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.     

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.     

Characterization of 25 monoclonal antibodies to factor VIII-von Willebrand factor: relationship between ristocetin-induced platelet aggregation and platelet adherence to subendothelium

We have studied the role of factor VIII-von Willebrand factor (FVIII- vWF) in both platelet adherence to subendothelium and ristocetin- induced platelet aggregation using monoclonal antibodies to human FVIII- vWF. Twenty-five monoclonal antibodies were obtained, two of which were directed to the factor VIII moiety of FVIII-vWF; one of these two completely inhibited the procoagulant activity (FVIII:C). The remaining 23 monoclonal antibodies were directed to the von Willebrand factor moiety of FVIII-vWF. The ability of the latter monoclonal antibodies to inhibit platelet adherence to arterial subendothelium was investigated with a perfusion model. According to the number of platelets adhering to the subendothelium, three groups of monoclonal antibodies could be discerned: (A) antibodies not affecting platelet adherence; (B) antibodies that inhibited platelet adherence to the level as observed when von Willebrand's disease plasma was tested; and (C) antibodies that completely inhibited both platelet adherence to subendothelium and ristocetin-induced platelet aggregation. The two antibodies present in group C competed for the same or closely related epitope(s) present on FVIII-vWF. These results demonstrate that a domain is present on the FVIII-vWF molecule that is associated both with ristocetin-induced aggregation and with the ability of FVIII-vWF to support platelet adherence to the subendothelium. Based on these observations, it is concluded that ristocetin-induced binding of FVIII-vWF to platelets reflects, at least in part, a physiologic mechanism regulating the function of FVIII-vWF in primary hemostasis.     

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.     

Investigation of the role of von Willebrand factor in thrombotic thrombocytopenic purpura

Von Willebrand factor (vWF) has been implicated to function as a cofactor in platelet aggregation induced by thrombotic thrombocytopenic purpura (TTP) plasma. To investigate further this role of vWF, we have used rabbit monospecific anti-FVIII/vWF antibodies and a monoclonal antibody to platelet glycoprotein Ib (GP Ib) that blocks the ristocetin- induced platelet aggregation. The monoclonal anti-platelet GP Ib antibody inhibited the platelet aggregation induced by ristocetin in the presence of normal plasma, but not that by any of the five TTP plasma samples. The TTP plasma samples from five patients were incubated with the monospecific antibodies to FVIII/vWF. In all of the samples, the FVIII/vWF:Ag was drastically reduced; however, there was almost no effect on the platelet-aggregating activity. Therefore, it is concluded that vWF is unlikely to play a major role in platelet aggregation induced by majority of TTP plasmas and that the site of platelet GP Ib, to which vWF binds in the presence of ristocetin, is not involved in TTP plasma-induced aggregation.     

The differentiation of delayed hemolytic and delayed serologic transfusion reactions: incidence and predictors of hemolysis

BACKGROUND: After differentiation of the entities of clinically detectable delayed hemolytic (DHTR) and delayed serologic transfusion reactions (DSTR), previous investigators calculated a DHTR:DSTR incidence ratio of 18:72 from a retrospective review of patients with serologic evidence of DHTR or DSTR. There are no published data on factors that may influence the occurrence of DHTR versus DSTR in a given patient. STUDY DESIGN AND METHODS: Retrospective review was conducted of 292 patients at the Mayo Clinic who, between 1980 and 1992, received a clinical diagnosis of DHTR or DSTR concurrently with a serologic diagnosis. Red cell alloantibody specificity, the activity of the patient's reticuloendothelial system, and concurrent immunosuppression were evaluated as potential predictors of the occurrence of DHTR versus DSTR in different patients. RESULTS: The incidence of DHTR or DSTR was 1 in 1899 allogeneic red cell units transfused, with a DHTR:DSTR ratio of 36:64. Alloantibody specificity was the only variable that affected the occurrence of DHTR versus DSTR at the clinical level, with the anti-Jka and anti-Fya specificities, as well as multiple coexisting specificities, significantly associated with detectable hemolysis (p < 0.05). CONCLUSION: Clinically detectable DHTRs are found to occur more commonly than previously believed when the clinical and serologic diagnoses are made concurrently and appropriate work-ups for hemolysis are ordered. The association of certain alloantibody specificities with detectable DHTRs may have implications for clinical transfusion practice.     

Association between genetic variants in key vitamin-D-pathway genes and external apical root resorption linked to orthodontic treatment

This study evaluated the association between single-nucleotide polymorphisms (SNPs) in vitamin-D-related genes and the amount of external apical root resorption linked to orthodontic treatment. One hundred and forty-three individuals were assessed. The amount of external apical root resorption of upper central incisors (EARR_inc) and lower first molars (EARR_mol) were evaluated in radiographs. Seven SNPs were genotyped across four genes including the vitamin D receptor [VDR], group-specific component [GC], cytochrome P450 family 27 subfamily B member 1 [CYP27B1], and cytochrome P450 family 24 subfamily A member 1 [CYP24A1]. Linear regressions were implemented to determine allele-effects on external apical root resorption. Individuals carrying the AA genotype in VDR rs2228570 had a 21% higher EARR_mol than those having AG and GG genotypes (95% CI: 1.03,1.40). EARR_mol in heterozygous rs2228570, was 12% lower than for homozygotes (95%CI: 0.78,0.99). Participants with the CCG haplotype (rs1544410-rs7975232-rs731236) in VDR had an EARR_mol 16% lower than those who did not carry this haplotype. Regarding CYP27B1 rs4646536, EARR_inc in participants who had at least one G allele was 42% lower than for homozygotes AA (95%CI: 0.37,0.93). Although these results did not remain significant after multiple testing adjustment, potential associations may still be suggested. Further replication studies are needed to confirm or refute these findings.