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Salvage haploidentical hematopoietic cell transplantation for graft rejection following a prior haploidentical allograft

Allogeneic hematopoietic cell transplantation is associated with late adverse effects of therapy, including secondary solid cancers. Most reports address risk factors; however, outcomes after secondary solid cancer development are incompletely described. Our objective was to estimate survival probabilities for transplant recipients dependent on secondary solid cancer subtype. We used a previously identified and published cohort who developed secondary solid cancers following allogeneic transplant. Follow-up for these 112 previously identified patients was extended and their survival probabilities were studied. Median duration of follow-up from the development of secondary cancer for survivors was 11.9 years (range: 0.8-23.4) and 75% were followed >7.0 years. The 5- and 10-year overall survival probabilities were 50% (95% confidence interval (CI): 41-60) and 46% (95% CI: 37-57), respectively. Overall survival varied by secondary cancer type. Secondary cancer was the cause of death in most patients who died following development of melanoma, central nervous system, oral cavity, thyroid, lung, lower gastrointestinal tract and bone cancers. Extended follow-up allowed for the most comprehensive longitudinal evaluation to date of this rare condition. These findings will enhance clinicians' ability to predict outcomes and counsel transplant survivors who develop secondary solid cancers.

Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment-related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings.

Impact of haploidentical hematopoietic cell transplantation conditioning intensity on the incidence and severity of post-transplantation viral infections

Historically, sickness symptomatology in cancer patients has been studied as aggregated phenomena arising from a similar inflammatory etiology. A parent clinical trial analyzed depression, anxiety, fatigue, sleep, and pain as separate variables in hematopoietic cell transplant (HCT) recipients experiencing cytokine blockade with an interleukin-6 receptor antagonist, tocilizumab. Contrary to initial hypotheses, tocilizumab recipients had worse post-HCT levels of depression, anxiety, pain, and sleep. Interestingly, we found that fatigue, as assessed by the Fatigue Symptom Inventory (FSI) administered at baseline and post-transplant days + 28 (D + 28), D + 100, and D + 180, was not similarly affected. Fatigue levels did not differ between the 25 patients who received one prophylactic dose of tocilizumab prior to allogeneic HCT and a historical control group of 63 HCT patients who did not receive tocilizumab. In addition, whereas fatigue scores pre- and post-HCT were correlated in control patients (0.54 at D + 28, p

Patient/caregiver out-of pocket costs associated with hematopoietic cell transplantation (HCT) are not well known. We conducted a pilot study to evaluate patient/caregiver out-of-pocket costs in the first 3 months after allogeneic HCT. Thirty patients were enrolled at three sites. Before HCT, participants completed a baseline survey regarding household income and insurance coverage. Subsequently, they maintained a paper-based diary to track daily out-of-pocket expenses for the first 3 months after HCT. Telephone interviews were conducted to follow-up on the missing/incomplete diaries and on study completion. Twenty-five patients/caregivers completed the baseline survey. Among these, the median pre-tax household income was $66 500 (range, $30-$375 000) and 48% had to temporarily relocate close to the transplant center. Insurance coverage was managed care plan (56%), Medicaid (20%), Medicare (17%) and other (8%). Twenty-two patients/caregivers completed 4 diaries; the median out-of-pocket expenses were $2440 (range, $199-$13 769). Patients/caregivers who required temporary lodging had higher out-of-pocket expenses compared with those who did not (median, $5247 vs $716). Patients/caregivers can incur substantial out-of-pocket costs over the first 3 months, especially if they need to temporarily relocate close to the transplant center. Our study lays the foundation for future research on the early and long-term financial impact of allogeneic HCT on patients/caregivers.

To assess the impact of spleen status on engraftment and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil and platelet engraftment were 15 vs. 18 days and 22 vs. 24 days for the SP and NS groups, respectively (p5.7x106/kg improved platelet engraftment at day+28. After adjusting variables by Cox regression, the incidence of graft-versus-host disease (GVHD) and overall survival were not different among groups. Splenomegaly is associated with delayed engraftment while splenectomy prior to HCT facilitates early engraftment without impact on survival.

Beta-adrenergic signaling regulates multiple molecular pathways that contribute to cancer progression; beta-adrenergic antagonists efficiently block many of these effects in animals. We previously demonstrated that hematopoietic cell transplant (HCT) patients exposed to socioeconomic stress show activation of a conserved transcriptional response to adversity (CTRA) transcriptome profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled trial to evaluate whether the beta-antagonist propranolol is effective in decreasing gene expression of CTRA-related genes of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for one week prior to transplant and 4 weeks following transplant. Blood was collected at baseline, Day −2, and Day +28. Intention-to-treat analyses assessed effects on the 53-gene CTRA indicator profile and measures of CTRA-related cellular processes. Twelve participants were randomized to the intervention group and 13 to the control arm. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to Day −2 and Day +28 for both CTRA gene expression (p = .017) and bioinformatic measures of CD16- classical monocyte activation (p = .005). Propranolol-treated patients also showed up-regulation of CD34+ hematopoietic progenitor cells (p = .011). Peri-transplant administration of propranolol can down-regulate CTRA gene expression, inhibit myeloid-based cellular dynamics, and up-regulate the CD34+ cells. Ongoing follow-up and future replication studies will be required to assess impacts on clinical outcomes.

We describe long-term outcomes of autologous hematopoietic-cell transplantation (HCT) for 315 acute myeloid leukemia (AML) patients in first or second complete remission (CR). All patients were in continuous CR for ≥2-years post-HCT. Patients were predominantly transplanted in CR1 (78%) and had good or intermediate cytogenetic risk disease (74%). Median followup of survivors was 106 (range, 24-192) months. Overall survival at 10-years post-HCT was 94% (95% confidence intervals, 89-97%) and 80% (67-91%) for patients receiving HCT in CR1 and CR2, respectively. The cumulative incidence of relapse at 10-years post-HCT was 6% (3-10%) and 10% (3-20%) and that of non-relapse mortality was 5% (2-9%) and 11% (4-21%), respectively. On multivariate analysis, HCT in CR2 (vs. CR1), older age at transplantation and poor cytogenetic risk disease were independent predictors of late mortality and adverse disease-free survival. The use of growth factors to promote engraftment following HCT was the only risk factor for relapse. Relative-mortality of these 2-year survivors was comparable to that of age-, race- and gender-matched normal population. Patients who receive an autologous HCT for AML in CR1 or CR2 and remain in remission for ≥2-years have very favorable long-term survival. Their mortality rates are similar to that of the general population.

We retrospectively compared clinical outcomes in 1593 T-repleted URD marrow transplant recipients with AML, MDS and CML who received myeloablative conditioning regimens of either busulfan and cyclophosphamide (BuCy), standard-dose Cy/TBI (1,000-1,260 cGy) or high-dose Cy/TBI (1,320-1,500 cGy). Subjects were drawn from patients transplanted between 1991 and 1999 facilitated by the National Marrow Donor Program (NMDP). Patients who received high-dose Cy/TBI regimens were slightly younger, more likely to receive a mismatched transplant and to have intermediate or advanced disease compared to patients in the BuCy or standard-dose TBI group. Neutrophil recovery was significantly higher in the standard dose CY/TBI group compared to the high-dose Cy/TBI or BuCy group. Patients who received the high-dose Cy/TBI regimen had an increased risk of developing grade III-IV aGVHD when compared to the control group who received BuCy (p=0.011). Overall survival (OS), disease free survival (DFS), transplant-related mortality (TRM) and relapse were not significantly different between any of the regimens. We conclude that BuCy, standard-dose and high dose Cy/TBI regimens have equivalent efficacy profiles for OS, DFS, TRM and relapse risk in patients undergoing T-replete URD marrow transplantation for AML, CML and MDS.

Much research into the impact of hematopoietic cell transplantation (HCT) on recipients' symptoms, functioning and health-related quality of life uses diverse patient-reported outcome (PRO) measures. Robust conclusions regarding PROs in HCT patients are constrained by methodological issues, including the use of multiple different and noncomparable assessment measures. We reviewed 114 publications addressing PROs in HCT patients. Although three multi-item measures were most frequently used (FACT-BMT, n=28; European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, n=26; and SF-36, n=26), 25 additional measures were used in more than one study. Another 50 measures were used in single studies. Over 50% of studies used more than one measure. We recommend that the field agrees upon a set of measures to address the core domains important to patients, to reduce heterogeneity and allow comparisons across studies and between different populations. Measures should be available in a free and easily accessible manner internationally. We discuss the relative benefits of the National Institutes of Health-supported Patient-Reported Outcomes Measurement Information System (PROMIS) system to achieve these goals. To further address these issues, the Blood and Marrow Transplant Clinical Trials Network has recently created a task force to implement PROMIS measures alongside traditional PRO measures in future clinical trials. Robust comparisons between measures in this setting may allow for the development of a standard for HCT patients.

More than 40,000 hematopoietic cell transplants (HCTs) are performed worldwide each year. With improvements in transplant technology, larger numbers of transplant recipients survive free of the disease for which they were transplanted. However, there are late complications that can cause substantial morbidity. Many survivors are no longer under the care of transplant centers and many community health-care providers may be unfamiliar with health matters relevant to HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Blood and Marrow Transplantation (ASBMT) have developed these recommendations to offer care providers suggested screening and prevention practices for autologous and allogeneic HCT survivors.

Metastatic breast cancer has been a common indication for autologous hematopoietic stem cell transplantation (HSCT). Previous reports indicate 3-year survival and progression-free survival (PFS) rates after autotransplant to be about 30 and 15%, respectively. Most deaths are from recurrent disease. One potential cause for high relapse rates is graft contamination with tumor. We describe 14 women with metastatic breast cancer transplanted between 1991 and 1998 with hematopoietic cells from identical twins. Median age was 41 y (range 34-50). Most women (12 of 14) were treated with mastectomy, and all received anthracycline-based regimens in their pretransplant course; nine women also received a taxane, seven radiotherapy and three hormonal therapy. Four women were in complete remission (one CR, three CRU) at transplant, five were in partial remission, two had stable disease and two had progressive disease. Eight women have died, one of treatment-related causes and seven of progressive breast cancer. Three-year survival was 48% (21-71%) and 3-year PFS was 21% (5-45%). Although the number of patients is small, outcomes for women transplanted with syngeneic grafts are similar to those of women receiving autologous grafts. This suggests that residual cancer in the patient is the major contributor to relapse after transplantation for breast cancer.

Center effects are differences in outcome among treatment centers that cannot be explained by identifiable differences in patients treated or specific treatments applied and are presumed to result from differences in the ways health care is delivered. This paper will briefly review studies of association between treatment center factors and clinical outcomes in general medicine and surgery and look more closely at studies involving hematopoietic stem cell transplantation. We will also attempt to identify conceptual domains to study further the processes and mechanisms that may be associated with better outcomes.

In this paper, we address methods of multivariate regression. We discuss the value of regression compared to matched pairs analysis, methods of coding variables, basic concepts of the Cox model and interpretation of results of the Cox model. We present methods of handling variables whose effect changes with time. We present methods to check the assumptions of the Cox regression. Finally, and perhaps most importantly, we provide suggestions for presenting the results in clear and thorough tables and graphs.

In this paper, we describe modern statistical methods for presentation of the results of studies of bone marrow transplantation. We focus here on 'univariate' or unadjusted techniques to describe the outcomes of such studies. In another paper we will discuss multivariate methods. We discuss the type of data one may have available to make inference about outcomes. We explain the differences between the Kaplan-Meier estimator of the survival function and the cumulative incidence curve, how these curves should be interpreted and when each is the appropriate summary statistic. We discuss the weighted log rank statistic and show how different weights can be used to put emphasis on detecting differences between groups in different time periods. We also present a simple estimate of current leukemia-free survival which is useful in summarizing post-transplant events.

Patient registries, frequently referred to as outcome registries, are 'organized systems' that use observational study methods to collect uniform data. Registries are used to evaluate specified outcomes for a population defined by a particular disease, condition or exposure that serves one or more predetermined scientific, clinical or policy purposes. Outcome registries were established very early in the development of hematopoietic SCT (HSCT). Currently, myriads of national and international HSCT registries collect information about HSCT activities and outcomes. These registries have contributed significantly to determining trends, patterns, treatment practices and outcomes. There are many different HSCT registries, each with different aims and goals; some are led by professional organizations, others by government authorities, health care providers or third parties. Some registries simply assess activity and others study outcomes. These registries are complementary and are gradually developing interoperability with each other to expand future collaborative research activities. A key development in the last few years was the incorporation of recommendations into the World Health Organization guiding principles on cell, tissue and organ transplantation. The data collection and analysis should be an integral part of therapy and an obligation rather than a choice for transplant programs. This article examines challenges in ensuring data quality and functions of outcome registries, using HSCT registries as an example. It applies to all HSCT-related data, but is predominantly focused on HSCT registries of professional organizations.

International audience; With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient-physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients.

Psychosocial and socioeconomic factors have predicted morbidity and mortality following hematopoietic cell transplantation (HCT). However, previous studies suffer from methodological limitations, and few investigate biobehavioral pathways. This multi-center study assessed whether pre-HCT psychosocial and socioeconomic measures are associated with each other and predictive of clinical outcomes including hematopoietic recovery, acute graft versus host disease, hospitalization days, and overall survival (OS) in the 711 participants in the BMT CTN 0902, an RCT of pre-transplant exercise and stress management for autologous and allogeneic HCT recipients. Pre-transplant Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores (MCS and PCS) of the SF-36 were tested in baseline correlations with socioeconomic assessments; all were evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors ( p p = .002); lower pre-transplant income was related to worse physical functioning ( p = .005) and increased distress ( p = .008); lack of employment at the time of transplant was associated with worse physical functioning ( p p = .003). In this large heterogeneous cohort of HCT recipients, while socioeconomic and psychosocial factors were correlated at baseline, they were not associated with any clinical outcomes as has been previously reported, highlighting the complexity of biobehavioral relationships in HCT.

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

About 50,000 hematopoietic stem cell transplantations are performed yearly, primarily for malignancies. Use of this therapy increased dramatically over the past 30 years due to its proven and potential efficacy in diverse diseases, better understanding of appropriate timing of transplantation and patient selection, and greater availability of allogeneic donors. The International Bone Marrow Transplant Registry (IBMTR) and the Autologous Blood and Marrow Transplant Registry (ABMTR) collect data on consecutive allogeneic and autologous transplants, respectively, in more than 400 participating centers worldwide. The IBMTR/ABMTR database contains information on more than 120,000 transplant recipients. Among 11,347 patients transplanted in 101 IBMTR/ABMTR research centers in North America during 1995-1997, 66% received autologous transplants, 24% related-donor transplants, and 10% unrelated-donor transplants. More than 90% of transplantations were for malignant disease, with more than half of these done in patients with advanced disease. Of the recipients, 70% were younger than 50 years. Posttransplant survivals varied substantially by disease, transplant type, recipient age, and disease status at transplantation. IBMTR/ABMTR data provide an important tool for assessing transplant use and outcome, identifying prognostic factors for transplant outcomes, evaluating new transplant therapies, comparing transplant and nontransplant therapies, evaluating late transplant complications, and planning prospective phase II and III clinical trials.

Can a modest exercise program really improve physical functioning and quality of life among recipients of hematopoietic SCT?

Donation-related data for 1488 allogeneic peripheral blood stem cell (PBSC) transplants reported to the International Bone Marrow Transplant Registry (IBMTR) or the European Blood and Marrow Transplant Group (EBMT) by 152 teams worldwide between 1994 and 1998 were reviewed. In 1998, 26% of allografts registered with the IBMTR were collected from blood. Median age of PBSC donors was 38 years (range

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range

A capillary electrophoresis-laser-induced fluorescence (CE-LIF) method to quantitate reverse transcription-polymerase chain reaction (RT-PCR) products of NAD(P)H:quinone acceptor oxidoreductase (NQO1) derived from whole blood after amplification with a reaction-specific internal standard is reported. The internal standard eliminates variability within the PCR (Hoffman-La Roche, Inc., Nutley, NJ, U.S.A.), while analysis by CE-LIF adds sensitivity and reduces variability associated with isotopic detection. Both the PCR and CE aspects of the assay are precise, with migration time precision of less than 1% and peak area ratio precisions of 9.8-15%. Future applications of this technique may include the analysis of gene therapy, oligonucleotides, and point mutations.

Intermediate filaments of epithelial cells generally consist of specific combinations of keratins. However, cultured epithelial cells from certain tissues and some epithelial tumors have been shown also to express vimentin. In the present study, the expression of vimentin by epithelial cells in healing corneal wounds (partial thickness penetrating wounds) and in tissue culture was analyzed. Both immunohistochemical and immunotransblot analyses indicated that although vimentin was not detected in the normal rabbit corneal epithelium in vivo, cultured rabbit corneal epithelial cells co-express keratins and vimentin. At 1 day post-wounding, vimentin was not detectable in the epithelial cells that had covered the denuded stroma. However, at 2 days postwounding, the epithelium at the base of the epithelial plug immunoreacted with both anti-vimentin and antikeratin monoclonal antibodies. Immunotransblot analyses of the extracts of the epithelial plugs confirmed the presence of vimentin (Mr = 58k). The 58k band was not detected in the extract of normal rabbit corneal epithelium. At day/5, vimentin was no longer detectable in the epithelium. This study demonstrated that corneal epithelial cells transiently co-express vimentin and keratins in vivo during wound healing and in tissue culture. The time-course of the transient expression of vimentin suggests that the vimentin expression in the epithelial cells during healing is not linked to cell proliferation or to the centripetal migration of the epithelium during early stages (first 24 h) of healing, but may be linked to cell-matrix interactions or the migration of basal cells in the upward direction at the following stage of healing.

Organ transplantation has become widely applied as a therapy of end-stage organ dysfunction and is finding increasing application in the pediatric population. This has become possible largely through the use of improved immunosuppressive agents, such as OKT3. Aseptic meningitis associated with OKT3 has been previously reported, with a frequency rate of 3% to 14%, in adult renal allograft recipients. Aseptic meningitis after OKT3 therapy has not been reported in children. Meningitis, however, is a frequent infection encountered in young children, and the development of meningeal irritation during therapy with OKT3 may present a diagnostic dilemma. We describe aseptic meningitis in a 10-month-old infant after treatment of cardiac allograft rejection with OKT3.

14011 Background: TSP-1 reduces angiogenesis and tumor growth in vivo, and induces endothelial cell apoptosis in vitro. CVX-045 was produced by fusing a peptide derived from TSP-1, known to have anti-vascular activity, to a proprietary monoclonal antibody. CVX-045 possesses the potency and specificity of the TSP-1 mimetic peptide, along with the advantageous PK of an antibody. Methods: Anti-tumor activity of CVX-045 was evaluated in A549, A431, and HT-29 human adenocarcinoma xenograft models. Cells were implanted SC in female nu/nu mice, and tumors were staged to 300–400 mm3 prior to initiation of weekly treatments: CVX-045 IV 10–30 mg/kg; 5-FU or CPT-11 IP 100 mg/kg. Results: CVX-045 (10 mg/kg) significantly reduced A549 and A431 tumor growth 73% (day 49) and 51% (day 22), respectively, but was not effective in the HT-29 xenograft (10 or 30 mg/kg). CVX-045 demonstrated significant anti-vascular activity, reducing tumor microvessel density 51% in A549, 49% in A431, and 36% in HT-29 xenografts. CVX-045 (30 mg/kg) plus 5- FU significantly decreased HT-29 tumor growth 70% and microvessel density 61.2% on day 30 (both P3. CPT-11 alone extended the time to reach tumor load from day 28 to day 39, while the combination of CPT-11 with CVX-045 extended this further to day 60. Conclusions: CVX-045 exhibits significant anti-angiogenic activity in several tumor models and enhances anti-tumor activity in combination with standard chemotherapies in a highly aggressive colon tumor model. No significant financial relationships to disclose.

6026 Background: “Center effects” are differences in outcomes that cannot be explained by identifiable differences in patients' diseases or treatments, and are presumed to result from variation in ...

The microbiological metabolism of warfarin was examined as a model of metabolism in higher organisms, including humans, and to determine the chirality of microbial reductases for application in organic synthesis. Nineteen cultures were examined based on their reported abilities to reduce ketonic substrates, and several were shown to catalyze the desired reaction. Nocardia corallina (ATCC 19070) exhibited complete substrate and product stereoselectivity as it reduced S-warfarin to the corresponding S-alcohol. Arthrobacter species (ATCC 19140) exhibited marked substrate and complete product stereoselectivity since S-warfarin, and to a lesser extent R-warfarin, were reduced to the corresponding S-alcohols. These reductions parallel those reported to occur in mammalian species.