Management of Primary Central Nervous System Lymphoma Using Intra-Arterial Chemotherapy With Osmotic Blood-Brain Barrier Disruption: Retrospective Analysis of the Sherbrooke Cohort.

BACKGROUND: Primary central nervous system lymphomas (PCNSL) are rare and aggressive CNS tumors. Current management involves high-dose methotrexate (HD-MTX) typically administered intravenously (IV), despite the existence of the blood-brain barrier (BBB), which significantly decreases its bioavailability. Cerebral intra-arterial chemotherapy (CIAC) coupled with osmotic BBB disruption (OBBBD) can theoretically circumvent this issue. METHODS: We performed a retrospective analysis of patients with newly diagnosed PCNSL treated with HD-MTX-based CIAC+OBBBD at our center between November 1999 and May 2018. OBBBD was achieved using a 25% mannitol intra-arterial infusion. Patients were followed clinically and radiologically every month until death or remission. Demographics, clinical and outcome data were collected from the medical record. All imaging studies were reviewed for evidence of complication and outcome assessment. Kaplan-Meier analyses were used to compute remission, progression-free survival (PFS) as well as overall survival times. Subgroup analyses were performed using the log rank test. RESULTS: Forty-four patients were included in the cohort. Median follow-up was 38 months. Complete response was achieved in 34 patients (79%) at a median of 7.3 months. Actuarial median survival and PFS were 45 months and 24 months, respectively. Age, ECOG and lesion location did not impact outcome. Complications included thrombocytopenia (39%), neutropenia (20%), anemia (5%), seizures (11%), stroke (2%), and others (20%). CONCLUSION: CIAC using HD-MTX-based protocols with OBBBD is a safe and well-tolerated procedure for the management of PCNSL. Our data suggests better PFS and survival outcomes compared to IV protocols with less hematologic toxicity and good tolerability, especially in the elderly.

Hormonal and spatial regulation of nitric oxide synthases (NOS) (neuronal NOS, inducible NOS, and endothelial NOS) in the oviducts.

Nitric oxide (NO) is a free radical produced by the action of NO synthases (NOS) and is known to be involved in the regulation of many reproductive events that occur in the oviducts. The oviducts are highly specialized organs that play crucial roles in reproduction by providing an optimal environment for the final maturation of gametes, fertilization, and early embryo development. In this study, we analyzed the expression, hormonal regulation, and cellular distribution of neuronal, inducible, and endothelial NOS in different bovine oviduct segments to better understand the roles played by these enzymes in oviductal functions in vivo. Quantitative RT-PCR analysis revealed that NOS isoforms are hormonally regulated and differentially expressed along the oviduct throughout the estrous cycle. All NOS were highly expressed around the time of estrus, and immunohistochemistry studies determined that neuronal NOS, inducible NOS (iNOS), and endothelial NOS are differentially distributed in cells along the oviduct. Interestingly, our results showed that estradiol selectively up-regulates iNOS expression in the oviduct during the periovulatory period corresponding to the window of ovulation, oocyte transport, and fertilization. The resulting NO production by this high-output NOS may be of crucial importance for reproductive events that occur in the oviduct. This study provided the first demonstration that NO production is hormonally regulated in the mammalian oviducts in vivo. Our results suggest that neuronal NOS, iNOS, and endothelial NOS contribute to oviductal functions in a timely and site-specific manner.