Phase I trial of gross total resection, permanent iodine-125 brachytherapy, and hyperfractionated radiotherapy for newly diagnosed glioblastoma multiforme

PURPOSE: To evaluate the feasibility of gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy for patients with newly diagnosed glioblastoma. METHODS AND MATERIALS: From April 1999 to May 2002, 21 patients with glioblastoma multiforme were enrolled on a Phase I protocol investigating planned gross total resection and immediate placement of permanent I-125 seeds, followed by postoperative hyperfractionated radiotherapy to a dose of 60 Gy at 100 cGy b.i.d., 5 days per week. Median age and Karnofsky performance status were 50 years (range, 32-65 years) and 90 (range, 70-100), respectively. Toxicity was assessed according to Radiation Therapy Oncology Group criteria. RESULTS: Eighteen patients completed treatment according to protocol. The median preoperative tumor volume on magnetic resonance imaging was 18.6 cm(3) (range, 4.4-41.2 cm(3)). The median brachytherapy dose measured 5 mm radially outward from the resection cavity was 400 Gy (range, 200-600 Gy). Ten patients underwent 12 reoperations, with 11 of 12 reoperations demonstrating necrosis without evidence of tumor. Because of high toxicity, the study was terminated early. Median progression-free survival and overall survival were 57 and 114 weeks, respectively, but not significantly improved compared with historical patients treated at University of California, San Francisco, with gross total resection and radiotherapy without brachytherapy. CONCLUSIONS: Treatment with gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy as performed in this study results in high toxicity and reoperation rates, without demonstrated improvement in survival.     

A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme

Background

Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM).

Objectives

To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM.

Patients and methods

Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150–200 mg/m²/day on days 1–5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1–28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%.

Results

Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32–84); median Karnofsky performance status was 80% (range 60–100%). Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3–4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12–38%]. The median time to progression is 15 weeks (95% C.I. 10–20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome.

Conclusion

This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.     

Continued Smoking in Lung Transplant Patients: A Cross Sectional Survey

Introduction

Smoking is associated with a higher incidence of post-lung transplantation complications and mortality. Prior to inclusion on the lung transplant waiting list in the Czech Republic, patients are supposed to be tobacco free for at least 6 months. Our aim was to determine the prevalence of smoking, validated by urinary cotinine, among patients post lung transplantation and prior to inclusion on the transplant waiting list.

Methods

Between 2009 and 2012, we conducted a cross-sectional survey of urinary cotinine to assess tobacco exposure in 203 patients in the Lung Transplant Program in the Czech Republic. We measured urinary cotinine in 163 patients prior to inclusion on the transplantation waiting list, and 53 patients post bilateral lung transplantation.

Results

15.1% (95% CI 0.078 to 0.269) of all lung transplant recipients had urinary cotinine levels corresponding to active smoking; and a further 3.8% (95% CI 0.007 to 0.116) had borderline results. Compared to patients with other diagnoses, patients with COPD were 35 times more likely to resume smoking post- transplantation (95% CI 1.92 to 637.37, p-value 0.016). All patients who tested positive for urinary cotinine levels were offered smoking cessation support. Only one Tx patient sought treatment for tobacco dependence, but was unsuccessful.

Conclusion

Smoking resumption may be an underrecognized risk for lung transplantation recipients, particularly among patients with chronic obstructive pulmonary disease. More rigorous screening, as well as support and treatment to stop smoking among these patients are needed.     

Impaired nicotinamide adenine dinucleotide synthesis in pyruvate kinase- deficient human erythrocytes: a mechanism for decreased total NAD content and a possible secondary cause of hemolysis

Erythrocytes from individuals with pyruvate kinase (PK) deficiency have approximately half the total (oxidized and reduced) nicotinamide adenine dinucleotide (NAD) of normal erythrocytes. In order to elucidate the mechanism(s) for the decrease in total NAD, we examined NAD synthesis in intact erythrocytes. It is demonstrated that NAD synthesis is impaired in PK-deficient erythrocytes to a degree that is dependent on the PK activity and adenosine 5'-triphosphate (ATP) concentration of these cells. After incubation in the presence of fluoride, which simulates the characteristics of PK deficiency by inhibiting enolase, normal erythrocytes had impaired NAD synthesis and decreased ATP concentrations. Fluoride did not inhibit NAD synthesis in a hemolysate system that is not dependent on glycolysis for ATP generation. These data suggest that fluoride does not inhibit the enzymes of NAD synthesis and that impairment of NAD synthesis by fluoride is mediated by decreased ATP formation. Thus, it is concluded that impaired NAD synthesis in PK-deficient erythrocytes is caused by decreased ATP formation due to the PK deficiency. Since the rate of glycolysis is limited by the availability of NAD+, it is suggested that impaired NAD synthesis causes further ATP depletion and thereby may enhance hemolysis in PK-deficient erythrocytes.     

Lysozyme Activity in the Plasma of Rodents Infected With Their Homologous Trypanosomes

Background

In this study the concentration of lysozyme in blood plasma of Microtus agrestis, Clethrinomys glareolus, Apodemus sylvaticus, BK rats and outbred white mice before and after infection with culture forms of Trypanosoma microti, T, evotomys, T. grosi, T. lewisi and T. musculi respectively was measured.

Methods

Blood samples of rodents, Microtus agrestis, Clethrionomys glareolus, Apodemus sylvaticus, BK rats and outbred mice infected with T. microti, T. evotomys, T. grosi, T. lewisi and T. musculi respectively were collected in heparinized micro- tubes immediately before inoculation and 3, 6, 12, 24, 48, 96 and more than 400 days after intra- perituneal inoculation with 5×10⁵of their homologous trypanosome parasites of which more than half were metacyclic trypomastigote in 0.2 ml of culture medium. Micro- tubes were centrifuged and plasma samples were separated and the lysozyme activity was measured by the agar method.

Results

Levels of lysozyme rose rapidly three to six days after the inoculation to ten to twenty than their pre- infection levels. They then gradually decreased, although after more than one year they were still two to ten folds higher than controls. The highest level measured occurred in rats infected with T. lewisi and the lowest in A. sylvaticus infected with T. grosi. After one year the highest concentration of lysozyme was in mice infected with T. musculi and lowest in A. sylvaticus.

Conclusion

Persistent enhanced lysozyme levels may prevent re- infection with trypanosomes.     

Decrease in subunit aggregation of phosphoribosylpyrophosphate synthetase: a mechanism for decreased nucleotide concentrations in pyruvate kinase-deficient human erythrocytes

Pyruvate kinase (PK)-deficient RBCs have several unexplained metabolic abnormalities, such as decreased concentrations of total adenine nucleotides (AMP, ADP, and ATP) and total (oxidized and reduced) nicotinamide adenine dinucleotide (NAD). Because 5-phosphoribosyl-1- pyrophosphate (PRPP) is an intermediate in the synthesis of adenine nucleotides and NAD, we investigated PRPP synthetase (PRPPS), the enzyme responsible for PRPP synthesis. This enzyme is regulated, in part, by changes in its state of subunit aggregation. The proportion of aggregated PRPPS can be altered in vitro by ATP and 2,3- diphosphoglycerate (DPG). Because PK-deficient RBCs have decreased ATP and increased DPG concentrations, we examined the state of subunit aggregation of PRPPS in RBCs from normal and PK-deficient subjects, using gel permeation chromatography. Young normal RBCs have more aggregated PRPPS than do older RBCs. In contrast, due to their decreased ATP and increased DPG concentrations, PK-deficient RBCs contain less aggregated PRPPS than do RBCs of comparable age without PK deficiency. These data suggest that PRPPS should be less active in vivo in PK-deficient RBCs. This may play a key role in mediating the decreases in total adenine nucleotide and total NAD concentrations in these RBCs.     

Adhesion of sickle neutrophils and erythrocytes to fibronectin

The pathophysiology of vaso-occlusive crisis in sickle cell disease involves interactions among blood cells, plasma proteins, and vessel wall components. The initial goal of this work was to quantify the adhesion of sickle red blood cells (RBCs) to fibronectin immobilized on glass under both static and dynamic shear stress conditions. High-power microscopic inspection of static assay plates showed striking numbers of adherent neutrophils as well as RBCs. Sickle neutrophils and RBCs were significantly more adherent to fibronectin than the corresponding normal cells in static adhesion assays. Adhesion of both sickle neutrophils and sickle RBCs in dynamic adhesion assays was promoted by a period of static incubation preceding initiation of shear stress conditions. Adherent neutrophils remained attached at shear stresses up to 51 dyne/cm2; most adherent RBCs were attached at shear stresses up to 13 dyne/cm2, but detached at a shear stress of 20 dyne/cm2. Sickle neutrophil adhesion was enhanced significantly by autologous plasma. Elevated levels of plasma interleukin-6 (IL-6; but not IL-1 or IL-8) were found in 6 of 9 sickle cell disease samples examined, and elevated levels of tumor necrosis factor were found in 2 of 9 samples. Plasma IL- 6 levels correlated positively with both the number of sickle neutrophils adherent to fibronectin and the ability of sickle plasma to enhance adhesion of normal neutrophils to fibronectin. These data suggest possible roles for neutrophil activation and for fibronectin in mediating sickle neutrophil and RBC adhesion.