviews its implementation, showing the characteristics, advantages and limitations of this method in Phase I studies as an alternative to the classical 'Fibonacci' escalation schema. A two center, dose escalation phase I study of rViscumin was carried out.

Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate.

Purpose: The majority of gastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA), and respond to treatment with the tyrosine kinase inhibitor imatinib. Some tumors, however, show primary resistance to imatinib treatment, and most others become resistant during treatment. The most common mechanism of imatinib resistance involves specific mutations in the kinase domains of KIT or PDGFRA.

Establishment of a mouse gastrointestinal stromal tumour model and evaluation of response to imatinib by small animal positron emission tomography.

Background: Gastrointestinal stromal tumours (GIST) predominantly express activating mutations of the KIT tyrosine kinase receptor and are successfully treated with imatinib mesylate, a KIT inhibitor. As resistance to imatinib causes therapy failure, our aim was to develop an in vivo GIST model to evaluate KIT inhibitors and monitor therapy with small animal positron emission tomography (PET).

Materials And Methods: The first mouse model of GIST xenografts was successfully established by injecting GIST882 cells subcutaneously into nude mice.

Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines.

Imatinib and AMN107 are protein tyrosine kinase inhibitors which reduce KIT autophosphorylation with similar potency. This report describes the cellular uptake of these compounds in two human gastrointestinal stromal tumor (GIST)-derived cell lines (GIST882 and GIST GDG1), which both express constitutively activated KIT. In GIST882 and GIST GDG1 cell lines, HPLC analysis revealed AMN107 intracellular concentrations to be 7- and 10-fold greater than those of imatinib.

Does a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer?

The purpose of this study was to determine whether baseline patients' self reported health-related quality of life (HRQOL) parameters could predict survival beyond key biomedical prognostic factors in patients with metastatic colorectal cancer. The analysis was conducted on 299 patients. HRQOL baseline scores were assessed using the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core30 (EORTC QLQ-C30).

Capecitabine/oxaliplatin, a safe and active first-line regimen for older patients with metastatic colorectal cancer: post hoc analysis of a large phase II study.

Purpose: The tumor-activated fluoropyrimidine capecitabine achieves response rates superior to those of bolus 5-fluorouracil/leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer (CRC), with favorable safety and fewer hospitalizations. Capecitabine is also at least as effective as bolus 5-FU/LV in the adjuvant setting, again with a favorable safety profile. Improved outcomes with capecitabine versus bolus 5-FU/LV in the adjuvant setting have been shown in overall trial populations and in patients aged >or= 70 years.

Phase I study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor in patients with refractory solid tumors.

Purpose: OSI-7904L is a liposomal formulation of a potent noncompetitive thymidylate synthase inhibitor (TSI) that does not require polyglutamation for activity. This phase I study was done to establish the safety, tolerability, maximum tolerated dose, recommended dose, and pharmacokinetics of OSI-7904L in patients with advanced solid tumors refractory to standard therapy.

Design: OSI-7904L was given as a 30-minute i.

Role of postchemotherapy surgery in the management of patients with liver metastases from germ cell tumors.

Objective: To evaluate the role of postchemotherapy adjunctive surgery in patients with liver metastases from germ cell cancer (GCT).

Patients And Methods: Forty-three male patients with nonseminoma were treated in different multicenter treatment protocols between 1990 and 1999, and they underwent hepatic surgery. The results of postchemotherapy surgical resection, histologic findings found during postchemotherapy surgery, and prognostic factors for survival were assessed.

Adaptation and performance of an immuno-PCR assay for the quantification of Aviscumine in patient plasma samples.

An immuno-polymerase chain reaction (IPCR) assay is used to evaluate the kinetic behaviour of the novel anti-cancer drug Aviscumine in plasma samples taken from 41 patients during a 3-year clinical trial. The ultrasensitive IPCR assay employed the amplification of a detection-antibody linked marker-DNA and an internal competitor DNA for standardization, thus enabling the detection of the antigen in concentrations far below the detection limit of conventional enzyme-linked immuno-sorbent assay (ELISA). The quantification of Aviscumine was carried out using external calibration curves obtained from individual patient plasma samples, collected previous to the administration of Aviscumine, which were spiked with known amounts of the reference substance Aviscumine.

A phase I and pharmacologic study of the matrix metalloproteinase inhibitor CP-471,358 in patients with advanced solid tumors.

Background: Matrix metalloproteinases play a role in the process of tissue invasion and metastasis by degrading the extracellular matrix. Inhibitors of matrix metalloproteinases are therefore of interest as anticancer drugs. CP-471,358 is a matrix metalloproteinase inhibitor that in vitro demonstrates strong inhibition of matrix metalloproteinases 2 and 9.

Acral necrosis after inadequate excessive administration of bleomycin in a testicular cancer patient.

Background: Testicular cancer has a favorable prognosis in the majority of patients due to the excellent susceptibility to chemotherapy with cisplatin, etoposide and bleomycin (BEP), which is commonly administered over 3-4 cycles of treatment.

Case Report: A 22-year-old male failed to achieve complete response after unconventional treatment with 6 courses of BEP for intermediate-risk metastasized testicular cancer. The patient developed chemotherapy-induced digital necrosis and substantial loss of digital function after this excessive treatment.

XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer.

Purpose: Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens.

The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors.

The fluoropyrimidine anticancer agent 5-fluorouracil (5-FU) is active in a wide range of solid tumors, particularly gastric, colorectal, and head and neck cancers. Whilst infusional 5-FU is associated with higher response rates and a favorable safety profile as compared to the classical i.v.

Plasma P-selectin levels are elevated in patients with chronic liver disease.

P-selectin is a leukocyte receptor and platelet activation marker that has been shown to be involved in thrombogenesis as well as bleeding disorders and may represent a possible link between inflammation and thrombosis. In animal models, high plasma levels correlated with a procoagulant tendency. In acute liver damage models such as hepatic ischaemia-reperfusion-injury, P-selectin was found to be a key mediator of liver injury.

Ghrelin in chronic liver disease.

Background/aims: Ghrelin is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor involved in energy metabolism, glucose homeostasis and food intake. We investigated the role of ghrelin and insulin-like growth factor-1 (IGF-1), the mediator of the GH axis, in patients with chronic liver diseases (CLD).

Methods: Ghrelin and IGF-1 serum levels were determined in 105 CLD patients and 97 healthy controls and correlated with clinical and biochemical parameters.

Development of an optimal pharmacokinetic sampling schedule for rubitecan administered orally in a daily times five schedule.

Purpose: Our aim was to develop an optimal sampling strategy for the description of the pharmacokinetics of rubitecan and its active metabolite 9-aminocamptothecin (9-AC) for use in phase II/III studies with oral rubitecan administered in a daily times five schedule.

Methods: Concentration-time data of rubitecan and 9-AC were obtained from 14 patients who had received 1.5 mg/m(2) per day rubitecan orally.