Serum BCL2/IGH DNA in follicular lymphoma patients: a minimal residual disease marker

The majority of follicular lymphoma patients carry a t(14,18) juxtaposing the BCL2 oncogene to the immunoglobulin heavy chain joining region (IgH). Molecular analysis for follicular lymphoma-specific DNA translocations may permit evaluation of minimal residual disease (MRD). We identify extracellular BCL2/IGH transgene DNA in the serum of patients with follicular lymphoma, and evaluate its utility as a surrogate marker. DNA was harvested from both the sera and bone marrow of 5 stage IV follicular lymphoma patients prior to and after chemotherapy and following a novel vaccine-based regimen. Serial PCR amplifications were performed using heminested BCL2-specific major breakpoint cluster region (MBR) primers and the immunoglobulin heavy chain consensus primer. Amplification products were detected by agarose gel electrophoresis, and comparison was made to amplification products from the original tumor biopsy. Results show that four of the five lymphoma patients carried extracellular BCL2/IGH transgene DNA in their serum. The remaining patient did not have an amplification product from either the tumor or the serum, suggesting either the absence of a translocation or the presence of a variant translocation not detectable with this primer set. Transgene DNA was detectable in serum even in patients with MRD, comparing favorably with bone marrow results. In at least one patient, the presence of the transgene in serum at the conclusion of therapy preceded relapse. In conclusion, it seems that tumor-specific, extracellular DNA is present in the serum of follicular lymphoma patients, including those with MRD. Because extracellular DNA may be released into the bloodstream by tumor throughout the body it may be less subject to sampling error, and appears to be an ideal surrogate marker.     

Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: the Sherbrooke experience

BACKGROUND: The treatment of malignant brain tumors is hampered by the presence of the blood-brain barrier, which limits chemotherapy penetration to the central nervous system (CNS). In recent years, different strategies have been designed to circumvent this physiologic barrier. The osmotic blood-brain barrier disruption (BBBD) procedure is one such strategy, and has been studied extensively in preclinical and clinical studies. The authors detail their experience so far with the procedure in the context of an open Phase II study in the treatment of malignant brain tumors. METHODS: Patients with histologically proven malignant gliomas, primitive neuroectodermal tumors, primary CNS lymphomas, and metastatic disease to the brain were eligible. Patients enrolled were treated every 4 weeks (1 cycle) for < or = 12 cycles. A methotrexate-based regimen was offered to patients with lymphomas, whereas a carboplatin-based regimen was offered to patients with all other histologies. Before intraarterial chemotherapy infusion, patients were submitted to an osmotic BBBD procedure. RESULTS: Seventy-two patients were included in the current report. The overall median survival times (MST) from treatment initiation for glioblastoma multiforme (GBM), anaplastic oligodendrogliomas, primary CNS lymphomas, and metastases were, respectively, 9.1, 13.9, not reached, and 9.9 months, whereas time to disease progression was 4.1, 9.2, 12.3, and 3.3 months. The MST from diagnosis was 32.2 months for GBM. CONCLUSIONS: These encouraging results prompted the authors to further refine their knowledge of the potential contribution of this procedure in the treatment of brain tumors. These authors designed a randomized Phase III study for patients with GBM that is now open.     

Nonsteroidal antirheumatics and the kidney

The renal side effects of nonsteroidal anti-inflammatory drugs are very often and could be seen in 5% of patients who are treated with this drugs. These side effects could be separated in 5 clinical syndromes: 1. acute renal failure, 2. acute interstitial nephritis with nephrotic syndrome, 3. electrolyte and fluid disorders, 4. hypertension and 5. analgesic nephropathy. There are a lot data in the literature which suggest that selective COX-2 inhibitors (rofecoxib and celecoxib) produce the similar effects on the kidney as traditional nonsteroidal anti-inflammatory drugs (inhibitors of COX-1 and COX-2).     

Expression of CD97 and adhesion molecules on circulating leukocytes in patients undergoing coronary artery bypass surgery

OBJECTIVE: Leukocyte activation is thought to be responsible for the adverse effects and postoperative complications following cardiopulmonary bypass (CPB). A novel cell surface molecule, CD97, is a sensitive marker of leukocyte and primary lymphocyte activation. The present study aimed to determine the activation of different leukocyte subsets by comparing the expression of CD97 and adhesion molecules (CD11, CD18) in patients receiving coronary surgery with or without CPB. METHODS: 30 patients were enrolled and scheduled for coronary bypass surgery under CPB (20 patients, group A) and with off-pump (OP) operation (10 patients, group B). Blood samples were taken before and during surgery, and over the following first week. RESULTS: Here, we report an early decrease in CD97 expression of granulocytes (PMN) and monocytes (MC) followed by an intensive increase reaching the maximum on postoperative days 2 and 3 in patients operated with CPB. The rate of active CD97-positive lymphocytes showed a marked, gradual increase until postoperative day 3 and remained elevated up to day 7 after CPB. OP surgery resulted in moderate alteration in the presence of CD97 on PMN, MC and lymphocytes. The expression of adhesion molecules was similar to CD97 in all leukocyte subsets. CONCLUSION: The findings about CD97 expression suggest considerable leukocyte activation following coronary bypass with CPB compared to OP surgery. The collected data show that the lymphocytes are highly activated and involved in leukocyte sequestration after CPB. Moreover, the importance of CD97 in CPB-related inflammatory response can be stated.     

Chronic maternal methanol inhalation in nonhuman primates (Macaca fascicularis): exposure and toxicokinetics prior to and during pregnancy

Toxicokinetic studies were conducted following daily inhalation exposure to methanol vapor prior to and throughout pregnancy in adult female Macaca fascicularis monkeys. They were part of a larger study to investigate the effects of chronic methanol exposure on maternal reproductive performance and early offspring effects. In a two-cohort study design, 48 females (24/cohort) were assigned to parallel exposure groups at 0 (control), 200, 600, or 1800 ppm methanol vapor for approximately 2.5 h/day, 7 days/week throughout breeding and pregnancy. Blood methanol at 30 min postexposure was monitored biweekly. The time course for the clearance of blood MeOH concentrations following exposure was characterized on four occasions: twice during the prebreeding period and during mid- and late pregnancy. Average blood methanol concentrations at 30 min postexposure were 5, 11, and 35 microg/ml across all four toxicokinetic studies in the 200, 600 and 1800 ppm groups, respectively. Blood concentrations in the 200 ppm group were barely above basal (preexposure) blood methanol concentrations or those observed in the control group (approximately 3 microg/ml). Nonlinear elimination kinetics were observed in most of the 1800 ppm group females. There was a decrease in elimination half-life (7-20%) and an increase in clearance (30%) after 3-months of daily MeOH exposure compared to the initial exposure. There were no statistically significant changes in the first-order blood methanol half-life or clearance during pregnancy, but the mean distribution volume per kilogram body weight decreased by 22% and 17% in the 600 and 1800 ppm groups. Plasma formate levels did not differ between the methanol and control exposure groups. Plasma formate and serum folate concentrations increased slightly over the course of this study in both the exposed and control groups but these increases were not related to methanol exposure.