A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome

Background

The treatment of primary CNS lymphoma (PCNSL) comprises high dose methotrexate (HDMTX) based chemotherapy followed by whole brain radiotherapy (WBRT), the major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in PCNSL in the Indian setting.

Methods

We screened 32 patients and enrolled 22 eligible patients with PCNSL from 2015 to 2017 in a prospective phase II trial. The patients underwent five 2-weekly cycles of induction chemotherapy with rituximab, methotrexate, vincristine, procarbazine. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4 Gy/13 fractions/2.5 weeks while those with partial response (PR), stable or progressive disease (SD or PD) were given standard dose WBRT 45 Gy/25 fractions/5 weeks. Thereafter two cycles of consolidation chemotherapy with cytarabine were given. The primary endpoints of the study were assessment of response rate (RR) and progression free survival (PFS). The secondary endpoints of the study were assessment of overall survival (OS), toxicity profile of treatment and serial changes in quality of life and neuropsychological parameters.

Results

Out of 19 patients who completed HDMTX based chemotherapy, 10 (52.63%) patients achieved CR, 8 (42.11%) patients had PR and 1 patient had PD. After a median follow-up period of 11.25 months, the estimated median OS was 19 months. The actuarial rates of PFS and OS were respectively 94.1 and 68.2% at 1 year and 50.2 and 48.5% at 2 years. Three patients in reduced dose WBRT arm had recurrence and two of them died of progressive disease, whereas there was no recurrence or disease related death in standard dose WBRT arm. On univariate analysis of PFS, age?≤?50 years and use of standard dose WBRT (45 Gy) led to significantly improved outcome (p value 0.03 and 0.02 respectively).

Conclusion

In patients with PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression and early death. Trial Registration No CTRI/2015/10/006268

     

Mediation of Oxidative Stress in HCH-Induced Neurotoxicity in Rat

Effect of repeated oral administration of hexachlorocyclohexane (HCH) (10 and 20 mg/kg body weight/day for 7 and 30 days) on the antioxidant defense system and lipid peroxidation (LPX) of rat cerebral hemisphere (CH) was evaluated. The level of LPX was elevated after 7 days of treatment in crude homogenate (endogenous and FeSO₄- and ascorbic acid–stimulated) and subcellular fractions except the nuclear fraction in which induction was seen after 30 days. The pesticide elicited a significant decrease in the activities of cytosolic total and CN⁻-sensitive superoxide dismutase (SOD) after 7 and 30 days of HCH treatment, but failed to evoke any change in CN⁻-resistant SOD. Catalase activity decreased throughout the treatment period. Cerebral glutathione peroxidase activity (both selenium-dependent and -independent isoenzymes) and the level of glutathione content were decreased after 7 and 30 days of treatment, respectively. Activity of glutathione reductase and content of ascorbic acid, however, were enhanced following the pesticide exposure. The results suggest that repeated HCH administration induced oxidative stress in rat CH. Received: 14 September 1999/Accepted: 2 February 2000     

Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity

Model cell lines developed from MCF7 breast carcinoma cells were used to examine the roles of glutathione S-transferase P1-1 (GSTP1-1) and multidrug resistance protein (MRP) in the protection of cells from 4- nitroquinoline 1-oxide (4NQO) toxicities. Increased expression of GSTP1- 1 alone in MCF7 cells results in limited protection from the formation of 4NQO-derived covalent adducts of nucleic acids but affords no protection from 4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formation and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO- SG) conjugate formation and a MRP-dependent increase in QO-SG efflux. These data indicate that MRP is an important export transporter for the glutathione conjugate of the carcinogen, 4NQO. Moreover, this MRP- dependent efflux activity is necessary to achieve the full protection from 4NQO toxicity-protection that is potentiated by GSTP1-1-mediated QO-SG formation.      

Mini-papad containing cheese powder--a novelty snack food

The present work reports on attempts to develop mini-papads containing cheese powder to create a novel taste, with potential for urban and export markets. Cheese powder was added to black gram flour at 0-50% levels and papads were prepared in the conventional manner by rolling the dough and drying. These papads were deep-fat fried at 180 degrees C. Upto 20% addition of cheese powder gave no perceptible change in taste or flavour of the mini-papads. At 30% addition brown colouration was observed which decreased the sensory appeal. At 40 and 50% levels, although the mouthfeel and flavour of cheese was desirable, browning increased markedly, which drastically lowered the overall acceptability. Ascorbic acid addition at 0.5-1.0% markedly decreased the browning. The papads had a higher fat content on frying as compared to the control but were excellent organoleptically, suggesting them to be a tasty and crunchy snack food.     

A specific and sensitive assay for blood levels of glycated CD59: A novel biomarker for diabetes

Increasing evidence links the complement system with complications of human diabetes. The complement regulatory protein CD59, an inhibitor of formation of membrane attack complex (MAC), is inhibited by hyperglycemia‐induced glycation fostering increased deposition of MAC, a major effector of complement‐mediated tissue damage. CD59, an ubiquitous GPI‐anchored membrane protein, is shed from cell membranes by phospholipases generating a soluble form present in blood and urine. We established an enzyme‐linked immunosorbent assay (ELISA) to measure serum/plasma glycated human CD59 (hCD59) (GCD59) and evaluated its potential as a diabetes biomarker. We used a synthetic peptide strategy to generate (a) a mouse monoclonal antibody to capture hCD59, (b) a rabbit monoclonal antibody to detect GCD59, and (c) a GCD59 surrogate for assay standardization. ELISA conditions were optimized for precision, reproducibility, and clinical sensitivity. The clinical utility of the assay was initially evaluated in 24 subjects with or without diabetes and further validated in a study that included 100 subjects with and 90 subjects without a diagnosis of diabetes. GCD59 (a) was significantly higher in individuals with than in individual without diabetes, (b) was independently associated with HbA1c, and (c) identified individuals with diabetes with high specificity and sensitivity. We report the development and standardization of a novel, sensitive, and specific ELISA for measuring GCD59 in blood. The assay distinguished individuals with diabetes from those without, and showed strong correlation between GCD59 and HbA1c. Because GCD59 likely contributes to the pathogenesis of diabetes complications, measurement of blood levels of GCD59 may be useful in the diagnosis and management of diabetes. Am. J. Hematol. 88:670–676, 2013. © 2013 Wiley Periodicals, Inc.