First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Structure of the sucrose-specific porin ScrY from Salmonella typhimurium and its complex with sucrose.

The X-ray structure of a sucrose-specific porin (ScrY) from Salmonella typhimurium has been determined by multiple isomorphous replacement at 2.4 A resolution both in its uncomplexed form and with bound sucrose. ScrY is a noncrystallographic trimer of identical subunits, each with 413 structurally well-defined amino acids. A monomer is built up of 18 anti-parallel beta-strands surrounding a hydrophilic pore, with a topology closely similar to that of maltoporin. Two non-overlapping sucrose-binding sites were identified in difference Fourier maps. The higher permeability for sucrose of ScrY as compared to maltoporin is mainly accounted for by differences in their pore-lining residues.

Crystallization and preliminary X-ray diffraction analysis of ScrY, a specific bacterial outer membrane porin.

The sucrose-specific outer membrane porin ScrY of Salmonella typhimurium was isolated from Escherichia coli K-12 strain KS 26 containing the plasmid pPSO112. The protein was purified to homogeneity by differential extraction of the cell envelope in the presence of the detergents sodium dodecyl sulfate and lauryl (dimethyl)-amine oxide (LDAO). The porin had apparent molecular weights of 58 kDa and 120 kDa for the monomer and for the trimer, respectively, on SDS/PAGE. The purified trimers were crystallized using poly(ethylene glycol) 2000 and the detergents octylglucoside (OG) and hexyl-(dimethyl)-amine oxide (C6DAO). X-ray diffraction of the crystals showed reflections to 2.3 A. The space group of the crystals was R3 and the lattice constants of the hexagonal axes were a = b = 112.85 A and c = 149.9 A. The crystal volume per unit of protein molecular weight was 3.47 A3/Da.

Antitumor activity of liposome-encapsulated doxorubicin in advanced breast cancer: phase II study.

Previous studies in animals have demonstrated liposome-encapsulated doxorubicin (LED) has substantially less cardiac toxicity than free doxorubicin but retains antitumor activity. In a phase I clinical study of LED, the maximum tolerated dose was 90 mg/m2 and dose-limiting toxicity was considered to have been reached when granulocytopenia was produced. We used LED to treat 20 patients with advanced, measurable breast cancer. LED was given at doses of 60-75 mg/m2 every 3 weeks as an intravenous infusion. Regression of disease was objectively measured in nine patients; in five of these patients, complete regression of the index lesion occurred. The mean duration of the responses was 7 months. Hematologic toxicity consisted of grade 1-2 leukopenia in some patients. Gastrointestinal toxicity and mucositis were generally mild and tolerable. Alopecia occurred in all patients and usually was complete. Twelve patients received cumulative doses of LED of greater than 400 mg/m2 and were evaluated with radionuclide ventriculograms. In eight patients, the cumulative dose was greater than 500 mg/m2, and five had endomyocardial biopsies. Four of these biopsy results were Billingham grade 0, while one (cumulative LED dose, 750 mg/m2) showed grade 1 changes with mild myofibrillar loss and dilatation of the sarcoplasmic reticulum involving less than 5% of cardiac myocytes. Two patients had decreases in left ventricular ejection fraction. One of these patients had received a total dose of LED of 630 mg/m2 and had a decline of 13% in left ventricular ejection fraction, but had no clinical evidence of congestive heart failure and had a Billingham grade 0 endomyocardial biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin.

We have treated 14 cancer patients with liposome-encapsulated doxorubicin (LED) at doses of 30, 45, 60, and 90 mg/m2. Nausea and vomiting, phlebitis, and stomatitis were minimal or absent at each dose, but dose-limiting granulocytopenia occurred at 90 mg/m2. Thrombocytopenia and/or anemia also occurred in all patients treated at 60 or 90 mg/m2. Complete alopecia was seen in one of three cases at 60 mg/m2 and all cases at 90 mg/m2. No hepatic, renal, or other major organ toxicities were encountered. Clinical cardiac toxicity did not occur in any patient, but the cumulative doxorubicin doses in 13 cases were less than 400 mg/m2. The plasma elimination of LED out to 24 hours was analyzed in terms of a two-compartment model. Depending upon the dose and the infusion time, maximum plasma concentrations ranged from 2.6 mumol/L to 36.89 mumol/L and the area under the plasma concentration x time curve (AUC) values ranged from 1.86 mumol/L x h/L to 49.57 mumol x h/L. These values are significantly higher than those expected for free doxorubicin. Urinary excretion of LED was approximately 10% after 24 hours. Doxorubicinol and doxorubicinone appeared at low levels in plasma 12 to 24 hours after injection. LED pharmacokinetics differ from those of free drug by the higher plasma levels and AUC of doxorubicin achieved, and by the low conversion of LED to metabolites. Overall, LED was well tolerated and produced only moderate nausea and vomiting and little stomatitis at myelosuppressive doses. The study also suggested that LED produces less venous sclerosis than free doxorubicin, but this requires further clinical verification.

A phase I/II study of intraperitoneally administered doxorubicin entrapped in cardiolipin liposomes in patients with ovarian cancer.

A phase I and II clinical trial of intraperitoneally administered liposome-encapsulated doxorubicin in patients with advanced ovarian cancer is being evaluated. Doxyrubicin liposomes were prepared with cardiolipin, phosphatidyl choline, cholesterol, and sterarylamine and sized by flow cytometry before administration. Fifteen patients have been treated with 42 cycles of intraperitoneal liposome-encapsulated doxrubicin. Liposome-encapsulated doxorubicin in 2 L of normal saline solution was infused over 1 hour through an infusaport into the peritoneal cavity with a dwell time of 4 hours every 21 days. Liposome-encapsulated doxorubicin has been administered at escalating doses up to 100 mg/2 L and has been well tolerated. Increased bowel motility with mild-to-moderate abdominal distress has been encountered during the first 24 hours after administration. There has been one patient with presumed chemically induced peritonitis after a temperature elevation to 39.5 degrees C. There has been no myelosuppression, abnormalities of liver function tests, or alopecia. Nausea and vomiting were minimal. Liposome-encapsulated doxorubicin was extravasated in two patients without sequelae. Drug levels were measured after completion of infusion. At a dose of 70 mg, the peak intraperitoneal concentration was 28.6 micrograms/microliter, which was reduced to 23.6 micrograms/microliter by 2 hours. Concurrent plasma levels were in the range of 0.2 to 0.5 micrograms/microliter. A similar pattern was observed at other doses. The maximum tolerable dose has not yet been obtained. There were three responders in the 10 evaluable patients. The preliminary experience with intraperitoneal liposome-encapsulated doxorubicin is encouraging.

Modulation of multidrug resistance in Chinese hamster cells by liposome-encapsulated doxorubicin.

A Chinese hamster cell line (LZ), selected for multidrug resistance (MDR), exhibits a 3,000-fold resistance to doxorubicin, compared to parental V-79 cells. These drug resistant cells have amplified MDR genes, overexpress P-glycoprotein, and in the presence of doxorubicin show reduced intracellular drug accumulation. Using liposome-encapsulated doxorubicin (Rahman et al. Cancer Res. 45:796-803; 1985), we observed partial reversal of the resistance of LZ cells to this drug and a higher intracellular drug accumulation, compared to free drug. Parental V-79 cells, however, did not exhibit differences in survival or in drug accumulation when treated with encapsulated or free doxorubicin. Comparison of the effect of liposome-encapsulated doxorubicin with that of verapamil in reversing drug resistance showed that the liposomal preparation was as effective as verapamil used at its maximum clinically relevant concentration (1.5 microM). These results suggest that the use of liposomes as carriers of anticancer drugs may offer a strategy for overcoming MDR in tumor cells.

Comparative hemodynamic effects of digoxin vs nitroprusside in conscious dogs with aortocaval fistula-induced chronic left ventricular volume overload and normal systolic performance.

We compared the effects of IV digoxin (0.04 mg/kg) and nitroprusside (NP) (1.2 and 1.8 microgram/kg/min) on left ventricular (LV) performance in six preinstrumented conscious dogs with 3 and 6 hours after digoxin administration (serum level, 3.5 +/- 0.6 ng/ml), there were no changes in heart rate, LV systolic (LVSP) and end-diastolic (LVEDP) pressures, LV dimensions, LV dP/dtmax, or percent minor diameter shortening as compared to control values in the resting state, after beta blockade, or during phenylephrine infusion. By contrast, NP produced a significant reduction (p less than 0.05) in LVEDP (16 +/- 3 to 10 +/- 3 mm Hg) at the smaller dose which caused no change in mean aortic pressure. The larger dose of NP further reduced LVEDP and evoked significant (p less than 0.05) decreases in LVSP (124 +/- 5 to 117 +/- 7 mm Hg), mean aortic pressure (85 +/- 3 to 78 +/- 5 mm Hg), and LV end-diastolic dimension (LVEDD) (53.0 +/- 5.5 to 52.0 +/- 5.7 mm), while augmenting LV dp/dtmax (3288 +/- 266 to 3647 +/- 130 mm Hg/sec). Beta blockade with IV propranolol (2.0 mg/kg) prevented the rise in LV dP/dtmax after high-dose NP administration but did not alter the reductions in mean aortic pressure, LVEDP, and LVEDD. This study indicates that NP, but not digitalis, has a favorable effect on LV hemodynamics in the volume-overloaded heart with normal LV systolic contraction and high-output CHF resulting from increased blood volume and reduced LV diastolic compliance. At least part of the apparent improvement in LV performance observed with high-dose NP is sympathetically mediated since it can be attenuated by beta blockade.