The pathogenesis of peripheral aneurysms of the central nervous system: a subject review from the AFIP

Most central nervous system aneurysms occur around the circle of Willis, and are congenital or arteriosclerotic in origin when in that location. Peripherally located aneurysms are either idiopathic or secondary to infection, tumor embolus (from choriocarcinoma and cardiac myxoma), Moyamoya disease, or trauma. The pathophysiologic features of these aneurysms are discussed.     

Activation of the CPP32 protease in apoptosis induced by 1-beta-D- arabinofuranosylcytosine and other DNA-damaging agents

The response of human myeloid leukemia cells to treatment with 1-beta- arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C induced apoptosis is associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. However, the signals involved in this response are unknown. The present studies show that ara-C treatment of U-937 cells is associated with induction of a protease activity that cleaves the tetrapeptides Ac-DEVD- pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta, respectively. The ara-C-induced protease activity was sensitive to overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus protein p35. By contrast, overexpression of the cowpox virus protein CrmA blocked apoptosis induced by engagement of the Fas receptor but not that induced by ara-C. CrmA overexpression also had no detectable effect on ara-C-induced cleavage of PKC delta. The results further show that ara-C induces activation of the CPP32 protease by a CrmA- insensitive and p35-sensitive mechanism. Similar results were obtained with cisplatinum, etoposide, and camptothecin. These findings indicate that ara-C and other DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving CPP32 and that these signals differ from those associated with apoptosis induced by the Fas receptor.     

Phase II trials of fosquidone (GR63178A) in carcinoma of the breast, head and neck, ovary and melanoma.

A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.     

Extensive cytoreductive surgery combined with intra-operative intraperitoneal perfusion with cisplatin under hyperthermic conditions (OVHIPEC) in patients with recurrent ovarian cancer: a feasibility pilot.

AIMS: The feasibility, morbidity and toxicity of an intensified surgical treatment strategy consisting of aggressive cytoreductive surgery, intra-operative intraperitoneal perfusion of cisplatin and hyperthermia were evaluated in women with recurrent ovarian cancer. METHODS: Five heavily pre-treated patients with extensive abdominal tumour bulk entered this pilot study. In all cases aggressive cytoreduction leaving tumour remnants <5 mm in diameter could be performed. This was followed intra-operatively by perfusion of the abdominal cavity with hyperthermic cisplatin 50-70 mg/m(2)for 90 min. During perfusion the intra-abdominal temperature was maintained at 40 degrees C. The median duration of surgery was 10 hours (range 9-11 hours). RESULTS: No major intra- or post-operative complications emerged. Median post-operative ileus (resuming of soft diet) was 11 days (9-13 days). The mean period of hospitalization was 25 days (range 17-42). Toxicity due to i.p. cisplatin was mainly metabolic and of grade 1-2, while no nephrotoxicity was observed. The pharmacokinetics of cisplatin indicated that the maximum concentration of cisplatin measured in the perfusate was 15 times higher than in plasma. CONCLUSIONS: We conclude that aggressive cytoreduction combined with hyperthermic intra-operative intraperitoneal cisplatin was feasible in a small group of heavily pre-treated ovarian cancer patients with extensive tumour bulk with acceptable morbidity and toxicity. Further studies are required in larger groups of patients to further establish the feasibility of this intensified treatment strategy. We stress that OVHIPEC is not a treatment modality on its own for advanced ovarian cancer. The effectiveness of OVHIPEC is likely to be dependent on the effectiveness of post-operative adjuvant chemotherapeutic regimens.