We evaluated the safety and biologic activity of the BH3 mimetic protein, navitoclax, combined with rituximab, in comparison to rituximab alone. One hundred and eighteen patients with chronic lymphocytic leukemia (CLL) were randomized to receive eight weekly doses of rituximab (arm A), eight weekly doses of rituximab plus daily navitoclax for 12 weeks (arm B) or eight weekly doses of rituximab plus daily navitoclax until disease progression or unacceptable toxicity (arm C). Investigator-assessed overall response rates (complete [CR] and partial [PR]) were 35% (arm A), 55% (arm B, p = 0.19 vs. A) and 70% (arm C, p = 0.0034 vs. A). Patients with del(17p) or high levels of BCL2 had significantly better clinical responses when treated with navitoclax. Navitoclax in combination with rituximab was well tolerated as initial therapy for patients with CLL, yielded higher response rates than rituximab alone and resulted in prolonged progression-free survival with treatment beyond 12 weeks.

Blood-brain barrier disruption with a hyperosmolar agent, mannitol, has previously been demonstrated to increase intracerebral methotrexate levels in rats. To determine the optimum conditions for blood-brain barrier disruption without producing neurological sequelae, adult Sprague-Dawley rats were infused with mannitol via the internal carotid artery at rates varying from 0.25 to 0.5 ml.s-1.kg-1. Methotrexate and Evans blue were used as markers of blood-brain barrier disruption. The optimum rate of mannitol that produced blood-brain barrier disruption without neurological sequelae was 0.25 ml.s-1.kg-1 for 20 s. The duration of blood-brain barrier opening was maximal for approximately 5 min and then rapidly reversed. Methotrexate levels on the mannitol-infused side were four to five times that of the noninfused hemisphere. Light microscopy and electron microscopy did not demonstrate any consistent changes that could be attributed to blood-brain barrier disruption nor did it elucidate the mechanism. This model should prove useful in the investigation of the treatment of intracerebral tumors with blood-brain barrier disruption. This study shows that maximal intracerebral methotrexate levels were obtained when methotrexate was infused before or within 5 min of the mannitol infusion.

This study shows that helical CT is a highly accurate technique for estimating volume, even in the presence of simulated respiratory motion.

Aims To determine whether lean body mass (LBM), a possible surrogate of liver and kidney volumes, correlates with hepatic and renal drug clearances. Methods Twenty-one disease-free patients with a history of cancer and with normal hepatic and renal function were studied. Salivary pharmacokinetics of oral antipyrine (1200 mg ) and 24 h creatinine clearance were determined following the determination of LBM by dual energy X-ray absorptiometry and the determination of liver and kidney volumes by helical CT scanning. Stepwise multiple regression analysis, incorporating the independent variables of age, height, weight, sex, BSA, LBM, alcohol consumption, smoking status and liver volume and the dependent variable antipyrine clearance, indicated that LBM was the only independent correlate of antipyrine clearance. A stepwise multiple regression analysis with kidney volume in the independent variables, and creatinine clearance as dependent variable, showed that kidney volume and age were the only independent correlates of creatinine clearance. A nomogram using serum creatinine and LBM was comparable with the Cockcroft and Gault nomogram in calculating creatinine clearance.Conclusions Of the anthropometric variables tested, LBM was the only determinant of antipyrine clearance, but this was not due to a relationship between LBM and liver volume. By contrast, the relationship between creatinine clearance and LBM appeared to be due to a relationship between LBM and kidney volume.

Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.

The results of a questionnaire answered by 205 medical patients are reported (100 patients with cancer and 105 with other medical conditions). The questionnaire examined beliefs and preferences regarding various aspects of cancer, including expectations of medical management and treatment. The issues examined relate to beliefs and preferences about information giving, trust of doctors' control of decision making, expectations of help, expectations of treatment, the treatment of cancer pain including morphine use, and issues of terminal care. Some patients appear to hold the inconsistent beliefs that doctors should tell them all they want to know, but that doctors do not know a lot of what they would like to be told. They were also ambivalent about who should make decisions, patient or doctor, suggesting a preference for collaborative consensus decision making. It may be important to inform patients more clearly about what doctors can and cannot reasonably be expected to know and do. Some incorrect beliefs about management were related to fear about having cancer. The results suggest the need for better communication between patients and their professional carers and the need for accessible health information about cancer management to be available to the general public.

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