Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO.

BACKGROUND: The management of gastrointestinal stromal tumors (GIST) has evolved very rapidly in the last 4 years. The objectives of this international consensus meeting were to describe the optimal management procedures for patients with GIST in localized and advanced stages, as well as research issues for the future. MATERIALS AND METHODS: A panel of experts from six specialties, including pathology, molecular biology, imaging, surgery, medical oncology and methodologists for clinical practice guidelines from different European and extra European sarcoma societies were invited to a 2-day workshop. Several questions were selected by the organizing committee prior to the conference. Selected panelists reviewed the current levels of evidence for each point, and presented their conclusions during the meeting. These proposals were discussed, and consensus points were identified and categorized according to the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers and National Comprehensive Cancer Network (NCCN). RESULTS: Thirty-two consensus points were identified, most from categories 2A of the NCCN and B2 of the SOR. Among these, the standard histological examination with immunohistochemical analysis using CD117, CD34, PS100, desmin and smooth muscle actin is considered standard. Molecular biology for the identification of KIT and PDGFRA mutation is an optional diagnostic procedure for GIST with negative CD117 staining, and otherwise is considered a research procedure. Complete tumor resection with negative tumor margins is the standard surgical treatment. Adjuvant imatinib after optimal tumor resection as well as neo-adjuvant imatinib remain experimental approaches to be performed within prospective clinical studies. Imatinib should be started at the date of diagnosis of metastatic relapse and given until development of intolerance or progressive disease. The optimal criteria for tumor response to imatinib remain to be delineated, and should include not only tumor size reduction or disease stabilization, but also reduction of tumor density (Hounsfield Units) on computed tomography and metabolic activity (i.e. reduction of FDG uptake on positron emission tomography). In a substantial proportion of patients, stable disease and even increase in tumor size may be associated with pathologic response to imatinib therapy, and available survival data indicate that the survival of these patients is similar to that of patients with conventional tumor response. Metastasis resection is an experimental procedure. CONCLUSIONS: Consensus points in clinical management of GIST as well as questions for future clinical trials were identified during this consensus conference on GIST management.

Solidifying the solid angle.

This paper evaluates the position of the solid angle in its application to modeling in electrocardiology. Particular attention is paid to the use of the solid angle for linking cardiac electric activity to the potentials observed on the body surface. In this application, the solid angle is a dominant factor in the expression of the sources during depolarization known as the uniform double layer. In the related equivalent double layer model, the contributions of the elementary sources are also expressed in terms of solid angles, their strength not being uniform. A recently developed theory allows the equivalent double layer to be applied to both depolarization and repolarization.

In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment.

PURPOSE: Interference with the tumor blood vessels through anti-angiogenesis or vascular targeting can indirectly suppress tumor growth. Vascular targeting of solid tumors, using tubulin-compromising agents, seems a promising and selective novel treatment. We aimed to evaluate the potential (hypothesis-based) benefit from combinations of vascular targeting using combretastatin A-4 phosphate (combreAp) with either ionizing radiation or anti-angiogenesis. METHODS AND MATERIALS: Rhabdomyosarcoma tumor pieces were inplanted subcutaneously (s.c.) in the lower flank region of syngeneic adult WAG/Rij rats. Tumors were grown until different sizes and stratified for the various treatment groups: small (1-3 cm3), medium (3.1-7 cm3), and large (7.1-14 cm3). CombreAp was injected i.p.; injections of TNP-470 were s.c. in the neck area. Localized single-dose (8 Gy) irradiations of tumors were done under Nembutal anesthesia, always 1 day before a single combreAp (25 mg/kg) injection. The TNP-470 treatment (3 times 30 mg/kg in 1 week) started 1 day after a double (8 days interval between both) combreAp administration. Tumor responses were evaluated by the growth delay assay, and statistical significance of tumor growth change was computed. RESULTS: Large tumors responded better to combreAp treatment given alone than did the smaller ones, confirming our previous data with this tumor model. Combining irradiation with combreAp also resulted in a tumor size-dependent growth delay. With small and medium tumor volumes, a similar response was measured after the combination treatment when compared with irradiation only. Large tumors, however, showed a strong (at least additive) increase of the growth delay with the combined therapy; the difference in tumor growth between the two treatment groups was very significant (p < 0.0001). m When TNP-470 was combined with combreAp, no significant lengthening of the growth delay, irrespective of the tumor size, was present with the applied schedule. CONCLUSION: The current data show a significant advantage in the combination of combreAp with irradiation in rhabdomyosarcomas having a large size (7-14 cm3) at treatment. Such a benefit in tumor response was not observed with the smaller tumors, seemingly because irradiation as such was very effective. No significant gain in growth delay for any tumor size was observed when TNP-470, showing efficacy on its own specifically with tumors measuring <7 cm3, was added to the combreAp treatment. This presumably reflects only little angiogenesis during the first week of rhabdomyosarcoma regrowth after the combreAp treatment.

Predictive testing in cancer chemotherapy. II. In vitro.

During the last thirty years several in vitro techniques have been developed to predict sensitivity of individual tumours. When the results of these techniques were correlated with the clinical response in larger groups of patients, the accuracy for predicting resistance was greater than for predicting sensitivity. Amongst the culture techniques the colony-forming assays have received much attention. Research with tumour cell lines and the sound biological basis do support this preference on other techniques. Studies on these assays have come from several independent laboratories, who report comparable results. Improvement of the culture technique and more insight into the in vitro pharmacology is needed, before application on wider scale is justified. Colony-forming culture techniques have not only been propagated for individualized chemotherapy, but also for drug screening. New antitumour agents and analogous can be screened in a short time for their sensitivity in many histologic tumour types.

Predictive testing in cancer chemotherapy. I. In vivo.

Several in vivo methods have been assessed for their capacity to predict sensitivity for anticancer agents in humans. Standard strategies have been developed for screening purposes. Adjustments of these strategies are frequently suggested in reports in which the correlation between assay results and clinical therapeutic efficacy is analysed. Low predictivity and high costs of these assays are important reasons for changing the screening strategy. In vivo methods which predict the clinical response in the individual patient, are under investigation. Only the results of the subrenal capsule assay (in normal mice) have been correlated with the clinical response in a larger study. The criticism of the method and the low predictivity for sensitivity in a prospective study provide no reason for optimism. Methods which study changes predicting the clinical response in patients are still in a developmental phase.

Determination of the underivatized antineoplastic drugs cyclophosphamide and 5-fluorouracil and some of their metabolites by capillary gas chromatography combined with electron-capture and nitrogen-phosphorus selective detection.

A rapid and sensitive method for the determination of cyclophosphamide (CP) and 5-fluorouracil (5-FU) and some of their metabolites in one analysis has been developed. Surface-coated open-tubular OV-275 columns were combined with electron-capture detection and nitrogen-phosphorus selective detection. The influence of the column diameter on the separation is shown. Extraction with 2-propanol-diethyl ether (22:77) allows the isolation of CP, 5-FU and their analogues in one extraction step. The assay was applied to some pharmacokinetic experiments with chemotherapeutically treated patients and with a WAG/Rij rat.