MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16.

OBJECTIVES: To identify the first time point of an MRI-verified response to certolizumab pegol (CZP) therapy in patients with rheumatoid arthritis (RA). METHODS: Forty-one patients with active RA despite disease-modifying antirheumatic drug therapy were randomised 2:1 to CZP (CZP loading dose 400 mg every 2 weeks at weeks 0-4; CZP 200 mg every 2 weeks at weeks 6-16) or placebo→CZP (placebo at weeks 0-2; CZP loading dose at weeks 2-6; CZP 200 mg every 2 weeks at weeks 8-16). Contrast-enhanced MRI of one hand and wrist was acquired at baseline (week 0) and weeks 1, 2, 4, 8 and 16. All six time points were read simultaneously, blinded to time, using the Outcome Measures in Rheumatology Clinical Trials RA MRI scoring system. Primary outcome was change in synovitis score in the CZP group; secondary outcomes were change in bone oedema (osteitis) and erosion scores and clinical outcome measures. RESULTS: Forty patients were treated (27 CZP, 13 placebo→CZP), and 36 (24 CZP, 12 placebo→CZP) completed week 16. In the CZP group, there were significant reductions from baseline synovitis (Hodges-Lehmann estimate of median change, -1.5, p=0.049) and osteitis scores (-2.5, p=0.031) at week 16. Numerical, but statistically insignificant, MRI inflammation reductions were observed at weeks 1-2 in the CZP group. No significant change was seen in bone erosion score. Improvements across all clinical outcomes were seen in the CZP group. CONCLUSIONS: CZP reduced MRI synovitis and osteitis scores at week 16, despite small sample size and the technical challenge of reading six time points simultaneously. This study provides essential information on optimal MRI timing for subsequent trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01235598.

A complex genitourinary injury following gunshot in a 12 Year old and systematic review.

We highlight the case of a 12 year old male who presented after sustaining a gunshot injury to the scrotum resulting in testicular, prostatic, and urethral transection in addition to pelvic fracture, extra peritoneal bladder injury, and transmural injury to recto sigmoid and ileum. The patient underwent a left orchiectomy, primary repair of the bladder and urethra, placement of universal plate on superior pubic rami, and segmental rectosigmoid and ileum resection. These findings illustrate the collaborative efforts of trauma surgery and urology to treat complex lower genitourinary (GU) injuries and how the direct prioritization of surgical efforts provides acceptable outcomes.

Unrelated-donor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children.

PURPOSE: Bone marrow transplantation (BMT) for Philadelphia chromosome-positive (Ph1) chronic myelogenous leukemia (CML) results in a 55% to 64% disease-free survival (DFS) rate in 20% to 30% of cases with a matched-sibling donor (MSD). Studies that include primarily adults with CML, using unrelated-donor (URD) BMT, have expanded this option to those without an MSD. We review and compare the efficacy of URD and MSD BMT in children with Ph1 CML. PATIENTS AND METHODS: Eleven children with URD BMTs were reviewed and compared with 11 children with MSD BMTs for Ph1 CML. Among the URD BMT recipients, there were three with fully matched marrows and 10 with advanced CML. The median time from diagnosis to transplant was 2.6 years. Among the MSD BMT recipients, 11 had fully matched marrows and five had advanced CML. The median time from diagnosis to BMT was 0.7 years. All received non-T-depleted marrows after cyclophosphamide and fractionated total-body irradiation. RESULTS: Both groups had similar engraftment times. Late graft failure occurred in two URD patients. Graft-versus-host disease (GVHD), > or = grade II, was similar in both groups (77% for URD BMT, 45% for MSD BMT), although more severe acute disease and more persistent chronic disease was seen in the URD group. The Kaplan-Meier estimate of DFS was 45% +/- 15% (SE) and 78% +/- 14% (SE) in the URD and MSD groups, respectively, at 3 years. All had Karnofsky scores of more than 70%, except one URD patient debilitated from GVHD. CONCLUSION: CML is eventually fatal to all patients without BMT. The high survival rate seen among children who receive a URD BMT, despite several adverse factors, opens this important therapeutic option to those without an MSD.

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.

Therapy of chronic myelogenous leukemia with allogeneic bone marrow transplantation.

From December 1982 to January 1986, 57 patients received allogeneic bone marrow transplantation as therapy for Philadelphia chromosome (Ph') positive chronic myelogenous leukemia (CML). All patients were prepared for transplantation with cyclophosphamide 60 mg/kg (day -6, -5) and fractionated total body irradiation, 165 cGy twice daily (day -4, -3, -2, -1) and received major histocompatibility (MHC) matched donor marrow (day 0). All patients received graft-v-host disease (GVHD) prophylaxis with methotrexate, prednisone, and either antithymocyte globulin (ATG) (55 patients) or OKT3 infusion (two patients). The projected survival of 29 chronic phase patients is 64% (95% confidence interval [Cl] 42% to 86%); and of 28 accelerated phase patients, 30% (95% Cl, 12% to 48%) at 30 months (P = .005). Multivariate regression analysis of pretransplant patient characteristics demonstrated that the presence of chronic phase and age less than 30 years were the only prognostic features studied that independently predicted survival. No evidence of persistent or recurrent disease has occurred in chronic phase patients; however, reappearance of the Ph' was observed in seven accelerated-phase patients, and hematologic relapse occurred in three of these seven patients. The incidence of grade II to IV acute GVHD is 63% (95% Cl, 50% to 76%) at 100 days, and that of extensive chronic GVHD is 53% (95% Cl, 33% to 74%) at 30 months. The median Karnofsky activity assessment of survivors is 100% (range, 60% to 100%), and all activity assessments less than 100% can be attributed to complications of GVHD. Bone marrow transplantation therapy for CML after preparation with cyclophosphamide and fractionated total body irradiation results in a high proportion of disease-free survival in chronic-phase patients. Survival in accelerated phase is significantly worse and is associated with relapse. GVHD has emerged as a significant cause of morbidity and mortality in this study.

The spectrum of non-Candida fungal infections following bone marrow transplantation.

We evaluated a consecutive series of patients who underwent bone marrow transplantation (BMT) at a single institution between 1974 and 1989 for the occurrence of a non-Candida fungal infection in the first 180 days after BMT. Of the 1186 patients, 129 (11%) patients developed a total of 138 significant non-Candida fungal infections in this period. Eight patients had multiple distinct infections. The most common isolate was Aspergillus spp. (n = 97), followed by Fusarium (n = 10), and Alternaria (n = 6). The 4 clinical subtypes of infections were minor skin or soft-tissue infections (n = 7), infections of a single organ or site (n = 61), disseminated fungal infection (n = 58), and isolated fungemia (n = 12). The respiratory tract was involved in 95% of single organ or site infections, and 84% of disseminated infections. Outcome was poor, with only 18% of patients surviving. The cause of death was directly related to the non-Candida fungal infection in 66% of patients who died. Mortality rates were significantly higher in patients with either single-organ or site infections (41%) or disseminated infections (83%). The cause-specific mortality rate was greatest following infections with Aspergillus, Chrysosporium, Fusarium, Mucor, or Scopulariopsis, in which there was a high potential for invasive disease and disseminated infection. In contrast, the cause-specific mortality rate was lowest in infections which were either isolated fungemia or were localized and amenable to surgical debridement, most often seen with those infections caused by Acremonium, Alternaria, Penicillium, and Saccharomyces. The spectrum of clinical infections caused by these uncommon non-Candida fungal isolates both in our series and in the literature is reviewed. These unusual opportunistic fungal isolates are now gaining recognition in immunosuppressed patients such as the BMT population, and have a significant impact on patient outcome. Effective therapy of non-Candida fungal infections remains difficult. Early aggressive surgical debridement appears to be important in control of localized invasive infections. Prolonged therapy with amphotericin B is the standard of care, although the role of the newer antifungal agents is not yet well-defined. Ancillary roles may also be provided by granulocyte transfusions and the colony-stimulating factors.

Avascular necrosis of bone: a common serious complication of allogeneic bone marrow transplantation.

PURPOSE: To describe the incidence, presentation, clinical course, and management of avascular necrosis of bone following bone marrow transplantation, and to identify risk factors related to its development and outcome. PATIENTS AND METHODS: All patients developing avascular necrosis after transplantation between March 1974 and May 1988 were identified by means of the Minnesota Bone Marrow Transplant Database and hospital records and included in analysis. Of 902 consecutive patients undergoing bone marrow transplantation, 28 developed avascular necrosis of bone. RESULTS: Twenty-eight of 642 allogeneic transplant recipients (10.4% by product limit estimate) developed avascular necrosis compared to zero of 260 autologous transplant recipients. Symptoms developed 1 to 62 months (median 12 months) after transplantation. In the 28 patients a total of 91 joints were affected (mean 3.3 per patient, range one to eight joints). The hip joint was most often involved (64% of patients), followed by knee (61%), ankle (29%), shoulder (21%), and elbow (7%). Initial standard radiographs were negative in 13 patients, while in nine patients, technetium-99 scans and/or magnetic resonance imaging demonstrated changes of osteonecrosis before changes on routine radiographs. Almost all patients had received steroid prophylaxis and therapy for graft-versus-host disease (GVHD). We observed a significant correlation between the total cumulative dose of steroids and number of joints involved (p less than 0.01). A multivariate analysis (allogeneic transplant patients only) identified acute or chronic GVHD requiring steroid therapy (p = 0.003), and increasing age (p = 0.002) as significant and independent risk factors. Fourteen patients required surgery, including joint replacement in 11 patients. In six of six patients, hip core decompression failed to halt disease progression, and total hip arthroplasty was subsequently required. CONCLUSION: Avascular necrosis of bone is a frequent late complication of bone marrow transplantation, causing significant morbidity and often requiring surgery; diagnosis using conventional imaging techniques may be difficult and treatment remains inadequate.

Non-Candida fungal infections after bone marrow transplantation: risk factors and outcome.

PURPOSE: To determine the incidence, risk factors, and outcome of non-Candida fungal infections in a bone marrow transplant population. PATIENTS AND METHODS: A consecutive series of 1,186 patients who underwent bone marrow transplant at the University of Minnesota Hospital between 1974 and 1989 were analyzed for the occurrence of a post-transplant non-Candida fungal infection. The risk factors were analyzed with regard to clinical characteristics such as age, sex, primary disease process, type of transplant, recipient cytomegalovirus serostatus, time to engraftment, and the presence of graft-versus-host disease. RESULTS: In this population, 123 of 1,186 patients (10%) developed a non-Candida fungal infection within 180 days of transplant. The majority of infections (85%) occurred in allogeneic recipients, and 58% of infections were prior to white blood cell engraftment. The most common isolates were Aspergillus species (70%), Fusarium species (8%), and Alternaria species (5%). Although 47% of infections involved a single organ or site, 44% were disseminated and 9% were isolated fungemias. Only 17% of patients survived. Sixty-eight percent of deaths were related to the fungal infection. In univariate analysis, allogeneic transplant, positive recipient cytomegalovirus serostatus, delayed engraftment, and recipient age of greater than or equal to 18 years were identified as risk factors for non-Candida fungal infection. All of these factors except for recipient age were independently significant in multivariate analysis. In allogeneic recipients, positive cytomegalovirus serostatus, delayed engraftment, and age of greater than or equal to 18 years were each significantly associated with a greater risk of fungal infection; none of these factors were independently significant in the autologous recipients. CONCLUSION: Fungal infections remain a major cause of morbidity and mortality in patients undergoing bone marrow transplant. More effective antifungal prophylaxis and therapy, earlier diagnosis, and transplant regimens incurring a brief period of neutropenia may substantially reduce the incidence and clinical impact of these infections.

Autologous bone marrow transplantation in non-Hodgkin's lymphoma: monoclonal antibodies plus complement for ex vivo marrow treatment.

PURPOSE: Patients with non-Hodgkin's lymphoma who fail to achieve a complete remission or who relapse are rarely cured with conventional therapies. For this group of patients, intensive therapy and bone marrow rescue may be curative. Our goal was to assess the effects of autologous transplantation in patients with B-cell lymphomas and a poor prognosis. To avoid occult or overt contamination with lymphoma, monoclonal antibodies BA-1, BA-2, and BA-3 were used for ex vivo marrow treatment. PATIENTS AND METHODS: Seventeen patients underwent intensive therapy and autologous bone marrow transplant using the aforementioned marrow. Ten of the 17 patients (Group I) had disease that was in complete or partial remission. The other seven patients either had disease that was not responsive to treatment or had bone marrow transplant as their initial therapy at relapse. RESULTS: The ex vivo treatment did not adversely affect engraftment. For those patients who could be evaluated, the median time to white cell engraftment was 24 days; the median durations of red cell and platelet support were 24 and 29 days, respectively. Eleven of the 17 patients had complete remissions at the evaluation 28 days after transplant. Three patients subsequently experienced a relapse, three died while their disease was in complete remission, and five are alive and disease-free 405 to 1,674 days after transplant. Group I patients had an estimated 40 percent disease-free survival rate at three years compared with 0 percent for Group II patients (p less than 0.01). CONCLUSION: Our data support autologous bone marrow transplantation as an important treatment modality for the non-Hodgkin's lymphomas. With the current preparative regimens available, however, its use should be limited to patients with disease that is still responding to conventional therapies.

Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission.

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976-June 1983) were prepared with cyclophosphamide, 60 mg/kg/day, IV for 2 days and single fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983-December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median follow-up of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapse-free survival, survival, and relapse rates at 3 years are 56, 58, and 19% in Group I and 69 (p = 0.22), 77 (p = 0.07), and 10% (p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival.

Hemorrhagic cystitis after bone marrow transplantation. Risk factors and complications.

Hemorrhagic cystitis (HC) is a major cause of morbidity after BMT; we have analyzed its incidence, risk factors, and complications in 977 patients undergoing BMT between 1974 and 1988. Despite vigorous hydration and frequent voiding in all patients receiving cyclophosphamide, 135/977 (15% by Kaplan-Meier projection) developed HC (micro- or gross hematuria, dysuria, bladder pain) between -11 and +100 days (median +22) after BMT. Of these, 60 had severe HC, including major urinary obstruction (4/60), renal failure (13/60), or need for surgical or chemical bladder cauterization (16/60). By univariate analysis, allogeneic BMT recipients had more frequent HC than autologous patients (17% vs. 9%, P = 0.002). In addition, allogeneic patients with adenoviruria were at increased risk for the development of HC. Patients with aplastic anemia conditioned with high dose cyclophosphamide and total lymphoid irradiation had the highest rate of HC (22%) versus those with hematologic malignancies (15%, P = 0.03). A Cox proportional hazards regression model was used to further identify those factors independently associated with HC. In all regression models, the factor most highly associated with the development of HC was the finding of adenovirus in the urine preceding the onset of hematuria. HC-related morbidity, and its associated increased hospitalization costs, frequently complicates BMT. Improved prophylactic measures, perhaps including the use of 2-mercaptoethane sulfonate, are needed, at least for allogeneic BMT patients with their attendant risk of adenovirus infection.

Cytomegalovirus pneumonia after bone marrow transplantation. Risk factors and response to therapy.

Cytomegalovirus pneumonia complicated bone marrow transplantation in 75 (63 allogeneic and 12 autologous) of 1136 recipients (Kaplan-Meier incidence 8.8%). CMV pneumonia occurred more frequently in allogeneic (12.4%) than autologous recipients (3.3%). Increased risk for CMV pneumonia was observed in allogeneic recipients who were seropositive (relative risk = 2.9), older age (RR = 1.4 per decade), those conditioned with total-body irradiation (RR = 2.7), who received antithymocyte globulin (RR = 2.9) or T cell-depleted marrow (RR = 2.7) or who had CMV viruria (RR = 4.0) or viremia (RR = 5.9). Autologous recipients were also at increased risk if they were seropositive (RR = 6.1), or developed viruria (RR = 7.0) or viremia (RR = 15.4). Thirteen of 14 untreated patients died without improvement. Prognosis was poor in patients who were ventilator-dependent at initiation of therapy (median survival 17 days), with only 1 long-term survivor. In contrast, patients ventilator-independent at initiation of therapy with ganciclovir and immunoglobulin (n = 22) had a median survival of > 274 days, with 9 long-term survivors. Ganciclovir alone or acyclovir with immunoglobulin in ventilator-independent patients was less effective (median survivals 80 and 10 days, respectively). Overall, 10 of 75 patients were surviving 10-73 months (median 47) from diagnosis; 9 of these were ventilator-independent at initiation of therapy and received ganciclovir with immunoglobulin. CMV pneumonia was less common, but was severe in autologous recipients, with only 2 of 12 surviving. CMV pneumonia remains a prominent cause of death following BMT. Early therapy with ganciclovir and immunoglobulin before respiratory failure supervenes may improve survival.

T cell depletion with anti-CD5 immunotoxin in histocompatible bone marrow transplantation. The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease.

Twenty-nine patients with advanced leukemias (median age 34 years) received histocompatible sibling marrow that had been depleted of T cells by ex vivo incubation with anti-CD5 monoclonal antibody-ricin immunotoxin (T101-R) for the purpose of graft-versus-host disease prophylaxis. Donor cell engraftment was documented in 28/29 patients by DNA restriction fragment length polymorphisms. In this pilot study the dose of T101-R incubated with donor marrow was increased in a stepwise manner from 300 ng (10 patients) to 600 ng (5 patients) to 1000 ng immunotoxin (IT)/10(7) bone marrow mononuclear cells (14 patients) in an attempt to achieve more effective GvHD prophylaxis. A statistically significant reduction in acute GvHD was achieved for patients receiving marrow pretreated with 1000 ng of immunotoxin (34%) compared to recipients of BM treated with 300 ng immunotoxin (100%, P = 0.0004). T-depleted marrow samples were evaluated for residual T cell activity using several in vitro assays including proliferation to the purified mitogen PHA (HA-17) and in mixed lymphocyte culture (MLC), T cell cytotoxicity, a limiting dilution assay for detecting precursors of proliferating T cells (LDApPTL), and phenotypic analysis of viable T cells expanded in 16-day culture with interleukin 2. The extent of T cell depletion determined by LDA assay varied widely at each immunotoxin concentration used. Thus, there was no correlation between the dose of T cells infused and subsequent GvHD. Phenotyping of lymphocytes recovered from immunotoxin-treated marrow demonstrated that residual T cells were CD5 negative in all cases tested. The only in vitro parameter that predicted subsequent acute or chronic GvHD was the demonstration of viable CD5 negative lymphocytes with T cell phenotype (CD2, CD3, and/or CD7 positive) after 16-day culture with IL-2 of the T-depleted bone marrow. We observed that such CD5 negative cells expressing other T cell markers have cytotoxic function and speculate that these cells may be capable of mediating GvHD in allogeneic transplantation.

Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation.

In a randomized trial we studied the impact of providing total parenteral nutrition (TPN) to bone marrow transplant (BMT) patients during their cytoreductive therapy, and for 4 weeks following BMT, on 8 parameters of outcome. A total of 137 patients over 1 year of age and with normal nutritional status were randomized either to receive TPN starting one week prior to transplant or to receive hydration with a 5% dextrose solution containing electrolytes, minerals, trace elements, and vitamins. TPN was ultimately required by 40 of the 66 control patients when nutritional depletion was documented. Average total calorie and protein intake was significantly higher for the TPN group than for the control group. Minimum follow-up was 1 year and median was 2 years. Overall survival, time to relapse, and disease-free survival were significantly improved in the TPN group. Engraftment, duration of hospitalization, and incidences of acute and chronic graft-vs.-host disease and bacteremia were not different. Thus TPN during BMT had a positive effect on long-term outcome. Prophylactic nutritional therapy appears to be indicated even for well-nourished individuals during cytoreduction and BMT.

Graft-versus-host disease prevention in allogeneic bone marrow transplantation from histocompatible siblings. A pilot study using immunotoxins for T cell depletion of donor bone marrow.

Seventeen patients, ages 7-53 years were transplanted with histocompatible bone marrow that had been depleted of T lymphocytes by ex vivo immunotoxin (IT) treatment. Twelve patients had high-risk acute leukemias, and five had chronic myelogenous leukemia. No other graft-vs.-host disease (GVHD) prophylaxis was used. A mixture of three anti-T-cell monoclonal antibodies conjugated to ricin were used in this study: TA-1, UCHT-1 (anti-CD3), and T101 (anti-CD5). The mean number of bone marrow cells infused was 1.5 X 10(8) mononuclear cells/kg recipient weight. Thirteen of the 17 patients demonstrated complete and sustained engraftment. Four patients experienced autologous marrow recovery and/or graft rejection. Compared with an historical group of leukemic patients who received GVHD prophylaxis with methotrexate alone or combinations of methotrexate, and prednisone plus antithymocyte globulin, (ATG) or OKT3, the IT patients with stable engraftment demonstrated shorter time to recovery of leukocytes greater than or equal to 1000mm3 for three consecutive days (median, 20 days vs. 26 days, P = .03). The recovery of total lymphocytes, B and T cell subsets, and T cell function by day 28 was highly variable, but similar, for patients in both the IT-treated group and historical controls. Four patients (ages 13, 18, 21, and 38) developed grade II skin GVHD, but none had severe GVHD. Eight of the 13 patients with durable engraftment have had posttransplant leukemic relapse. Currently only four patients remain alive; two have not relapsed posttransplant, while the other two achieved remission following posttransplant relapse. We conclude that severe GVHD was not observed in this small series with ex vivo T cell depletion for GVHD prophylaxis, and that favorable recovery of hematologic and lymphocytic function was demonstrated for cases where primary engraftment was sustained. A larger randomized controlled study will be needed to establish whether T cell depletion of donor bone marrow with IT can significantly reduce GVHD, and/or improve disease-free survival.

Lack of correlation of MLC reactivity with acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation.

Acute graft-versus-host disease (AGvHD) is a significant cause of morbidity and mortality in patients receiving a bone marrow transplant from an unrelated donor, and in an effort to reduce this problem, donors are selected for the least possible HLA incompatibility with the recipient. Selection criteria have included minimal incompatibility for the HLA-A, -B, and -DR loci and low reactivity in mixed lymphocyte culture (MLC); however, the value of MLC reactivity for prediction of development of AGvHD has been questioned. We therefore examined the correlation of MLC reactivity with AGvHD in recipients of unrelated bone marrow transplants. Reactivity in the GvH direction was assessed as relative response (RR) of donor lymphocytes to recipient stimulator lymphocytes. In 126 transplanted pairs with technically satisfactory MLC tests, the RR was divided into quartiles (0-1, 2-5, 6-16, and 17-117% RR). HLA-DRB1 incompatibilities were more frequent in the highest quartile (P < 0.001); there were no significant differences among quartiles in donor or recipient age, diagnosis, or frequency of HLA-A or -B incompatibility. Incidence of AGvHD during the first 100 days post-transplant was assessed by Kaplan-Meier analysis. There was no significant difference in incidence of AGvHD among quartiles for the entire group of 126 pairs, for a subset with hematologic malignancy, for a subset selected by a more stringent standard for "technically satisfactory" MLC, or for a subset matched for A, B, and DRB1. The MLC response of donor lymphocytes to recipient stimulator lymphocytes is thus not predictive of development of AGvHD in our patient population receiving unrelated donor bone marrow. Since there was no difference in mortality related to high and low MLC responses, our data also suggest that MLC results are not predictive of survival in this population.

Depressed central respiratory drive causing weaning failure. Its reversal with doxapram.

A patient failed to wean from mechanical ventilation. Her problem was unique in that she had a depressed central drive to breathe manifested by hypopnea when removed from the ventilator. After excluding the known problems that impair successful weaning, we empirically administered three separate infusions of doxapram, a respiratory stimulant. These infusions produced a dramatic improvement in spontaneous ventilation and led to successful weaning and hospital discharge.

Lupus inhibitors following bone marrow transplant.

Lupus inhibitors have been reported in a number of pathologic states in which there is a disruption of normal immunoregulation. We report here the development of new lupus inhibitors following bone marrow transplantation. Retrospective analysis of 1292 patients undergoing transplantation at the University of Minnesota over a 10 year period demonstrated newly recognized lupus inhibitors in 3% of the patients. These inhibitors were usually detected in the first 1-2 months after transplant. They occurred more frequently in children, with a particularly high incidence in patients with Hurler syndrome. The development of inhibitors was associated with the use of cyclosporine A (CsA) or T depletion for GVHD prophylaxis, with the use of busulfan/cytoxan as a preparative regimen (which includes phenytoin for seizure prophylaxis) and with the occurrence of viral infections. Lupus inhibitors were not associated with development of GVHD, or with any diagnosis other than Hurler syndrome. Thrombotic complications were rare as would be expected in this severely thrombocytopenic population. The incidence of lupus inhibitors that we recognized may substantially underestimate the true incidence as frequent routine coagulation studies were not performed in these patients. Prospective evaluation of lupus inhibitors during bone marrow transplant may provide insight into the pathogenesis of these inhibitors in other disease states.

Early herpes zoster infection in adult patients with Hodgkin's disease undergoing autologous bone marrow transplant.

The incidence of varicella-zoster-virus infection/reactivation in adult patients with Hodgkin's disease undergoing autologous bone marrow transplantation (BMT) at the University of Minnesota Hospital and Clinic was determined. Seven of 28 evaluable patients (25%) developed varicella-zoster infections in the first 150 days post-transplant. Two additional patients developed zoster after day 150 for a total incidence of 32%. We evaluated analysed risk factors to determine if there were any characteristics that could identify patients at risk for zoster early (less than 150 days) in their post-transplant course. Sex, age, prior radiation, and lack of immunity as determined by viral antibody titers were not associated with an increased incidence. Ten of the 28 patients had a history of zoster at some time after the diagnosis of Hodgkin's disease. Six of these 10 patients (60%) again developed zoster post-transplant. This compared to only one episode of varicella-zoster post-transplant among the 18 patients without a history of zoster following the diagnosis of Hodgkin's disease (p less than 0.01, Fisher's exact). We conclude that a prior history of zoster any time after diagnosis of Hodgkin's disease is strongly associated with developing zoster in the first 150 days after autologous BMT.

Varicella zoster infection after bone marrow transplantation: incidence, risk factors and complications.

The cellular immunoincompetence which follows bone marrow transplantation (BMT) allows both primary and reactivation infection with herpes viruses. We report the overall incidence and timing of varicella zoster virus (VZV) infections after BMT, including the clinical course, complications and associated clinical risk features. Of 1186 patients undergoing BMT through 1989, 216 patients developed VZV infection between 4 days and 10.8 years after BMT; 86% of them within the first 18 months. Of all patients transplanted, 15 +/- 3% by 6 months and 52 +/- 14% by 5 years had developed VZV infection. Dermatomal zoster represented 62% of the infections, while 32% had complicated VZV infection--CNS, disseminated or visceral zoster. All serious infections occurred within 7 months of BMT but only two patients died, both from VZV pneumonitis. Allogeneic and autologous recipients had a similar incidence of VZV infection. VZV seropositive patients had more frequent, earlier and often more complicated or disseminated infections. Age > or = 10 years and radiation in the pre-transplant conditioning were significantly and independently associated with higher rates of VZV infection within a multivariate regression model. Using this model, we could define clinical risk groups with distinctly different hazards of VZV infection: age > 10 years, radiation pre-BMT and VZV seropositive patients had a 44% incidence by 3 years versus age < 10 years, no radiation and VZV seronegative had a 0% incidence by 3 years. Acyclovir assigned for prophylaxis of CMV or HSV infection had no effect on the timing or incidence of VZV infection.(ABSTRACT TRUNCATED AT 250 WORDS)