Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors

BACKGROUND: The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood-brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers. METHODS: Patients with primary central nervous system lymphoma (PCNSL), primitive neuroectodermal tumor (PNET), germ cell tumor, cancer metastasis to the brain, or low or high grade glioma were eligible. Prior to entry, magnetic resonance imaging or computed tomography brain scan, medical history, neurologic status, and Karnofsky performance status were reviewed at the coordinating center. Standardized anesthesia and intraarterial catheterization guidelines were followed by a multidisciplinary team at each center. Between March 1994 and November 1997, 5 universities treated 221 adult patients with intraarterial chemotherapy with or without osmotic opening of the BBB (2464 procedures). RESULTS: Of evaluable patients with PCNSL, 40 of 53 (75%) achieved complete response (CR). All evaluable patients with PNET (n = 17), metastatic disease (n = 12), or germ cell tumor (n = 4) achieved stable disease (SD) or better. Of 57 evaluable patients with glioblastoma multiforme, 45 (79%) achieved SD or better. Asymptomatic subintimal tear occurred in 11 of 221 patients (5%), pulmonary embolism in 6 of 221 (2.7%), and renal toxicity in 4 of 221 (1.8%). One patient with extensive glioma expired within 48 hours after treatment. CONCLUSIONS: Using standard guidelines and protocols, intraarterial chemotherapy with or without osmotic opening of the BBB is feasible across multiple centers with a low incidence of catheter-related complications. In patients with chemotherapy-sensitive tumors, such as PCNSL, PNET, germ cell tumor, and cancer metastasis to the central nervous system, enhanced delivery results in a high degree of tumor response, with an efficacy profile that is reproducible across multiple centers.     

The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway

Thiols such as N-acetylcysteine (NAC) are increasingly used in clinical trials of platinum chemotherapy as chemoprotectants. NAC can prevent cisdiamminedichloroplatinum (cisplatin)-induced ototoxicity, nephrotoxicity, and gastrointestinal toxicity; however, the molecular mechanisms of NAC on apoptosis and cisplatin cytotoxicity remain unknown. We investigated cisplatin cytotoxicity and NAC chemoprotection in human tumor cell lines, as assessed by immunoblotting and immunocytochemistry. Cisplatin cytotoxicity was associated with nuclear translocation of apoptosis induction factor, expression of the pro-apoptotic Bax protein, cleavage of caspases 3 and 9, and cleavage of PARP. NAC administration reversed the cytotoxic and apoptotic effects if added concurrent with cisplatin or up to 2 h after cisplatin, but chemoprotection was reduced if NAC administration was delayed more than 2 h and was minimal by 8 h after cisplatin. Expression of tumor suppressor p53 and the cell cycle regulatory protein p21 was stimulated within 5 to 10 min by cisplatin in p53-positive LX-1 small cell lung carcinoma cells, and this effect was blocked by NAC. In p53-negative SKOV3 cells, cisplatin toxicity and NAC chemoprotection remained effective, suggesting that chemoprotection may be mediated through both p53-dependent and -independent pathways. Specific kinase inhibitors demonstrated that cisplatin induced apoptosis through the p38 mitogen-activated protein kinase (MAPK) pathway, not the extracellular signal-regulated kinase MAPK pathway. These results show that NAC blocks both the death receptor and the mitochondrial apoptotic pathways induced by cisplatin. The time course for NAC chemoprotection after cisplatin matches our previous in vivo results and provides an opportunity to manipulate route and timing to maintain cisplatin antitumor efficacy while protecting against chemotherapy side effects.     

Juvenile polyps of the colon and rectum

Summary All polypoid lesions at the Ferguson Clinic for the past 22 years were checked by our pathology department. Of these, 174 were found to be juvenile polyps and were studied in detail. Read at the meeting of the American Proctologic Society, Detroit, Michigan, June 10 to 14, 1973. This paper received the New York Society of Colon and Rectal Surgeons Award. Pathology Department.     

Multispectral analysis of magnetic resonance images

Magnetic resonance (MR) imaging systems produce spatial distribution estimates of proton density, relaxation time, and flow, in a two dimensional matrix form that is analogous to that of the image data obtained from multispectral imaging satellites. Advanced NASA satellite image processing offers sophisticated multispectral analysis of MR images. Spin echo and inversion recovery pulse sequence images were entered in a digital format compatible with satellite images and accurately registered pixel by pixel. Signatures of each tissue class were automatically determined using both supervised and unsupervised classification. Overall tissue classification was obtained in the form of a theme map. In MR images of the brain, for example, the classes included CSF, gray matter, white matter, subcutaneous fat, muscle, and bone. These methods provide an efficient means of identifying subtle relationships in a multi-image MR study.