Flexible granulocyte colony-stimulating factor dosing in ovarian cancer patients who receive dose-intense taxol therapy

As has been reported with other chemotherapeutic agents, evidence is emerging to suggest that increased taxol dose intensity is associated with improved therapeutic efficacy. Granulocyte colony-stimulating factor (G-CSF) effectively protects the bone marrow from taxol-induced neutropenia and allows for higher taxol dose administration. This report addresses the optimal use of G-CSF as a supportive agent for dose-intense taxol therapy. Forty-seven patients were evaluated. Each ovarian cancer patient received taxol with G-CSF support, with starting doses of 250 mg/m2 per 21 days and 10 micrograms/kg/d, respectively. Five patients were treated with the same dose of G-CSF for multiple cycles. Forty-two patients were given "flexible" G-CSF dosing. Instead of reducing taxol dose after a cycle of therapy complicated by febrile neutropenia (F+N+), the G-CSF dose was increased. Only after a second episode of F+N+ was the taxol dose reduced. The initial 5 patients who developed F+N+ after taxol (250 mg/m2) and G-CSF (10 micrograms/kg/d) were retreated at the same doses of both drugs; subsequently, 4 of 5 patients had another episode of F+N+. With flexible G-CSF dosing, taxol dose intensity could be maintained at the target level in 34 of 42 patients (81% of the cohort). Sixteen of these patients (38% of the cohort) would have required taxol dose reductions for F+N+ if flexible G-CSF dosing had not been used. By increasing the G-CSF dose when indicated, patients at high risk for recurrence of F+N+, because they had already experienced one episode, appeared to have a lower risk of developing a recurrent episode. These data suggest that flexible G-CSF dosing may have merit and may allow the administration of more dose- intense taxol. A prospective, randomized, controlled clinical trial of flexible G-CSF dosing versus fixed-dose G-CSF appears warranted.     

Donor immunization with Haemophilus influenzae type b (HIB)-conjugate vaccine in allogeneic bone marrow transplantation

Bone marrow transplant patients are at increased risk for infections with polysaccharide encapsulated organisms and respond poorly to polysaccharide vaccines. We evaluated the effect of donor immunization with Haemophilus influenzae type b (HIB) polysaccharide-conjugate vaccine on recipient antibody responses following allogeneic bone marrow transplantation. Thirty-two allogeneic transplant patients and their donors were immunized before transplantation with HIB-conjugate, tetanus toxoid and 23-valent pneumococcal vaccines. Following transplantation, patients received HIB-conjugate and tetanus toxoid vaccines at 3, 6, 12, and 24 months and 23-valent pneumococcal vaccine at 12 and 24 months. Thirty-three patients with unimmunized donors were immunized following transplantation in an identical manner. Patients whose donors were immunized had significantly higher total anti-HIB antibody concentrations at 3 months (P = .0001), 6 months (P = .0001), 12 months (P = .0001), and 24 months (P = .002) after transplant compared with patients whose donors were unimmunized. Higher antitetanus toxoid antibody concentrations were also noted in patients with immunized donors, whereas donor immunization with pneumococcal vaccine had no effect on antibody concentrations following transplantation. Donor immunization with HIB-conjugate vaccine resulted in higher antibody concentrations in patients as early as 3 months after allogeneic transplantation and may be an effective strategy to prevent HIB infections.     

Pivotal role of the B7:CD28 pathway in transplantation tolerance and tumor immunity

The above story illustrates the translation of basic scientific discoveries to the clinic. In vitro and preclinical in vivo experimentation suggests that modulation of the B7:CD28 pathway will result in either amplification or suppression of the immune response. Considering the frequency with which diseases characterized by either inadequate or dysregulated immune function present to the practicing hematologist or oncologist, it is not difficult to envisage clinical applications for reagents that modulate this pathway. However, we still have much to learn about the function and clinical potential of this and other potentially redundant costimulatory pathways and therefore we suspect that this story will become considerably more complex over the next few years.     

Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality

A prospective randomized trial of therapy for severe aplastic anemia was designed to compare early bone marrow transplantation with conventional treatments. All patients with a sibling matched at the major histocompatibility region were transplanted. Transplantation was performed with 17-100 (median 33) days of original diagnosis. Conventional treatments included transfusion support with or without androgens. Twenty-four of 36 patients intered on the transplant arm are alive after 4-20 (median 9) mo with full marrow reconstitution. Only two are limited by chronic graft-versus-host disease. In contrast only 12 of 31 conventionally treated patients are alive. Six of these survivors have improved, five incompletely. The 19 nontransplant deaths have occurred within 1-11 (median 3) mo of diagnosis. Compared to nontransplant regimens, early transplantation more effectively restores normal marrow function and decreases the acute mortality of severe marrow aplasia (p = 0.006). Pending longer follow-up, early marrow transplantation appears to be the most effective available treatment for severe aplastic anemia.     

Isolation of transplantable erythroleukemia cells from mice infected with helper-independent Friend murine leukemia virus

The Friend virus complex contains a helper-independent retrovirus, F- MuLV, and a replication-defective retrovirus, SFFV. Murine erythroleukemia cell lines (MEL) have been isolated previously from the leukemic tissues of mice infected with such stocks of Friend virus complex. Since our laboratory has shown that either F-MuLV or SFFV can induce a lethal erythroproliferative disease, it has been unclear which of the properties of conventional MEL cells were causally related to the infection of these cells by F-MuLV and which properties were related to the infection of these cells by SFFV. In this article, we have focused on the helper-independent component of the Friend virus complex, F-MuLV clone 57, which has recently been purified by molecular cloning. We report a method for the reproducible isolation of a new type of murine erythroleukemia cell that can be isolate from mice infected with F-MuLV clone 57. We have designated these cells as 57 TP- 1, indicating their origin from mice infected with F-MuLV clone 57 and their characteristics as transplantable erythroleukemia cells. Upon subcutaneous, intraperitoneal, or intravenous inoculation of these cells, 57 TP-1 cells grow in the hematopoietic organs of the recipient mice. No subcutaneous or intraperitoneal nodules occur. Both F-MuLV and a Friend MCF virus can be detected in these cells, but no evidence to SFFV can be found.     

Intracranial electrographic analysis of preictal spiking and ictal onset in uni‐ and bitemporal epilepsy

Aim. Ictal onset patterns in bilateral mesial temporal lobe epilepsy have not been comprehensively studied. A retrospective review of intracranial electrographic data was undertaken to establish whether it is possible to distinguish between unilateral and bilateral mesial temporal lobe epilepsy based on ictal onset patterns, including periodic preictal spiking. Methods. A total of 470 ictal onset patterns were analyzed by bitemporal extraoperative electrocorticography in 13 patients with medically intractable mesial temporal lobe epilepsy. Ictal onset patterns were categorized, by frequency, as type A (<12 Hz), type B (12–40 Hz) and type C (>40 Hz). Preictal rhythmic spiking, of at least five seconds duration, and time to contralateral propagation were also measured with each ictal event. We determined if the proportion of “ictal onset pattern frequencies” or “incidence of preictal spiking” differed between unilateral and bilateral mesial temporal lobe epilepsy. Results. Seven patients with unilateral mesial temporal lobe epilepsy received surgery and achieved Engel class I outcomes, while the remaining six did not undergo resective surgery, due to the bilateral ictal onsets in extraoperative electrocorticography. The proportion of patients experiencing any preictal spikes was higher in unitemporal than in bitemporal cases (100% vs 50%; p=0.069). Of the 470 ictal onset patterns analyzed (174 unitemporal and 296 bitemporal), a significant greater percentage of preictal spikes was found in unilateral cases (78% unitemporal vs 14% bitemporal; p=0.002). Low‐frequency patterns were more evident in bitemporal cases (45%) than in unitemporal (10%), although the difference was not statistically significant (p=0.129). No differences were detected between the unitemporal and bitemporal groups regarding age at onset or at presentation. Conclusion. A greater proportion of preictal spiking, based on extraoperative electrocorticography, was present in unilateral, compared to bilateral, mesial temporal lobe epilepsy. Further studies are warranted to determine the causal significance of preictal spiking in mesial temporal lobe epilepsy.     

Localization of factor VIII-procoagulant antigen: an immunohistological survey of the human body using monoclonal antibodies

Various organs, including liver, spleen, heart, lung, kidney, intestines, lymph nodes, pancreas, bone marrow, and thymus, were investigated for the presence of factor VIII-procoagulant antigen (VIIICAg) and factor VIII-related antigen (VIIIRAg), using a panel of monoclonal antibodies directed to factor VIII-von Willebrand factor in combination with a sensitive immunoperoxidase staining technique. In addition to hepatic sinusoidal endothelial cells, the presence of VIIICAg was demonstrated in mononuclear cells sporadically present in lymph nodes, in the alveolar septa of lung, and in the red pulp of spleen. The identity of these mononuclear cells could not be unequivocally determined. Based on morphological criteria, however, it is tentatively concluded that these cells are nonlymphoid and belong to the mononuclear phagocyte system. The presence of VIII-RAg was confined to vascular endothelial cells, hepatic sinusoidal endothelial cells, cells lining the venous sinuses of the red pulp of the spleen, cells lining renal glomeruli and lung capillaries, platelets, and megakaryocytes.     

Failure of recombinant human granulocyte-macrophage colony-stimulating factor therapy in aplastic anemia patients with very severe neutropenia

Four patients with very severe aplastic anemia refractory to antilymphocyte globulin were administered recombinant human granulocyte- macrophage--colony stimulating factor (GM-CSF). One patient with minimal residual myelopoiesis responded transiently to two separate courses of GM-CSF at 4 and 8 micrograms/kg/d administered intravenously and another course at 4 micrograms/kg/d administered subcutaneously. Septicemia and bilateral pneumonia that had been resistant to conventional therapy resolved. Three patients with no evidence of residual myelopoiesis did not respond to GM-CSF. In one patient, the dose was increased to 32 micrograms/kg/d with no effect on hematopoiesis. Immediate side effects were minimal at GM-CSF doses up to 16 micrograms/kg/d. GM-CSF may, however, have been involved in the pathophysiology of thrombosis of the inferior vena cava in the patient administered 32 micrograms/kg/d. We conclude that GM-CSF does not induce hematopoiesis in long-standing, severe, treatment-resistant aplastic anemia with complete myelopoietic failure. However, in patients with minimal residual myelopoiesis, GM-CSF could be a promising adjuvant therapy for severe infection.     

Metabolic Syndrome features and risk of neural tube defects

Background

Maternal obesity and pre-pregnancy diabetes mellitus, features of the metabolic syndrome (MetSyn), are individual risk factors for neural tube defects (NTD). Whether they, in combination with additional features of MetSyn, alter this risk is not known. We evaluated the risk of NTD in association with maternal features of the MetSyn.

Methods

We used a population-based case-control study design in the province of Ontario, Canada. Cases and controls were derived from women who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation. There were 89 maternal cases with, and 434 controls without, an NTD-affected singleton pregnancy. Maternal features of MetSyn were defined by the presence of pre-pregnancy diabetes mellitus, body weight ≥ 90th centile among controls, non-white ethnicity and/or serum highly sensitive C-reactive protein (hsCRP) ≥ 75th centile of controls. Since hsCRP naturally increases in pregnancy, analyses were performed with, and without, the inclusion of hsCRP in the model.

Results

Mean hsCRP concentrations were exceptionally high among study cases and controls (6.1 and 6.4 mg/L, respectively). When hsCRP was excluded from the model, the adjusted odds ratios for NTD were 1.9 (95% confidence interval 1.1–3.4) in the presence 1 feature of MetSyn, and 6.1 (1.1–32.9) in the presence of 2 or more features. When hsCRP was included, the respective risk estimates were attenuated to 1.6 (0.88–2.8) and 3.1 (1.2–8.3).

Conclusion

We found about 2-fold and 6-fold higher risk for NTD in the presence 1, and 2 or more features, of the metabolic syndrome, respectively. It is not clear whether this risk is altered by the presence of a high serum hsCRP concentration.