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This is a study of D. H. Th. Vollenhoven’s type-focused historiography of philosophy and its development with respect to pre-Socratic philosophy. It uses the work of Pierre Hadot on philosophical askesis, the work of Martha Nussbaum on therapeutic argument, and recent work on the transformative character of Aquinas’s Summa contra Gentiles and Summa theologiae to question some of the central assumptions of Vollenhoven’s methodology. In the process, Vollenhoven’s practice is compared to and contrasted with the historiographical practice of Aristotle in his Metaphysics. What emerges is a way to acknowledge the continued worth of type-focused reading and the religious intuitions that gave rise to it, but on the basis of different methodological assumptions and to different historiographical effects.

The prognosis of patients with primary refractory acute myelogenous leukemia (AML) is poor. Our initial report suggested that some patients could achieve durable remission after allogeneic stem cell transplantation (SCT). Herein, we update our initial experience and report further analysis of this group of patients to determine whether there are pre-SCT prognostic factors predictive of posttransplantation relapse and survival. We reviewed the records of 68 patients who consecutively underwent transplantation at the City of Hope Cancer Center with allogeneic SCT for primary refractory AML between July 1978 and August 2000. Potential factors associated with overall survival and disease-free survival were examined. With a median follow-up of 3 years, the 3-year cumulative probabilities of disease-free survival (DFS), overall survival (OS), and relapse rate for all 68 patients were 31% (95% confidence interval [CI], 20%–42%), 30% (95% CI, 18%–41%), and 51% (95% CI, 38%–65%), respectively. In multivariate analysis, the only variables associated with shortened OS and DFS included the use of an unrelated donor as the stem cell source (relative risk, 2.23 [OS] and 2.05 [DFS]; P = .0005 and .0014, respectively) and unfavorable cytogenetics before SCT (relative risk: 1.68 [OS] and 1.58 [DFS]; P = .0107 and .0038, respectively). Allogeneic SCT can cure approximately one third of patients with primary refractory AML. Cytogenetic characteristics before SCT correlate with transplantation outcome and posttransplantation relapse.

To reduce the morbidity and mortality associated with unrelated donor bone marrow (BM) transplantation and potentially extend the pool of suitable donors, cryopreserved unrelated donor umbilical cord blood was considered as an alternate source of hematopoietic stem cells for transplantation. Patients with leukemia, BM failure syndrome, or inborn error of metabolism were eligible for a phase I clinical trial designed to estimate the risk of graft failure and severe acute graft-versus- host disease after transplantation of umbilical cord blood from unrelated donors. As of December 21, 1995, unrelated donor umbilical cord blood was used to reconstitute hematopoiesis in eighteen patients aged 0.1 to 21.3 years weighing 3.3 to 78.8 kg with acquired or congenital lympho-hematopoietic disorders or metabolic disease. Patients received either HLA-matched (n = 7) or HLA-1 to 3 antigen disparate (n = 11) grafts collected and evaluated by the New York Blood Center (New York, NY). The probability of engraftment after unrelated donor umbilical cord blood transplantation was 100% with no patient having late graft failure to date. The probability of grade III-IV acute graft-versus-host disease at 100 days was 11%. With a median follow-up of 6 months (range, 1.6 to 17 months); the probability of survival at 6 months is 65% in this high risk patient population. We conclude that cryopreserved umbilical cord blood from HLA-matched and mismatched unrelated donors is a sufficient source of transplantable hematopoietic stem cells with high probability of donor derived engraftment and low risk of refractory severe acute graft-versus-host disease. Limitations with regard to recipient size and degree of donor HLA disparity remain to be determined.

The future role of IVIG remains unclear. Many, but not all, studies indicate efficacy in the prevention of late-onset disease in premature infants. The role of type-specific IVIG is evolving and may hold promise for both prevention and treatment of neonatal sepsis. Granulocyte transfusions, as adjuvant therapy in neonatal sepsis, seem to be beneficial. However, the difficulty and expense of collection, as well as the advent of colony-stimulating factors, have shifted the focus away from their routine use. Colony-stimulating factors present varied and exciting potential uses, including modulating neonatal hematopoiesis. Current studies are primarily aimed at understanding their effects on neonatal hematopoiesis. Future studies will need to expand on this knowledge and examine what effects they have on treating or preventing neonatal sepsis.

Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or with added cyclosporine or tacrolimus still has a very high failure and complication rate, and new treatment approaches are needed for both primary and salvage therapy. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently in use for acute graft-versus-host disease prophylaxis. To determine whether MMF had activity in the treatment of cGVHD, we added MMF to standard cyclosporine, tacrolimus, and/or PSE as salvage/second-line (n = 24) or first-line (n = 10) therapy in 34 patients. Nine (90%) of 10 patients receiving first-line and 18 (75%) of 24 receiving second-line MMF therapy responded. Twelve (35%) patients had a complete remission, 15 (44%) had a partial remission, 5 (15%) had stable disease, and only 2 (6%) had progressive disease. Out of 30 patients receiving PSE, 22 (73%) were able to decrease PSE doses (median decrease of 50%; range, 25%–100%). With a median follow-up of 24 months (range, 6–28 months), 29 (85%) patients are alive. Three patients had to discontinue MMF because of abdominal cramps within 3 months of starting treatment. These data suggest that MMF is an active, well-tolerated agent in the treatment of cGVHD and may have a beneficial effect on the survival of patients with this complication.

The Cord Blood Transplantation study group conducted a prospective study of unrelated cord blood transplantation (CBT) to better define the role of this stem cell source for subjects requiring unrelated allogeneic transplantation. We report on 1 stratum of the study designated for adult subjects. The primary end point of the study was survival at 180 days. Secondary end points included engraftment, graft-versus-host disease, relapse, and long-term survival. Eligibility criteria for malignant and nonmalignant diseases were specified. Subjects with active central nervous system disease, Karnofsky performance status 107 nucleated cells per kilogram of recipient weight and matched at ≥4 HLA-A and -B (low or intermediate resolution) and -DRB1 (high resolution) types. Thirty-four subjects were entered, with a median age of 34.5 years (range, 18.2-55 years). Most subjects (n = 23) had a 4 of 6 match, 10 subjects had a 5 of 6 match, and 1 subject had a 6 of 6 match. Diagnoses at transplantation included acute myelogenous leukemia (n = 19), acute lymphoblastic leukemia (n = 9), chronic myelogenous leukemia (n = 3), myelodysplastic syndrome (n = 1), paroxysmal nocturnal hemoglobinuria (PNH) (n = 1), and non-Hodgkin lymphoma (n = 1); 94% were classified as poor risk according to National Marrow Donor Program criteria. Subjects received total body irradiation/cyclophosphamide (n = 27) or busulfan/melphalan (n = 7) conditioning regimens. Four subjects died before CBT and are described here but are not included in the main analysis. The cumulative incidence rates and median times to neutrophil (500/μL) and platelet (>20 000/μL) engraftment were 0.66 by day 42 (median, 31 days) and 0.35 by day 180 (median, 117 days). The cumulative incidence rate for grade II-IV GVHD was 0.34 by day 100. For the primary end point, survival at 180 days, Kaplan-Meier survival estimates were 0.30 (95% confidence interval, 0.14-0.46) by day 180 after transplantation. To date there are 2 survivors, and both are >36 months from enrollment. A retrospective analysis was performed by using high-resolution HLA-A and -B typing, which revealed that approximately one third of subjects had 1 or more additional HLA mismatches compared with results of low- or intermediate-resolution HLA typing. The findings of high treatment-related mortality and slow engraftment kinetics indicate that CBT should continue to be performed in specialized centers with a research focus on cord blood cells.

Umbilical CB from term neonates contains increased numbers of committed progenitor cells compared to adult peripheral blood (Broxmeyer, et al,Proc Natl Acad Sci USA 86:3828, 1989). However, the neonatal immune system is developmentally immature at birth. Since 1988, CB has been used as a source of hematopoietic stem cells in young patients with sibling donors(Gluckman, et al, N Engl J Med 321:1174, 1989). Recently, we have demonstrated the feasibility of unrelated HLA-identical or 1 or 2 antigen mismatched cord blood transplantation (CBT) (Sweetman, et al, Blood 86:388a, 1995). We evaluated immune reconstitution following unrelated CBT. Five patients (median 4 years, range 0.9-21 years) received unrelated CBT for malignant (n=4, 1 ANLL, 2 ALL, 1 MDS in transformation) or non-malignant (n=1) conditions. Evaluation of immune reconstitution included the following: 1) B-cells (CD19), T cells (CD3), T-helper cells (CD3/CD4), T-suppressor cells(CD5/CD8) and natural killer (NK) cells (CD56); 2) mitogen responses to PHA, Con A, and PWM;3) quantitative immune globulin levels; 4) expression of C3bi. Three patients are alive (306, 260, and 159 days post transplant), one patient died of multi-organ failure on day + 19, and one pt died of grade IV GvHD. The number of B cells (CD19+) exceeded normal levels after day +75, with a mean at day +90 of 321/mm3 and 718/mm3 at day +120. T-helper and T-suppressor cells remained low even at day +180 with mean values of 414/mm3 and 256/mm3 respectively. The number of natural killer cells were within normal range throughout the first 180 days with day +30 -+180 means ranging from 252-518/mm3. Mean IgG levels were normal throughout the study period with mean day +120 levels of 845 mg/dl. IgA levels revealed a decreasing trend and most patients had low levels at day +120. IgM showed a similar trend but levels at day +120 were in the low normal range with a mean level of 44mg/dl. Mitogen response studies revealed low blastogenesis to PHA, Con A, and PWM from day of transplant through day +180. C3bi expression (CD11b) was within normal range throughout the study period with 70-96% of neutrophils and monocytes demonstrating C3bi expression. While reconstitution of B cells and NK cells is not impaired, recovery of both helper and cytotoxic T cell subpopulations is delayed in patients receiving CBT. This delay may play a role in reducing the incidence of GvHD as well as attenuating graft-versus-leukemia effect in patients undergoing CBT.

The increased susceptibility of neonates to infection may be due to defects in CB cellular immunity and cytokine production (Cairo, Blood 82:2269, 1993; Cairo, et al, Pediatr Res 30:362, 1991; and 31:574, 1992). These alterations may additionally account for the low incidence of GvHD post related and unrelated CBT (Wagner, et al, Blood 82:86a, 1993, Sweetman, et al, Blood 86: 388a, 1995). IL-15 is a novel cytokine that shares many biological properties with IL-12 in regulating many of the biologic functions of NK and T cells. In this study, we investigated the IL-15 gene expression in C and A MNC in order to examine the role of IL-15 in neonatal immunity. MNC were isolated from C and A PB with Ficoll-hypaque and stimulated with LPS (10 μg/ml, 6-48 hrs). Northern blots containing poly A+ RNA were hybridized with an antisense probe made by transcription of a human cDNA (kindly provided by Immunex) to detect IL-15 mRNA expression. Unstimulated C and A MNC did not constitutively express significant levels of IL-15 mRNA. Upon stimulation of cells with LPS (10μg/ml, 12 hrs), IL-15 mRNA expression was significantly induced in both C and A MNC. However, IL-15 mRNA expression in C MNC was only 25 ± 2.0% of that in A MNC. We next determined the relative rates of transcription of the IL-15 gene by nuclear run-on assays. The nuclei from unstimulated and LPS-stimulated cells were isolated and incubated with 32P-UTP. Newly elongated 32P-labeled transcripts were hybridized to slot blots of target DNA (0.5 kb IL-15 cDNA). The basal and stimulated levels of transcription were the same in C and A MNC. These preliminary data suggest that C MNC express less IL-15 mRNA compared to A in response to stimulation and this discrepancy is not secondary to the transcriptional regulation. Reduced expression of IL-15 mRNA from activated CB MNC may contribute to the immaturity of CB cellular immunity and to a decreased incidence of GvHD following both related and unrelated CB stem cell transplantation.