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.

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.

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.

A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant.

We performed a prospective, randomized trial in CMV seronegative marrow recipients to determine if filtered blood products were as effective as CMV-seronegative blood products for the prevention of transfusion-transmitted CMV infection after marrow transplant. Before transplant, 502 patients were randomized to receive either filtered or seronegative blood products. Patients were monitored for the development of CMV infection and tissue-documented CMV disease between days 21 and 100 after transplant. Infections occurring after day 21 from transplant were considered related to the transfusion of study blood products and, thus, were considered evaluable infections for the purpose of this trial. In the primary analysis of evaluable infections, there were no significant differences between the probability of CMV infection (1.3% v 2.4%, P = 1.00) or disease (0% v 2.4%, P = 1.00) between the seronegative and filtered arms, respectively, or probability of survival (P = .6). In a secondary analysis of all infections occurring from day 0 to 100 post-transplant, although the infection rates were similar, the probability of CMV disease in the filtered arm was greater (2.4% v 0% in the seronegative arm, P = .03). However, the disease rate was still within the prestudy clinically defined acceptable rate of < or = 5%. We conclude that filtration is an effective alternative to the use of seronegative blood products for prevention of transfusion-associated CMV infection in marrow transplant patients.

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.

Interleukin-1 alpha administered after autologous transplantation: a phase I/II clinical trial.

Interleukin-1 alpha (IL-1 alpha) can act as both a hematopoietic growth factor and a stimulant of cellular and humoral immune responses. To promote acceleration of hematologic recovery and induce immune antitumor activity, we initiated a phase I/II dose escalation trial of 6-hour daily infusions of recombinant human IL-1 alpha after autologous transplantation. Forty patients with Hodgkin's disease (n = 9) and non-Hodgkin's lymphoma (n = 31) transplanted with unmobilized autologous peripheral blood stem cells or bone marrow stem cells received daily 6-hour infusions of IL-1 alpha (day 0 to day +13) at daily doses between 0.1 to 10 micrograms/m2/d; 7 patients received only 7 planned days of IL-1 alpha (day 0 through 6). Most patients received all 14 days of therapy, although 5 patients discontinued treatment early (after 1 to 6 doses) because of fever and severe chills. Toxicity included IL-1 alpha-related fever (occurring on a median of 9 of 14 treatment days), fatigue, and severe chills. Hypotension was dose-limiting and led to discontinuation of IL-1 alpha in both patients receiving 10 micrograms/m2/d. IL-1 alpha-treated patients receiving 3.0 micrograms/m2/d (the maximum tolerated dose) achieved neutrophil recovery (absolute neutrophil count greater than 500/microL) significantly earlier (median, 12 days; range, 11 to 27) than untreated control patients or those receiving IL-1 alpha at 0.1 to 1.0 micrograms/m2/d (median, 27; range, 9 to 63; P < .0001). In addition, the IL-1 alpha patients' bone marrows at day +14 were significantly enriched with committed myeloid progenitor cells. Strong trends to earlier freedom from red blood cell (P = .06) and platelet (P = .09) transfusions were also noted after IL-1 alpha treatment. This earlier hematopoietic engraftment after 3.0 micrograms/m2/d IL-1 alpha allowed earlier hospital discharge (median, 25 v 37 days for control or low-dose IL-1 alpha patients [P < .0001]) and a concomitant reduction (by $38,000) in median hospital charges (P = .01). The clinical toxicities of IL-1 alpha infusion are substantial, though not life-threatening. The accelerated hematopoiesis and immune response activation observed in this trial suggest the value of its further investigation in controlled trials and perhaps in combination with other hemopoietins after transplantation.

Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation.

The availability of hematopoietic growth factors has introduced a new therapeutic modality to the treatment of graft failure after bone marrow transplantation (BMT). However, the clinical value of other therapeutic approaches to graft failure has not been reported in detail. We have studied the outcome of second infusions of BM for treatment of primary and secondary graft failure in 33 patients who received an allogeneic BMT at our institution between 1974 and 1992. Patients had received BM from a related (n = 28) or unrelated (n = 5) donor for hematological malignancy or BM failure. After primary graft failure, 57% (12 of 21) of reinfused patients engrafted and the Kaplan-Meier estimate of survival at 1 year is 24% (CI 6-42%). After secondary graft failure, 33% (4 of 12) of reinfused patients engrafted and survival is 25% (CI 0-50%) at 1 year. Infection, predominantly fungal, was the most frequent cause of death. Acute or chronic graft-versus-host disease (GVHD) developed in 52% of evaluable reinfused patients. We conclude that reinfusion of donor marrow can be an effective intervention in the treatment of primary and secondary graft failure. These data can serve as a comparative historical experience for the assessment of hemopoietic growth factors in the treatment of graft failure.

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.

Predictive factors for chronic graft-versus-host disease after histocompatible sibling donor bone marrow transplantation.

We analyzed factors associated with the development of chronic graft-versus-host disease (GVHD) in 469 consecutive patients receiving matched sibling allogeneic bone marrow transplantation (BMT). Overall, 41 +/- 6% (95% confidence interval) developed chronic GVHD between 2 and 50 months after BMT. Multivariate analysis showed that previous acute GVHD was the dominant independent risk factor predisposing to chronic GVHD (Relative Risk 4.82, p < 0.0001). In addition, recipient age of > or = 18 years and male recipient with female donor were also independent predictive factors for development of chronic GVHD. When acute GVHD and recipient age were considered, groups with distinctive risks of chronic GVHD were identified. Patients under 18 without previous grade II-IV acute GVHD had only a 10 +/- 5% risk of chronic GVHD. Patients over 18 with no prior grade II-IV acute GVHD had a 31 +/- 12% risk while patients with advanced acute GVHD, regardless of age, had the highest risk and 70 +/- 8% developed chronic GVHD. It is important to consider these factors when designing and assessing clinical trials of chronic GVHD prophylaxis and treatment.

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)

Comparison of engraftment in recipients of matched sibling of unrelated donor marrow allografts.

Bone marrow transplantation (BMT) from unrelated donors (URD) is being increasingly used as a treatment modality for patients with hematological malignancy and graft failure. We hypothesized that use of unrelated donors with increased degrees of histoincompatibility, as determined by standard serological techniques, would be associated with increased difficulty in achieving engraftment and more frequent graft failure. Engraftment was analyzed in 108 patients with hematologic disease who underwent BMT from a fully serologically HLA-matched unrelated donor (n = 40) or a partially serologically HLA-matched unrelated donor (n = 68). These patients were compared with 236 patients who received BMT from matched sibling donors (MSD group) over the same time period. Primary graft failure occurred in 5% of the MSD group, 6% of the serologically matched URD group and 15% of the partially serologically matched URD group (p = 0.06). Univariate and multivariate analysis of factors relating to primary graft failure showed the only significant variable to be full or partial serological HLA-matching in the URD group. Secondary graft failure occurred in 0.7% of the MSD group, 15% of the serologically matched URD group and 25% of the partially serologically matched URD group (p < 0.0001). Univariate and multivariate analysis of secondary graft failure showed the only significant variable to be a related or unrelated donor. We conclude that primary graft failure is a significantly more frequent event in recipients of bone marrow from partially serologically matched URD than in recipients of MSD or fully serologically matched URD marrow.(ABSTRACT TRUNCATED AT 250 WORDS)

Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: risk factors and clinical outcome.

We report 12 years' experience with histocompatible, related donor marrow transplantation for 123 patients with acute lymphoblastic leukaemia; 104 > or = second remission. Four regimens were studied: cyclophosphamide (Cy)-+total body irradiation (TBI) (n = 35); Cy+fractionated TBI (n = 45); TBI+high-dose cytarabine (n = 15); and hyperfractionated TBI+Cy (n = 28). 45 patients survive (34 +/- 9%; 95% confidence interval) between 1 and 12.7 years (median 7.8 years) following BMT and 29 +/- 8% survive leukaemia-free. Significantly improved disease-free survival was observed in patients with an initial WBC < 50 x 10(9)/l (P = 0.02). Conditioning regimens tested yielded similar outcomes, though TBI/cytarabine led to greater treatment-associated mortality. Leukaemia relapse was the most frequent cause of failure in 56 +/- 11%; median time of relapse 8 months following BMT, none beyond 2.2 years. Relapse was more frequent with higher WBC, shorter initial remission and previous CNS leukaemia. Acute and/or chronic GVHD was associated with a strong trend (P = 0.06) towards less relapse. Allogeneic BMT may be curative for a substantial fraction of patients with ALL, but additional anti-leukaemic measures beyond these conditioning modifications tested will be required to prevent post-transplant leukaemia recurrence.

Pretransplantation burden of leukemic progenitor cells as a predictor of relapse after bone marrow transplantation for acute lymphoblastic leukemia.

BACKGROUND: We developed a test to discern small numbers of residual leukemic progenitor cells in the bone marrow of patients with acute lymphoblastic leukemia (ALL) in remission. Preliminary studies revealed that before undergoing bone marrow transplantation such patients differed in their burden of leukemic progenitor cells. These observations suggested that the burden of these cells might influence the risk of relapse after transplantation. METHODS: The number of residual leukemic progenitor cells before bone marrow transplantation was determined for 83 patients with high-risk ALL. We combined multiparameter flow cytometry and cell sorting with assays for leukemic progenitor cells in a quantitative method for the detection of minimal residual disease. RESULTS: The count of leukemic progenitor cells in bone marrow specimens from patients in remission varied markedly between patients, ranging from 0 to 12,546 cells per million mononuclear cells, or from 0 to 1.255 percent (median, 51 leukemic progenitor cells per million mononuclear cells, or 0.005 percent). Patients whose count of leukemic progenitor cells exceeded the median value had a higher likelihood of relapse than did patients with values below the median (relapse rate at one year, 100 percent vs. 41 percent; P < 0.001). There was a statistically significant inverse relation between the leukemic progenitor-cell content of bone marrow before transplantation and the duration of remission after transplantation (P < 0.001). The estimated risk of relapse for patients with > or = 51 leukemic progenitor cells per million mononuclear cells was more than 3.5 times the risk for patients with lower counts, after adjustment for the effects of other covariates (P = 0.005). CONCLUSIONS: The count of residual leukemic progenitor cells is a powerful predictor of relapse after autologous bone marrow transplantation, particularly among male patients. Its measurement may be useful for analyzing and improving the treatment of patients with high-risk ALL in remission.

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.

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.

Viridans streptococcal shock in bone marrow transplantation patients.

We have recognized a rapidly progressive, often fatal shock syndrome associated with viridans streptococcal sepsis following bone marrow transplantation (BMT). Of 832 patients receiving a marrow transplant at the University of Minnesota between 1976 and 1988, including 123 with viridans streptococcal bacteremia, 10 patients (8%) developed clinical shock within an average of 2 days (range 0-4 days) of their first positive blood culture. Viridans streptococcal shock occurred in patients early in the transplantation course, between 1 and 28 (median 6) days following BMT when all 10 patients were neutropenic. Six of the 10 patients died as a consequence of their shock or from subsequent complications. The most frequent (6 of 10 patients) viridans streptococcal species isolated in the shock patients was Streptococcus mitis. Of multiple factors analyzed for increased risk of developing viridans streptococcal shock, only younger patient age was significantly associated with the development of shock. Although 58% of BMT recipients with viridans streptococcal bacteremia were younger than 15 years, all 10 patients comprising the shock population were < 15 years of age (P < 0.02). We speculate that certain streptococcal strains may trigger fulminant shock in the immunocompromised BMT patient.

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.

Autologous bone marrow transplantation in high-risk remission B-lineage acute lymphoblastic leukemia using a cocktail of three monoclonal antibodies (BA-1/CD24, BA-2/CD9, and BA-3/CD10) plus complement and 4-hydroperoxycyclophosphamide for ex vivo bone marrow purging.

Fourteen patients with high-risk B-lineage acute lymphoblastic leukemia (ALL) in complete remission underwent autologous bone marrow transplantation (BMT) using a combined immunochemopurging protocol. A monoclonal antibody (MoAb) cocktail of BA-1, BA-2, and BA-3 plus rabbit complement (C') plus 4-hydroperoxycyclophosphamide (4-HC) was used to eliminate residual occult leukemia cells from autografts. All patients were conditioned with single-dose total body irradiation (TBI) followed by high-dose Ara-C. All 14 patients engrafted at a median of 24 days (range, 12 to 36 days). Three patients are alive and disease free at 3.5 years, 3.9 years, and 4.1 years post-BMT. The Kaplan-Meiser estimate and standard error of the probability of sustained remission was 23% +/- 12% at 3.5 years post-BMT with a mean relapse-free interval of 1.4 +/- 0.4 years. The disease-free survival (DFS) at 3.5 years was 21% +/- 11%, with a mean DFS time of 1.3 +/- 0.4 years. A novel and quantitative minimal residual disease (MRD) detection assay, which combines fluorescence-activated multiparameter flow cytometry and cell sorting with leukemic progenitor cell (LPC) colony assays, was used to analyze remission BM samples from B-lineage ALL patients for residual LPC, and to evaluate the efficacy of ex vivo BM purging. Notably, the minimal residual leukemia burden before BMT, as measured by the percentage of B-lineage LPC in the pre-BMT remission BM samples, indicated the outcome of the BMT. The median value for the minimal residual leukemia burden before BMT was 0.0035% (35 LPC/10(6) mononuclear cells). The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 43% +/- 19% for patients whose BM samples contained less than or equal to 0.0035% LPC and 0% +/- 0% for patients whose BM samples contained greater than 0.0035% B-lineage LPC (P less than .05). In contrast to the minimal residual leukemia burden measured by the described MRD assay system, the percentage of blasts or TdT+ cells in the remission BM samples did not correlate with the probability of relapse. The applied purging protocol showed variable success in destroying target B-lineage LPC populations contaminating the autografts. While in some cases purging was highly effective, eliminating up to greater than or equal to 4 logs of residual B-lineage LPC, in other cases only 0.1 to 0.2 logs of B-lineage LPC were purged.(ABSTRACT TRUNCATED AT 400 WORDS)