Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial.

BACKGROUND: Continuous research into new strategies and chemotherapy agents for the treatment of malignant high-grade gliomas have led to the synthesis of a new chemotherapy drug, temozolomide (TMZ), with a lower toxicity profile compared to conventional chemotherapy agents, such as nitrosoureas. Temozolomide is an oral alkylating chemotherapy agent licensed for the treatment of recurrent high-grade gliomas, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Because of its favorable pharmacokinetic and pharmacodynamic properties and improved tolerability, TMZ is now under investigation for concomitant use with radiotherapy in patients with newly-diagnosed GBM. We present a phase II clinical trial investigating the efficacy and safety of radio-chemotherapy combined treatment using TMZ, followed by six cycles of adjuvant chemotherapy with TMZ, in patients with newly-diagnosed GBM who have undergone debulking surgery or biopsy only. PATIENTS AND METHODS: Twenty-one patients with newly histologically-diagnosed GBM were enrolled into this phase II clinical trial. In phase I of the study, TMZ (75 mg/m2/day per 7 days/wk for 6 weeks) was orally administered to patients concomitantly with radiotherapy (RT) (2 Gy per fraction once daily, per 5 days/wk for 6 weeks). In phase II of the study, four weeks after completion of RT, a monochemotherapy using TMZ was administered at the dosage of 200 mg/m2/day per 5 days every 28 days for 6 cycles. Primary end-points were the safety and tolerability profile of this two-phase combined treatment and secondary end-points were the objective response and survival rates at twelve months and eighteen months from study entry. RESULTS: The one-year survival rate of patients treated with the investigated multimodality treatment was 58% and median survival time was 15.7 months. Concomitant RT plus TMZ (phase I) followed by adjuvant TMZ (phase 2) were well-tolerated; indeed, nonhematological adverse events were rare and mild to moderate in severity; grade 3 and 4 neutropenia and thrombocytopenia were the major-related hematological side-effects observed in only 2 and 3 of all patients in phase I and 4 patients in phase II. We found that the combination of radio- and chemo-therapy, in phase I of the study did not significantly increase the incidence and severity of hematological toxicity caused by the adjuvant TMZ-based chemotherapy administered in phase II of the study. CONCLUSION: The investigated multimodality treatment regimen was well-tolerated and prolonged survival while improving patients' quality of life.

Linkage of proton binding to the thermal unfolding of Sso7d from the hyperthermophilic archaebacterium Sulfolobus solfataricus.

In this study the pH dependence of the thermal stability of Sso7d from Sulfolobus solfataricus is analyzed. This small globular protein of 63 residues shows a very marked dependence of thermal stability on pH: the denaturation temperature passes from 65.2 degrees C at pH 2.5 to 97.9 degrees C at pH 4.5. Analysis of the data points out that the binding of at least two protons is coupled to the thermal unfolding. By linking the proton binding to the conformational unfolding equilibrium, a thermodynamic model, which is able to describe the dependence upon the solution pH of both the excess heat capacity function and the denaturation Gibbs energy change for Sso7d, is developed. The decreased stability in very acid conditions is due to the binding of two protons on identical and noninteracting sites of the unfolded state. Actually, such sites are two carboxyl groups possessing very low pKa values in the native structure, probably involved in salt-bridges on the protein surface.

Radiation therapy and chemotherapy in the treatment of head and neck extranodal non-Hodgkin's lymphoma in early stage with a high grade of malignancy.

BACKGROUND: Optimal management of patients with localized head and neck extranodal lymphoma remains controversial, both because of the lack of randomized studies and because of the heterogenous grouping of most reported series. MATERIALS AND METHODS: Patients treated at our institution between 1974 and 1993 for extranodal head and neck lymphoma were retrospectively analyzed and classified. The therapy and outcome of 92 patients classified as having an intermediate (42) and high (50) level of malignancy according to the Working formulation and in stage I (39) or II (53) of the Ann Arbor Staging System were considered. Fifty-three patients (57.6%) received chemotherapy alone, and 39 (42.4%) combined radiochemotherapy. RESULTS: The different treatment schedules allowed these patients to achieve global actuarial 5-year overall, event-free, and relapse-free survival rates of 81.2%, 78.1% and 89.3%, respectively. The patients that received combined modality treatment reported actuarial 10-year event-free and relapse-free survival rates of 65.3% and 90.7%, respectively, with a suggestion of decreased treatment-related morbidity compared to patients treated with chemotherapy. CONCLUSIONS: Our results underscore the important treatment role of combined radiochemotherapy for early stage intermediate and high grade lymphomas.

Multicentre experience with combined hyperthermia and radiation therapy in the treatment of superficially located non-Hodgkin's lymphomas.

The combination of Radiation Therapy (RT) and Hyperthermia (HT) has proved to be an effective treatment for a wide variety of superficially located recurrences of different tumors, particularly those arising in previously irradiated areas. Few studies on the use of HT in the management of lymphomatous diseases have so far obtained interesting results. Eight patients with Non Hodgkin Lymphomas (LNH) - 4 with cutaneous lymphomas and 4 with nodal recurrences after RT-Chemotherapy (CHT) treatment treated in three different Italian institutions with combined RT and HT are here reported. Rt dose ranged from 15 to 40 Gy with different fractionations, on the basis of previously received treatment. Hyperthermia was delivered using 432 or 915 MHz external microwave applicators, according to extension and depth of the lesions and available equipment. All patients tolerated well the HT treatment, and in all cases average intratumoral temperatures were >42 degrees, with 3 out of 10 treated sites achieving the goal of average temperatures >42.5%. One patient, with recurrent NHL, is disease-free after 24 months from completion of combined therapy. Our results seem to confirm previous experiences, suggesting a role of HT/RT not only for palliative purposes in cutaneous lymphomas, but also as an adjunct to radiotherapy alone in selected patients with superficially located recurrences.