Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.

The National Marrow Donor Program (NMDP) maintains a registry of approximately 4 million volunteer unrelated donors for patients in need of a stem cell transplant. When several comparably HLA-matched volunteers are identified for a patient, various criteria are used to select a donor. A retrospective analysis of 6978 bone marrow transplantations facilitated by the NMDP from 1987 to 1999 was conducted to study the effects of various donor characteristics on recipient outcome. The evaluation addressed possible effects of donor age, cytomegalovirus serologic status, ABO compatibility, race, sex, and parity on overall and disease-free survival, acute and chronic graft-versus-host disease (GVHD), engraftment, and relapse. Age was the only donor trait significantly associated with overall and disease-free survival. Five-year overall survival rates for recipients were 33%, 29%, and 25%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.0002). A similar effect was observed among HLA-mismatched cases (28%, 22%, and 19%, respectively). A race mismatch between recipient and donor did not affect outcome. The cumulative incidences of grade III or IV acute GVHD were 30%, 34%, and 34%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.005). The corresponding incidences of chronic GVHD at 2 years were 44%, 48%, and 49% (P = 0.02). Recipients with female donors who had undergone multiple pregnancies had a higher rate of chronic GVHD than recipients with male donors (54% versus 44%; P <.0001). The use of younger donors may lower the incidence of GVHD and improve survival after bone marrow transplantation. Age should be considered when selecting among comparably HLA-matched volunteer donors.

Characterization of a late promoter from the Streptomyces temperate phage phi C31.

An operon expressed late in the lytic cycle of the Streptomyces temperate phage phi C31 was shown to be transcribed from an inducible promoter, phi lp (phage late promoter), which resembled the previously reported early promoters. mRNAs initiated at phi lp were processed at the 3' end (and possibly also the 5' end) of a tRNA(Thr)-like sequence, resulting in leaderless polycistronic mRNAs.

Unrelated-donor marrow transplants: the experience of the National Marrow Donor Program.

As of January 1996, more than 4,000 marrow transplants have been performed using unrelated donors provided by the NMDP. With more than 1.9 million donors listed in the registry, over 70% of patients now find an HLA-A, -B, -DR phenotypic match at the initial search. The success rate is dramatically lower for patients in racial minorities. For instance, African-Americans find donors only 34% of the time on the initial search. Analysis of the first 462 transplants, showed disease-free survival rates at 2 years to be approximately 40% in low-risk patients, and 20% in high-risk patients. A more recent analysis in single centers shows an increase in the probabilities to 60-70%. This increase in success is likely related to a number of factors, including the ability to control complications, such as GVHD, plus an increase in accuracy of HLA typing primarily based on DNA-based methodology.

Aspergillus fumigatus keratitis with intraocular invasion in 15-day-old chicks.

Eye infections were initially observed in single-comb white leghorn breeder chicks at 5 days of age, and morbidity increased from 0.05% to 1.5% after debeaking at 7 days of age. All chicks necropsied at 15 days of age had cheesy yellow exudate within the conjunctival sac of one eye and small (1 mm diameter) white nodular lesions in lungs and on thoracic air-sac membranes. Histopathologic examination of the eyes revealed septate fungal hyphae and inflammatory cells in the anterior chamber, cornea, and conjunctival sac. Similar fungal hyphae were present within lung granulomas. Aspergillus fumigatus was isolated from the eyes. Eye infections were the only health problem reported for several consecutive flocks on this farm. Elimination of moldy feed from the diet and environment and proper management of sawdust litter have prevented fungal ophthalmitis in subsequent flocks.

Unrelated-donor marrow transplants: the experience of the National Marrow Donor Program.

As of December 1994, more than 3,000 marrow transplants had been accomplished using unrelated donors provided by the National Marrow Donor Program. With more than 1.5 million donors listed in the registry, over 60% of patients now find an HLA-A,B,DR phenotypic match at the initial search. The HLA types of these patients are biased toward the common Caucasian haplotypes, but the likelihood of identifying donors for non-Caucasian patients has improved with time. Analysis of the first 462 transplants showed disease-free survival (DFS) at 2 years to be approximately 40% in good-risk patients and 20% in poor-risk patients. Chronic myelogenous leukemia transplanted within the first year after diagnosis had 45% DFS. Some recent reports from individual transplant centers demonstrate results closer to those obtained with sibling donors, while a limited retrospective comparison suggests that unrelated-donor transplants are at least equivalent to and probably better than autologous transplants. A single HLA mismatch at A, B, or DR can be tolerated, but results are better with phenotypic identity. The most recent NMDP analysis has also identified younger donors and male donors as favorable variables in evaluating one-year survival of unrelated-marrow recipients.

Characterization of IgE antibody binding profiles of sera from patients with atopic dermatitis to allergens of the domestic mites Dermatophagoides pteronyssinus and Euroglyphus maynei, using enhanced chemiluminescent immunoblotting.

A rapid, sensitive, chemiluminescent immunoblotting method was used to identify IgE-binding components of Dermatophagoides pteronyssinus and Euroglyphus maynei that were recognized by sera of 16 D. pteronyssinus-sensitive patients with atopic dermatitis. Some 28 components (14-200 kD) were found in the D. pteronyssinus extract, and sera bound between 1 and 13 of them (mean 6.0). At least one of four components (97, 28, 24 and 14 kD) were bound by 14/16 sera. E. maynei had 25 components (14-227 kD), 13 in common with those of D. pteronyssinus by molecular size. Sera bound between 1 and 11 of them (mean 5.2) and 14/16 sera bound 1 of 38 kD (unique to E. maynei) and/or 1 of 175 kD. There were positive correlations between the number of D. pteronyssinus and E. maynei components bound and anti-D. pteronyssinus and E. maynei serum IgE values (p less than 0.001 in both cases) and between the number of D. pteronyssinus and E. maynei components bound and total serum IgE values (p less than 0.01 in both cases). These results demonstrate a very considerable diversity of IgE antibody responses to domestic mite allergens amongst patients with atopic dermatitis.

The effect of a prolonged in vitro exposure to 1-beta-D arabinofuranosylcytosine and deoxycytidine on the survival of normal (CFU-GM) and leukemic (L-CFU) human myeloid progenitor cells in suspension culture.

We examined the effect of a 96-h exposure to 1-beta-D arabinofuranosylcytosine (Ara-C) and deoxycytidine (dCyd) in medium lacking an exogenous source of colony-stimulating activity (phytohemagglutinin-stimulated leukocyte-conditioned medium, PHA-LCM) on the survival of normal human committed myeloid progenitor cells (day-7 and day-14 granulocyte-macrophage colony-forming units [CFU-GM] as well as leukemic progenitors (leukemic colony-forming units, L-CFU) derived from myeloblasts obtained from 13 patients with acute nonlymphocytic leukemia (ANLL). Coadministration of Ara-C (20-50 microM) in conjunction with dCyd (50-100 microM) permitted the survival of an average of 9%-57% of day-7 CFU-GM and 32%-65% day-14 CFU-GM, depending upon the relative concentrations of dCyd and Ara-C. In contrast, exposure of leukemic myeloblasts to identical regimens resulted in considerably greater reductions in L-CFU survival, which in general exceeded 90% and in some cases was 100%. In addition, exposure of leukemic myeloblasts to Ara-C and dCyd for 96 h in culture medium lacking PHA-LCM eliminated the secondary plating efficiency (PE2) of leukemic colonies in 11 of 13 samples assayed and reduced values dramatically in the remaining 2. Substantial preservation of CFU-GM formation was also noted when normal bone marrow samples depleted of T cells and marrows obtained from two patients with ANLL in remission were assayed. These studies suggest that in contrast to certain normal committed myeloid progenitor cells, leukemic progenitors, particularly those with self-renewal capacity, are highly vulnerable to a prolonged exposure to Ara-C and dCyd in the absence of an exogenous source of colony-stimulating activity. They also raise the possibility that a combined regimen utilizing chemotherapeutic agents in conjunction with modifications of long-term culture techniques may represent a novel approach to the ex vivo purging of leukemic cells from bone marrow in conjunction with autologous bone marrow transplantation.

Lupus anticoagulant and cerebrovascular accident in a patient with neurofibromatosis.

This report describes the case of a young woman with biopsy-proven neurofibromatosis and a history of recurrent fetal wastage who had sudden onset of slurred speech and left-sided weakness. CT scan and MRI revealed multiple cerebral infarcts. Laboratory evaluation revealed lupus anticoagulant and high levels of anticardiolipin antibody. This case illustrates the thrombotic tendencies seen in patients with lupus anticoagulant and anticardiolipin antibody, and is the first reported case of LA in association with neurofibromatosis.

Allogeneic marrow grafting with partially mismatched, unrelated marrow donors.

Forty patients with advanced hematologic malignancies or severe aplastic anemia received marrow grafts from partially mismatched, unrelated marrow donors. All patients were administered conventional prophylaxis for acute graft-v-host disease (GVHD) consisting of methotrexate and low-dose glucocorticoids. All but two patients who survived at least 30 days showed durable engraftment. Six patients survive 17+ to 36+ months following transplantation. Severe acute GVHD was seen in 47% of the patients; however, no direct correlation between GVHD and the degree of mismatching could be determined. Fatal infections were seen in 29 patients, and in the majority the infection occurred after the granulocyte count had risen to greater than 500 cells/microL. We conclude that the problems encountered in this pilot study can potentially be solved, and that further studies with this type of marrow grafting are warranted.

Bronchoscopic diagnosis of cytomegalovirus pneumonia following pediatric bone marrow transplantation.

A pediatric bone marrow transplant (BMT) patient with cytomegalovirus (CMV) pneumonia is reported. The diagnosis was made with flexible fiberoptic bronchoscopy and bronchoalveolar lavage (BAL). The use of BAL in diagnosing CMV pneumonitis in an immunocompromised child after BMT is discussed.

The use of partially matched, unrelated donors in clinical bone marrow transplantation.

It is estimated that 60-70% of patients who might benefit from a bone marrow transplant will not have a suitably matched, related donor. We have, therefore, designed a clinical experiment to test the safety and feasibility of using marrow from partially matched, unrelated donors. This paper details our transplant experience in the first eight patients with leukemia. The first four patients had advanced leukemia at the time of transplantation. Each showed hematopoietic recovery, but all died from septic complications largely related to extended neutropenia encompassing both the pre-marrow-grafting and the post-marrow-grafting period. The next four patients were in remission at the time of transplantation. Each showed prompt and sustained hematopoiesis with variable graft-versus-host disease (GVHD). No acute or chronic GVHD was seen in two patients, grade II (skin only) was seen in one patient, and grade IV (skin, liver, and gut) was seen in one patient. One patient has died from sepsis five-and-one-half months following transplantation, and three are alive and well six-and-one-half to nine-and-one-half months postengraftment. This preliminary experience, together with several case reports in the literature, leads us to conclude that bone marrow transplantation with partially matched, unrelated marrow is a safe and feasible approach. If these results are confirmed by longer follow-up in a larger group of patients, the development of marrow donor pools would appear to be justified.

Antibodies to cell membrane antigens associated with human T-cell leukemia virus in patients with AIDS.

The acquired immune deficiency syndrome (AIDS), which has recently occurred at increasing rates in homosexual men, intravenous drug users, and others, is characterized by the development of Kaposi's sarcoma and several opportunistic infections including pneumonia caused by Pneumocystis carinii. Serum samples from patients with AIDS and from matched and unmatched control subjects were examined for the presence of antibodies to cell membrane antigens associated with human T-cell leukemia virus. Nineteen of 75 of the AIDS patients had antibodies directed to surface antigens of Hut 102, a reference T lymphoid cell line infected with leukemia virus, as did two of the 336 control subjects.