Nosocomial pneumonia in adult patients undergoing bone marrow transplantation: a 9-year study.

Two hundred seventy-five consecutive patients treated with bone marrow transplantation (BMT) during a 9-year interval were analyzed for the incidence and etiology of nosocomial pneumonia. Cases included adults who acquired pneumonia during the first hospitalization period within 100 days of the transplant. Fifty-five (20%) of the 275 patients developed nosocomial pneumonia, and the crude mortality during the hospitalization period was 74.5%. An etiology was established in 67.3% (37 of 55) of episodes. Thirty-six percent (20 of 55) of the cases were caused by Aspergillus species, either as the sole agent (15 patients) or in association with others. The crude mortality for patients with Aspergillus pneumonia was 95%. Elimination of 90% of Aspergillus cases in our unit would have the effect of reducing the overall attack rate of nosocomial pneumonia to 13.4% and the associated crude mortality to 43.4%.

Adult acute lymphoblastic leukemia: results of the Iowa HOP-L protocol.

Fifty-nine consecutive previously untreated adult patients with acute lymphoblastic leukemia (ALL) were entered onto a prospective single-arm trial of doxorubicin, vincristine, prednisone, and asparaginase (HOP-L) induction therapy followed by CNS prophylaxis and 3 years of maintenance therapy. Consolidation therapy was not administered. The study population included a large number of older (greater than 50 years) patients. Seventy-five percent of patients achieved complete remission. With a median follow-up of 6 years, the median duration of complete remission is greater than 4 years, with 53% of patients expected to remain in remission at both 3 and 5 years. Overall, median survival duration is 27.9 months, with 45% and 35% of all patients expected to survive 3 and 5 years, respectively. Multivariate analysis identified patients with T-cell disease and mediastinal masses (P less than .001) and those with low values of lactic dehydrogenase (LDH) (P = .057) as being at greatest risk of relapse. Therapy was well tolerated by patients under age 35, but older patients suffered appreciable mortality. We conclude that this treatment program is effective therapy for adult ALL, yielding a large proportion of durable remissions despite the exclusion of consolidation therapy.

Second lymphoid malignant neoplasms occurring in patients treated for Hodgkin's disease.

Patients who have been treated for Hodgkin's disease are at increased risk for second malignant neoplasms, particularly acute nonlymphoblastic leukemia and non-Hodgkin's lymphoid malignant neoplasms (NHLMs). We diagnosed five cases of NHLM in 242 patients initially treated for Hodgkin's disease between 1973 and 1980, giving a minimum incidence for this occurrence of 2.1%. The initial therapy for Hodgkin's disease, irradiation in three patients and chemotherapy in two patients, resulted in a complete remission in each case. The NHLM appeared 12, 13, 26, 30, and 54 months after the diagnosis of Hodgkin's disease. The cell type of NHLM and immunologic phenotype were as follows: large cell, immunoblastic T; large cell, immunoblastic null; large cell, cleaved and noncleaved B; large cell, cleaved and noncleaved (not studied); and lymphoblastic T. A review of 24 other cases of NHLMs, occurring in patients treated for Hodgkin's disease, reported in the literature, confirm the morphologic and immunologic heterogeneity. The poor response to therapy in our patients and those previously described demonstrate the seriousness of this phenomenon.

Erythema annulare centrifugum and Hodgkin's disease: association with disease activity.

The skin lesions of erythema annulare centrifugum developed in a 58-year-old woman who had Hodgkin's disease. Response of the neoplasm to vinblastine sulfate was accompanied by disappearance of the skin lesions. When therapy was discontinued, both disorders recurred, and both responded to reinstitution of vinblastine therapy. To our knowledge, this case is the first reported association of erythema annulare centrifugum and Hodgkin's disease. The cutaneous manifestation in this patient were a nonneoplastic concomitant of her neoplastic disorder.

Marrow transplantation for stable-phase chronic granulocytic leukemia.

Ten patients with chronic granulocytic leukemia in the stable phase underwent marrow transplantation from HLA-identical siblings (nine cases) or an identical twin (one case) following preparation with cytarabine, cyclophosphamide, and total body irradiation. Marrow cytogenetics on all patients prior to transplantation revealed the Philadelphia chromosome without other evidence of aneuploidy. The immediate posttransplant course was in most cases relatively uncomplicated with only two serious infections and one death. All patients recovered with cytogentically normal marrow and leukemia has recurred only in the syngeneic transplant recipient. At present, nine patients are surviving from 358 to 961 days (median 597 days) after bone marrow transplantation. Bone marrow transplantation is capable of eliminating the abnormal clone of myeloid cells in patients with stable-phase chronic granulocytic leukemia and can be performed relatively safely in this "healthy" group of patients.

Platelet-endothelial cell interactions.

We are in an era in which there has been a rapid accumulation of new information about the endothelium and the interactions of platelets with the vessel wall. The decade of the 70s could aptly be designated as the "prostaglandin and endothelium period." One can only speculate that the future will be equally interesting and challenging. It is quite possible that discoveries of congenital and acquired defects of the endothelium will parallel those already described for the platelet and coagulation factors. What is currently looked upon today as a baffling and frustrating case of resistant thrombosis by the clinician may be unraveled tomorrow by the talented and creative investigator who can develop better approaches to the study of the endothelium and platelet interactions with the vessel wall.

Acquired agranulocytosis with granulocyte specific cytotoxic autoantibody.

Multiple infections and severe neutropenia were found in a previously healthy 29 year old man with no history of similar syndromes in the family, drug ingestion or exposure to environmental toxins. There was no evidence at the time of presentation of diseases previously associated with agranulocytosis (e.g., neoplasia, thyrotoxicosis, chronic infection, collagen-vascular disease or leukoagglutinating antibody). His serum contained a nonagglutinating, complement-dependent, cytotoxic antibody, however, reactive with peripheral blood granulocytes from 35 per cent of normal donors. The neutropenia was not affected by steroids but resolved promptly after splenectomy. Microscopic examination of the spleen revealed ingestion of polymorphonuclear leukocytes by splenic macrophages. Family studies indicated that the target antigen was non-HLA and that the antibody was not absorbed by lymphocytes or platelets. We conclude that the agranulocytosis was autoimmune in origin and suggest that similar myeloid-specific immune responses could influence granulocyte tranfusion and bone marrow transplantation by alloimmune "rejection" that would not be avoided by matching only for HLA specificities.

Nosocomial Legionnaires' disease. Occurrence in recipients of bone marrow transplants.

Nosocomial pneumonia caused by Legionella pneumophila serogroup 1 occurred in five patients after bone marrow transplantation for hematologic malignancies. Two patients died as a result of the infection despite treatment with erythromycin. Serologic screening revealed no other cases of Legionnaires' disease in 40 consecutive recipients of bone marrow transplants, giving a frequency of infection of 13 percent. These five cases represent 23 percent of the pneumonia occurring in this group of patients. Patients undergoing bone marrow transplantation are highly susceptible to infectious complications. Legionnaires' disease must now be added to the list of pathogens infecting this group of patients. Erythromycin is not generally a part of standard empiric antibiotic regimens in febrile neutropenic patients, but appears to be a reasonable addition when pneumonia does not respond to conventional, empiric treatment. Even with appropriate therapy, Legionnaires' disease remains a highly lethal infection in immunocompromised hosts.

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.

High-resolution ultrafast chest CT in the clinical management of febrile bone marrow transplant patients with normal or nonspecific chest roentgenograms.

Plain chest roentgenograms may be normal or show nonspecific abnormalities during the frequent febrile episodes that occur in patients after bone marrow transplantation. In this group, ultrafast 10-mm and 3-mm high-resolution CT scans were prospectively performed in 33 patients to determine if useful information was provided that either changed the patient's clinical management or added confidence to the clinical diagnosis. The 36 symptomatic episodes that occurred in 33 patients included fever in 20 episodes and fever combined with cough, dyspnea, chest pain, or rales in 16. Fourteen chest roentgenograms were interpreted as normal, and 22 were interpreted as demonstrating nonspecific changes; however, none of the roentgenograms was considered helpful in that they did not provide sufficient information for further management. In 2 of 14 episodes in patients with normal chest roentgenograms and in 9 of 22 episodes in patients with nonspecific chest roentgenograms, CT scanning resulted in a change in clinical management that included performing bronchoscopy, increasing or changing antibiotic coverage, starting white blood cell transfusions, requesting surgical biopsy, or a combination of these. In 1 of 14 episodes in patients with normal chest roentgenograms and in 8 of 22 episodes in patients with nonspecific roentgenograms, CT added confidence to the diagnosis. In the remaining 16 episodes, CT scans provided no additional information. We conclude that in many instances, noncontrast ultrafast chest CT scans can provide information that may either change a patient's clinical management or more clearly establish the extent of pulmonary disease.

Cytomegalovirus infection presenting as polyarticular arthritis following autologous BMT.

A 39-year-old woman developed polyarticular arthritis secondary to cytomegalovirus (CMV) infection following an autologous BMT. Active CMV infection was documented by identification of CMV in cultures from synovial fluid and urine. Treatment with a combination of ganciclovir and intravenous immunoglobulin resulted in resolution of symptoms. CMV infection should be considered as a possible etiology of arthritis following transplantation.

Two-year adjustment of bone marrow transplant survivors.

Very little systematic analysis exists on the psychological and emotional factors involved in bone marrow transplantation, either during or after treatment. However, recent published findings, contrary to earlier anecdotal and case study evidence, indicate that bone marrow transplant survivors appear to be functioning adequately on a variety of 'quality of life' variables. The purpose of the present study was to compare bone marrow transplant survivors to a matched sample of patients undergoing maintenance chemotherapy in four areas of function; physical health, including symptoms and physician visits; personal functioning, emphasizing ability to care for self; psychological functioning; and role functioning, including employment and sexual difficulties. Our data reveal that the bone marrow transplant patients were experiencing greater difficulties than the maintenance chemotherapy patients in several areas. For example, the bone marrow transplant patients had experienced greater disruption of vocational functioning and reported more sexual difficulties. However, in spite of more objective difficulties, bone marrow transplant patients, compared to maintenance chemotherapy patients, viewed themselves as equally healthy and reported similarly low levels of psychological distress. The findings are discussed in the context of necessary future research on bone marrow transplant survivors.

Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation.

Reproducible and characteristic clinical findings of fever, skin rash, capillary leak and pulmonary infiltrates have been observed during engraftment in patients with autologous bone marrow (BM) and/or peripheral stem cell transplantation (PSCT). Two hundred and forty-eight patients were analyzed retrospectively to establish the clinical entity, to characterize the clinical course, and to find clinical variables affecting the incidence of the syndrome. One hundred and eight cases (83.7 +/- 9.4%) of fevers occurring in the periengraftment period (PEN) not associated with positive cultures, biopsies, or clinical signs of infection did not reveal delayed documentation of concealed infection in 2 weeks after engraftment. Capillary leak, pulmonary infiltrates, hypoxia, non-infectious neutropenic fever of engraftment and skin rash were found to be interrelated (all P < 0.01 except for hypoxia vs rash; P < 0.05). By stepwise discriminant analysis, one hundred and thirty-two patients (58.9 +/- 6.4%) were shown to have both skin rash and non-infectious neutropenic fever, thereby constituting the syndrome. Sepsis in the first week of neutropenia decreased the incidence of the syndrome (58.5 +/- 7.7% with sepsis, 89.6 +/- 4.7% without sepsis, P < 0.01). Post-transplant granulocyte colony-stimulating factor increased the incidence of the syndrome (79 +/- 4.6% with G-CSF vs 48.3 +/- 8.2% without G-CSF, P < 0.01). In bone marrow transplantation (BMT), the median time of onset of the syndrome was 7 days (range 4-22 days) post-transplant with a median duration of 11 days (range 4-28 days) of the initial phase. Thirty-nine patients (17.4 +/- 5.0%) revealed a recurrent pattern during the 5th week post-transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal cyclophosphamide cardiomyopathy: its clinical course and treatment.

Acute decompensating cardiomyopathy induced by cyclophosphamide is usually irreversible. To investigate the clinical course and the outcome of therapy, 13 patients (1.7%) with grade III acute cardiomyopathy and hypotension who were treated with ablative transplant regimens between January 1980 and September 1995 were analyzed. Eight of nine patients died of acute fatal restrictive cardiomyopathy with unresponsive hypotension (ARCH), whereas three of four patients who survived the initial episode died of subacute congestive heart failure (SCHF). Acute fatal restrictive cardiomyopathy was characterized with extreme sensitivity to volume overload, myocardial edema and a rapidly fatal course. It was associated with progressive, unresponsive hypotension, reduced left ventricular stroke work index (LVSWI: 29.29 +/- 9.74 g-m/beat/m2) and markedly reduced systemic and pulmonary vascular resistance indices (SVRI: 429.72 +/- 168.84, PVRI: 58.63 +/- 45.08 dyne.sec/cm5.m2). Subacute CHF was identified by myocardial edema, dilated chambers and biventricular pump failure represented by decreases in fractional shortening (FS: 19.5 +/- 4.9%). Of 10 patients who received conventional therapy, nine died and one sustained chronic CHF. One of three patients with ARCH on antioxidant therapy of ascorbic acid and theophylline survived the episode. The data suggests peripheral vascular collapse may also be responsible for fatal ARCH.

Disseminated Fusarium infections in patients following bone marrow transplantation.

Intensive immunosuppressive therapy and broad spectrum antibiotics predispose cancer patients to opportunistic fungal infections. Fusarium has rarely been reported as a pathogen in immunocompromised patients, but is almost uniformly fatal. Only six cases of disseminated Fusarium infection have been described in patients following bone marrow transplantation (BMT). We report here two additional cases. Fusarium infection initially presented with pyomyositis in one patient and with embolic skin lesions in another following T cell-depleted BMT. Both patients died with active Fusarium infection despite an extensive course of amphotericin B, rifampicin and granulocyte transfusions. From this experience and from a review of the literature, Fusarium infections appear to be increasing in prevalence as significant pathogens in immunocompromised hosts and are resistant to many conventional forms of therapy.

Prophylactic T cell infusion after T cell-depleted bone marrow transplantation in patients with refractory lymphoma.

Fifty-two patients with refractory lymphoma were prospectively treated with prophylactic T lymphocyte infusion after T cell-depleted allogeneic bone marrow transplantation, to induce graft-versus-lymphoma effect. Thirty-three patients had related donors; 19 had unrelated donors. After transplantation with marrow that had 0.8 +/- 0.4 x 10(5)CD3(+) cells/kg, T cells up to 1.75 x 10(6) CD3(+) cells/kg were given over 3 months provided > or = grade II acute graft-versus-host disease (GVHD) was not seen. The cumulative incidence of grades II-IV acute GVHD was 69%. Twenty of 32 evaluable patients (63%) developed chronic GVHD. Ten patients (19%) died of GVHD. The Kaplan-Meier 5-year overall survival of all patients was 34%. On multivariate analyses, chronic GVHD was significant for relapse (hazard ratio of 1.7, P < 0.05), and for overall survival (hazard ratio 1.4, P < 0.001). Chemosensitivity was significant for relapse only on univariate analysis. Patients who developed chronic GVHD had 4 years median survival, compared with 9 months in patients without chronic GVHD, P < 0.001. The study shows that patients with chronic GVHD have superior survivals, most probably related to a graft-versus-lymphoma effect, which could be modulated by prophylactic T cell infusion.

A dose escalation study for salvage chemotherapy in patients with refractory lymphoma prior to high-dose myeloablative therapy with stem cell transplantation.

Chemosensitive response prior to transplantation has been shown to be most significant for survival post transplant. To estimate toxicity of a dose-intensive regimen that was to improve chemosensitive response rate, 15 patients with primary refractory lymphoma were enrolled in dose escalation of pre-transplant salvage chemotherapy. The first cycle had a fixed dose of ifosfamide 6 g/m2 and mitoxantrone 12 mg/m2, with arabinosyl cytosine (Ara-C) 2 g/m2, and methylprednisolone 2.0 g. Each cycle of the second and third had cisplatin 90 mg/m2, Ara-C 6 g/m2, methylprednisolone 2.0 g, and escalated doses of ifosfamide from 7.5 g/m2 to 15 g/m2 and mitoxantrone from 16 to 28 mg/m2. Blood stem cells were collected before the second cycle and > or = 3 x 10(6) CD34 cells/kg were infused 2 days after the second and third cycles, respectively. The maximum tolerated doses of ifosfamide and mitoxantrone were 11.25 g/m2 and 16 mg/m2, respectively. Acute renal failure and bacterial infection occurred as non-hematologic dose limiting toxicities. Eleven patients completed therapy. Five patients achieved complete remission and five had partial remission. Nine patients received autologous and four received allogeneic transplants. Currently, six are alive without evidence of disease, with a 3-year survival of 40%. Although preliminary, the regimen suggests acceptable toxicity and significant activity that warrants further study.

Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft.

In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.

Cytogenetic analysis of adult acute lymphoblastic leukemia including a Ph+ case surviving more than 5 years.

We have performed cytogenetic analysis on 25 consecutive adult patients with previously untreated acute lymphoblastic leukemia (ALL) who were subsequently treated with the same protocol at this institution. Ten of the 25 patients studied (40%) demonstrated karyotypic abnormalities. The most frequent abnormalities were hyperdiploidy (six patients) and presence of the Philadelphia (Ph) chromosome (three patients). Univariate analysis of 12 features identified only immunophenotype as differing between patients with abnormal and normal karyotype. The cells of patients with an abnormal karyotype were more often non-B, non-T and less often T cell in phenotype. One patient initially with Ph remains cytogenetically normal in complete remission 272 weeks post diagnosis. We confirm that cytogenetic abnormalities are frequent in adult ALL. The attainment of disease free survival in Ph-positive ALL of more than 5 years with persistently normal cytogenetics demonstrates that aggressive multimodal therapy can induce long-term remissions and possible cure of this usually unfavorable situation.

Ultrafast computed tomography of the chest.

Improvements in scan speed and resolution are changing the role of the pulmonary imager. An understanding of airway mechanics and blood flow physiology is required to take full advantage of the new technology. Assessment of regional airflow and blood flow provides information that is currently unavailable from clinical tools.