New advances in biology and treatment of gastrointestinal stromal tumours (GISTs).

Gastrointestinal stromal tumours (GISTs) are a precise oncogenetic entity that has started the new era of targeted therapies in solid tumours. GISTs are now a model to understand the role of oncogenic kinase mutation in tumourigenesis, duplication, cell regulation, apoptosis and drug resistance. Ninety-five percent of GISTs have some activacting mutation of c-KIT or PDGFRA tyrosine kinase. The studies of the last two years have found concrete correlations between mutations and anatomical locations of GISTs, prognosis, response to therapy and resistance to therapy. Genotyping has increased of importance in the last years as a new field for translational researches. The important advances made in molecular studies are now a practical tool in diagnosis and therapy of GISTs.

PIP/GCDFP-15 gene expression and apocrine differentiation in carcinomas of the breast.

The frequency and the significance of apocrine differentiation in carcinomas of the breast are uncertain, because of the lack of reliable and reproducible criteria for morphological diagnosis. The 15 kDa glycoprotein of cystic breast disease (GCDFP-15) is regarded as a specific functional marker of apocrine cells. Expression of the prolactin-inducible protein (PIP)/GCDFP-15 gene was investigated by Northern blot analysis and in situ hybridization in breast cancer cell lines and in an unselected series (33 cases) of primary carcinomas of the breast. On the same cases, histological assessment of apocrine differentiation and immunocytochemical detection of GCDFP-15 were also performed and correlated with follow-up data. The presence of PIP/GCDFP-15 mRNA was a feature of a relatively high number of cases, but was incompletely correlated with histological and immunocytochemical evidences of apocrine differentiation. Expression of the PIP/GCDFP-15 gene was significantly associated with relapse-free survival, and may represent a novel variable of functional and prognostic relevance.

Low dose adriamycin and ifosfamide in the treatment of advanced adult soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are infrequent tumors (up to 1% of all neoplasms) in adult patients. Treatment of advanced disease is largely unsatisfactory. Only a few drugs are active agents and combination regimens offer limited and short-lived activity. High dose chemotherapy may be administered only to limited groups of patients. PATIENTS AND METHODS: We evaluated, in a phase II study, the adriamycin and ifosfamide combination regimen. The drugs were administered at 60 mg/sqm and 6 g/sqm dosage, respectively. The total number of treated patients was 42 of which 40 were evaluable. RESULTS: We observed 6 complete responses (14% response rate) and 6 partial responses (14%). The mean survival was 6 months (median 7.6 months). Toxicity was limited and reversible. CONCLUSION: While high dose chemotherapy may be reserved for selected groups of patients, an adriamycin and ifosfamide combination regimen at conventional doses can be administered to the great majority of patients with suboptimal performance status or with advanced age.

Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic soft tissue and bone sarcomas.

Ifosfamide is a leading drug in soft tissue sarcoma therapy. Recently high dose therapy (>9 g/m2) has been introduced in different schemes to obtain a higher response rate. All these higher doses can be administered following two different schedules: continuous infusion 24 hours a day for 4-5 days or bolus administration for 5 consecutive days. In this study we compare the differences in the pharmacokinetic profile between the two schedules. In both schemes we saw a very important autoinduction phenomenon, with a corresponding half-life decrease and total body clearance increase during the days of therapy. The clearances were not directly correlated with the administered dose. We can conclude that ifosfamide continuous infusion therapy is equivalent to fractionated administration, at least from a pharmacokinetic point of view. Short-term infusion is subjectively better tolerated and is therefore preferred.

Two episodes of ifosfamide-related neurotoxicity in the same patient following different schedules and doses of the drug. A case report.

We report the first case of recurrent ifosfamide-related neurotoxicity in the same patient following two distinct administrations of the drug at different doses and schedules and with a long interval between the two episodes. Remarkably, the first event was characterized by confusion and hallucinations, while the second, 29 months later, was characterized by partial and generalized seizures. Between the two episodes the patient had received high-dose cyclophosphamide, an oxazophoshorine agent closely related to ifosfamide, without any neurological side effects. We briefly discuss the diagnosis and management of ifosfamide-related encephalopathy.

Treatment of advanced colorectal cancer (CRC) in daily practice: results of a survey in two Italian regions, Piemonte and Valle d'Aosta.

AIMS AND BACKGROUND: Colorectal cancer (CRC) is one of the most important health problems in Western countries: it is the fourth cancer in terms of incidence and the second cause of cancer death. Surgery is the main therapeutic choice and there is broad consensus on the role of adjuvant chemotherapy (CT) after resection. Unfortunately, 50% of the patients will relapse and die of the disease. Palliative CT based on 5-fluorouracil (5FU) may induce a 9-48% response rate with a median survival of 11.5 months. At present there is no gold standard for CT In advanced CRC and the situation has become more complicated since the advent of new drugs (Raltitrexed, Irinotecan, Oxaliplatin). The aim of this study was the identification of the different approaches to treatment of advanced CRC among the clinicians (oncologists, radiologists, internal medicine specialists, surgeons) who practice CT. METHODS AND STUDY DESIGN: Forty-six clinicians from two Italian Regions (Piemonte and Valle d'Aosta) were interviewed by telephone. RESULTS: 5FU modulated with Lederfolin according to the classic Machover scheme is the main option in daily practice. More sophisticated therapies are reserved to patients with a good performance status (PS) and are prescribed only in the larger centers. The planned therapies usually consist of six courses. Restaging may be performed after three or six courses. A marked difference has been recorded in the evaluation of a situation of no change (NC): 25.5% of the clinicians evaluate stable disease as a positive result. In the event of disease progression or relapse, 35% of the clinicians do not prescribe second-line CT. In case of further treatment, the options are totally subjective. CONCLUSIONS: A national survey on this issue is necessary under the auspices of AIOM (Associazione Italiana Oncologia Medica) and involving oncologists, epidemiologists and statisticians, in order to define the reasons for variations in therapy in advanced CRC and determine the differences between clinicians of different age, specialization and location. This survey could lead to a definition of guidelines for the treatment of advanced CRC.

The integration of vascular surgical techniques with oncological surgical protocols in the treatment of soft tissue sarcomas of the limbs.

Soft tissue tumors, involving the vascular bundle, require a particular surgical approach: oncological and vascular surgical techniques must be integrated in order to perform a limb-saving surgery with adequate margins. Thirty-six soft tissue sarcomas of the thigh and popliteal region were treated from June 1999 to September 2002. Nineteen cases involving the vascular bundle were analysed and placed in two groups according to imaging and clinical information: Group A, 14 patients, with tumors close to femoral vessels without adventitial infiltration, and Group B, 5 patients, with vascular infiltration. Group A was treated with vascular blunt dissection performing adventitial excision. Group B was treated with vascular "en-bloc" resection and reconstruction. Imaging and clinical information together with surgical techniques, strategies and complications were analysed in order to plan the surgical approach in neoplastic vascular bundle involvement.

Lack of Activity of Docetaxel in Soft Tissue Sarcomas: Results of a Phase II Study of the Italian Group on Rare Tumors.

Purpose. The prognosis of advanced soft tissue sarcoma is poor, only a few drugs showing some activity with response rates around 15- 25%. Consequently drug development seems mandatory to improve treatment outcome. Following previous favourable EORTC experience, the Italian Group on Rare Tumors started a phase II study with docetaxel to confirm the activity of this drug in soft tissue sarcoma.Patients and methods. Thirty-seven patients with soft tissue sarcoma resistant to at least one anthracyclinecontaining regimen were enrolled in a phase II multicenter study evaluating docetaxel 100 mg/m(2) in a 1-h i.v. infusion q(3) weeks.Results.Thirty-seven patients were enrolled onto this phase II study and 36 were evaluable for response. Only one partial remission was observed [2.8% with 95% confidence interval (CI) 0.1- 16.2%]. Median progression-free and overall survival were 42 and 350 days, respectively. Neutropenia and leukopenia as well as cutaneous manifestations were the most common toxicities.Discussion. The results of this phase II study do not confirm a previous EORTC repor t on the activity of docetaxel in soft tissue sarcoma, but are consistent with other more recent phase II studies. The accumulated evidence does not justify the use of this drug in the management of patients suffering from this disease, resistant to anthracyclinecontaining regimens.