Safety and efficacy of FLAG-Ida-based therapy combined with venetoclax for the treatment for newly diagnosed and relapsed/refractory patients with AML - A systematic review.

Venetoclax (VEN) in combination with intensive chemotherapy (IC) is increasingly used to treat patients with high-risk acute myeloid leukemia (AML). We conducted a systematic review to assess the safety and efficacy outcomes of FLAG-IDA in combination with VEN. The primary safety outcome was infection rate; the primary efficacy outcome was response to treatment (composite complete remission (CRc) and overall response rate (ORR). Risk of bias was assessed according to the ROBINS-I tool. Six studies including 221 patients with newly-diagnosed (ND AML (n = 120)) and R/R AML (n = 101) disease, were included in this systematic review. Pooling of results was not conducted due to major differences between studies. The reported rates of neutropenic fever, bacteremia, pneumonia and invasive fungal infections were at 44-55 %, 24-48 %, 12-30 % and 11-36 % of assessed patients, respectively. Time to ANC and platelet recovery ranged between 23 and 29 and 23-31 days, respectively. Early death rate was 8.7 % (14/160) patients: four patients at 30 days, additional ten in 60 days. CRc rates ranged between 53 % and 78 % for R/R AML. CRc for ND was reported by one study only (89 %). ORR were reported in 60-78 % of patients with R/R AML. Only one study reported an ORR for ND patients of 98 %. In our systematic review, FLAG-Ida plus VEN proved to be a potentially tolerable and effective regimen in ND and R/R AML patients. We suggest further evaluation and confirmation for the safety and efficacy of this new protocol in future RCTs.

Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT.

Systemic anaplastic large cell lymphoma (sALCL) is a rare histological entity expressing the CD30 antigen that comprises around 11% of peripheral T-cell lymphoma. We analysed the outcome of patients with relapsed/refractory sALCL treated with autologous stem cell transplantation (auto-HCT). We included 65 adult patients (42 males; median age, 44 years); 24 patients had an ALK-ve sALCL. Fifty-one patients had chemosensitive disease at the time of transplant. Ten patients (15%) were treated with brentuximab vedotin (BV) before auto-HCT (median number of doses: 5). The median follow-up for surviving patients was 35 months (3-71). Three-year cumulative incidence of nonrelapse mortality and of relapse were 1.7% and 34%, respectively. Three-year progression-free survival and overall survival were 64% and 73%, respectively. No prognostic factors for any of the outcomes analysed were found in univariate analysis. There were no significant differences in any of the outcomes between patients who had received BV and the remainder. This is the largest analysis presented so far analysing the role of auto-HCT in patients with relapsed/refractory sALCL, showing a promising PFS and OS in this high-risk population. The potential impact of the administration of BV as salvage strategy before the procedure needs to be further elucidated.

Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single-centre before-after study.

OBJECTIVES: We aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). METHODS: This is a quasi-experimental, retrospective, before-after study. We compared the incidence of bacterial-related complications among 356 patients with multiple myeloma (MM) (n = 202) and lymphoma (n = 154) who underwent AHCT with (n = 177) or without (n = 179) ciprofloxacin prophylaxis between 03/2007 and 10/2012 and between 10/2012 and 07/2016, respectively, at a single centre. RESULTS: Febrile neutropaenia, bacteraemia, and pneumonia were significantly more common among patients who underwent AHCT during the second study period and did not receive antibacterial prophylaxis compared with patients who underwent AHCT during the first study period and received antibacterial prophylaxis (89.9% (161/179) vs. 83.1% (147/177), difference 6.9%, 95% CI 0-14.1%, P = 0.002; 15.1% (27/179) vs. 4.5% (8/177), difference 10.6%, 95% CI 4.4-16.9%, p < 0.0001; 12.3% (22/179) vs. 6.2% (11/177), difference 6.1%, 95% CI 0-12.3%, p = 0.04, respectively). The number-needed-to-treat to prevent one episode of bacteraemia, pneumonia, and febrile neutropaenia was 8.6, 8.5, and 13.7, respectively. Patients with ciprofloxacin prophylaxis had higher rates of ciprofloxacin-resistant bacteraemia (62.5% (5/8) vs. 18.5% (5/27), difference 44%, 95% CI 7-70%, p = 0.01). In multivariate analysis, ciprofloxacin prophylaxis significantly decreased the odds of bacteraemia (OR 0.19, 95% CI 0.07-0.52; p < 0.0001) and pneumonia (OR 0.37, 95% CI 0.16-0.85, p = 0.02). CONCLUSION: According to our single-centre experience, patients with MM and lymphoma undergoing AHCT may benefit from antibacterial prophylaxis with ciprofloxacin.

Risk factors and prognostic scale for cytomegalovirus (CMV) infection in CMV-seropositive patients after allogeneic hematopoietic cell transplantation.

AIM: We aimed to study the risk factors for first and subsequent cytomegalovirus (CMV) infection among patients who are CMV seropositive and underwent allogeneic hematopoietic cell transplantation (HCT). METHODS: We performed an historical cohort study of all sequential CMV-seropositive patients who underwent allogeneic HCT at a single center. Between May 2007 and December 2012, 121 patients fulfilled inclusion criteria. RESULTS: Multivariate model identified myeloablative preparative regimen (hazard ratio [HR] = 4.297, P = 0.033) and acute graft-versus-host disease (GVHD) prior to infection (HR = 5.091, P = 0.021) as risk factors for first CMV infection. The cumulative incidences of first CMV infection for patients with 0, 1, and 2 risk factors were 52%, 71%, and 91%, respectively. Multivariate analysis identified the diagnosis of lymphoma/myeloma (HR = 3.5, P = 0.049) and GVHD (HR = 1.280, P = 0.045) as risk factors for subsequent CMV infection. High graft CD3 stem cell dose was associated with a trend of lower rate of subsequent CMV infection (HR = 0.543, P = 0.056). The cumulative incidences for subsequent CMV infection in patients with 0, 1, and 2-3 risk factors were 11%, 41%, and 77%, respectively. CONCLUSION: In conclusion, in CMV-seropositive patients, myeloablative conditioning and acute GVHD are risk factors for first CMV infection, while lymphoma/myeloma, ongoing GVHD, and low CD3 graft content are risk factors for subsequent infection.

Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis.

We performed a systematic review and meta-analysis of randomized controlled trials comparing autologous hematopoietic cell transplantation (HCT) with other treatment modalities to analyze the risk for various secondary malignancies (SMs). Relative risks (RR) with 95% confidence intervals were estimated and pooled. Our search yielded 36 trials. The median follow-up was 55 (range 12-144) months. Overall, the RR for developing SMs was 1.23 ((0.97-1.55), I(2)=4%, 9870 patients). Subgroup analysis of trials assessing TBI-containing preparative regimens and of patients with baseline lymphoproliferative diseases, showed there was a higher risk for SMs in patients given autografts (RR=1.61 (1.05-2.48), I(2)=14%, 2218 patients and RR=1.62 (1.12-2.33), I(2)=22%, 3343 patients, respectively). Among all patients, there was a higher rate of myelodysplastic syndrome MDS/AML in patients given HCT compared with other treatments (RR=1.71 (1.18-2.48), I(2)=0%, 8778 patients). The risk of secondary solid malignancies was comparable in the short term between patients given HCT and patients given other treatments (RR=0.95 (0.67-1.32), I(2)=0%, 5925 patients). We conclude that overall the risk of secondary MDS/AML is higher in patients given autologous HCT compared with other treatments. In the subgroup of patients given a TBI-based regimen and in those with a baseline lymphoproliferative disease, there was a higher risk of overall SMs.

Cellular immune function monitoring after allogeneic haematopoietic cell transplantation: evaluation of a new assay.

Managing the patient's immune system after haematopoietic cell transplantation (HCT) is a challenge, mainly in the unstable period immediately after the transplant. Currently there is no standardized non-invasive diagnostic tool for the evaluation of immunological complications such as graft-versus-host disease (GVHD) and for managing the cellular immune function of the transplant recipient. The ImmuKnow assay for cellular immune function monitoring has been incorporated successfully into the clinical follow-up routine of solid organ transplant recipients. This study aims to explore the relevance and potential contribution of immune monitoring using the assay in the setting of HCT. We found that ImmuKnow-level measurement can distinguish between states of immune function quiescence and between events of acute GVHD. ImmuKnow levels were significantly higher in patients going through GVHD than the levels measured for the same patients during immunological stability. Moreover, we demonstrate a patient case where longitudinal monitoring using the ImmuKnow assay provided a trustworthy depiction of the patient's cellular immune function post-HCT. In conclusion, we provide evidence for the potential contribution of the ImmuKnow assay for longitudinal individualized cellular immune function monitoring of patients following HCT. Further studies are necessary in order to establish the optimal practice for utilizing the assay for this purpose.

Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease.

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF(+) cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.

Clinical characteristics of Stenotrophomonas maltophilia infection in hematopoietic stem cell transplantation recipients: a single center experience.

BACKGROUND: Recipients of hematopoietic stem-cell transplantation (HSCT) are at high risk for infections caused by Stenotrophomonas maltophilia. METHODS: We conducted a retrospective analysis of all infections caused by S. maltophilia in HSCT recipients in a single center in Israel during a 4 year period. RESULTS: Of 570 patients undergoing HSCT, 19 patients with an invasive S. maltophilia infection were identified. Sixteen had allogeneic HSCT and 3 had autologous HSCT. Seventeen patients (90%) had an indwelling central venous catheter (CVC) at the time of infection. S. maltophilia infections were detected in three clinical settings: as a complication of prolonged neutropenia (n = 9), as a CVC-related non-neutropenic infection occurring after CVC manipulation (n = 8) and as a respiratory tract infection (n = 2). Eleven patients (58%) had a polymicrobial infection. Ten patients (52.6%) received carbapenems during the previous month. The treatment for all patients included broad spectrum antibiotics, which were switched according to susceptibilities upon identification of the isolates. All isolates were susceptible in vitro to TMP-SMX. CVCs were removed in 12 patients (70%). Six patients, all after allogeneic HSCT, died. The CVC was removed in only two of the five patients with CVCs who died. CONCLUSIONS: Stenotrophomonas maltophilia is an emerging nosocomial pathogen in HSCT recipients, both in the early neutropenic phase and in the non-neutropenic phase. It is commonly associated with the presence and manipulation of an indwelling CVC. Removal of the CVC in addition to appropriate antibiotic therapy (TMP-SMX) is crucial for infection control.

Prophylaxis regimens for GVHD: systematic review and meta-analysis.

Opinions are divided regarding the best prophylactic regimen for GVHD. The aim of this study was to evaluate potential survival benefit of different prophylactic regimens for acute GVHD (aGVHD). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) including patients undergoing Allo-SCT. We included trials that assessed the addition of MTX, compared CsA and tacrolimus and evaluated the addition of steroids. Outcomes assessed were all-cause mortality (ACM) at the longest follow-up, aGVHD, chronic GVHD, TRM, relapse rate and regimen-specific adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. The regimen of MTX-CsA vs CsA alone (four trials) yielded no statistically significant difference in ACM (RR=0.84 (0.61-1.14)), but a significant decrease in aGVHD (RR=0.52 (0.39-0.7)). There was no difference in ACM for the comparison of MTX-CsA and MTX-tacrolimus (three trials); however, MTX-tacrolimus was superior to MTX-CsA in the reduction of aGVHD (RR=0.62 (0.52-0.75)) and severe aGVHD (RR=0.67 (0.47-0.95)). The addition of steroids did not affect the outcomes (four trials). We conclude that MTX-CsA and MTX-tacrolimus are both acceptable alternatives for GVHD prophylaxis, although MTX-tacrolimus may be superior in terms of aGVHD reduction.

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose intensity, we analyzed SCT outcomes of 112 consecutive patients with AML/MDS. A total of 45 patients met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). A total of 67 noneligible patients were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or a modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The overall survival (OS) at 2 years was 50, 49 and 47% after ivBuCy, FB4 and FB2, respectively (P=NS). Nonrelapse mortality was higher after ivBuCy, 22 vs 8% (P=0.05), but relapse rates were lower. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, P=0.0001). Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT; however, patients with active disease could only be salvaged by myeloablative conditioning. Among the latter, OS was 45% after ivBuCy but no FB2 recipient survived (P=0.02). Patients with active disease, ineligible for standard myeloablation, could tolerate modified myeloablation well; however, long-term outcome cannot be determined yet.

A 10-year median follow-up study after allogeneic stem cell transplantation for chronic myeloid leukemia in chronic phase from HLA-identical sibling donors.

We report long-term outcome in 102 patients with cCML transplanted from an HLA-identical sibling donor from 1982 to 1998. The conditioning regimen was based on cyclophosphamide associated with either total body irradiation (TBI) (37 patients) or with busulfan (63 patients). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporin and methotrexate in the majority of the patients. Fifteen year overall survival was estimated at 53% (95% confidence interval (CI), 44-65) with a plateau after 2.5 years. Long-term survival was adversely affected by: longer time from chronic myeloid leukemia (CML) diagnosis to transplantation, older age at time of transplantation and GvHD (acute grade III-IV or chronic extensive). The main cause of death was infection, related to GvHD in 69% of patients. Splenectomy also significantly increased the risk of bacterial infection. 15-year relapse was estimated at 8% (95% CI, 0.1-14). Late malignancies occurred in seven patients, four of whom had an invasive cancer. Other frequent late complications included cataracts, psychological depression, osteonecrosis and hypothyroidism. These complications were more frequent following splenectomy, TBI and in patients with chronic extensive GvHD. We conclude that allogeneic transplantation with a related donor can cure more than half of CML patients in chronic phase, although physicians should be alert to long-term complications.

Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning.

Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients with hematological malignancies. Reduced-intensity conditioning regimens allow SCT in elderly patients; however, there are only limited data on the feasibility and outcomes of unrelated donor SCT in these patients. In this study, we analyzed, retrospectively, data of 36 patients with various hematological malignancies and median age 58 years (range, 55-66), who were given unrelated donor SCT after reduced-intensity conditioning. The preparative regimen consisted of fludarabine combined with oral busulfan (8 mg/kg, n=8), intravenous busulfan (6.4 mg/kg, n=11), treosulfan (30 g/m(2), n=5) or melphalan (100-150 mg/m(2), n=12). Patients were also given serotherapy, ATG (n=32), or alemtuzumab (n=4). The probabilities of overall survival, disease-free survival, and nonrelapse mortality at 1 year after SCT were 52, 43, and 39%, respectively. Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD occurred in 31 and 45%, respectively. Multivariable analysis determined that survival rates were higher in patients with chemosensitive disease (HR 4.5), and patients conditioned with intravenous busulfan or treosulfan (HR 3.9). Unrelated donor SCT is feasible in elderly patients, with outcomes that are similar to younger patients. Favorable outcome was observed in patients with myeloid malignancies, and those transplanted in remission and early in the course of disease. Age alone should not be considered a contraindication to unrelated donor SCT.

A long-term follow-up of 33 patients with non-Hodgkin's lymphoma who received the BEAM high-dose intensification regimen with cytokine support only and no transplant.

High-dose intensification and autologous stem-cell transplantation (ASCT) is widely used to consolidate patients with non-Hodgkin's lymphoma (NHL), who have reached a stage of minimal residual disease. However, patients with persisting marrow and/or blood involvement and those who fail peripheral blood hemopoietic progenitor mobilization are excluded from ASCT. For such patients with no available graft to infuse, we developed 15 years ago, before the anti-CD20 monoclonal antibody therapeutic era, the use of the BEAM pretransplant regimen followed only by the administration of three cytokines (erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor). We report here on the long-term follow-up of 33 patients treated with this approach. In all, 33 NHL patients underwent the BEAM (carmustine, VP-16, cytosine-arabinoside, melphalan) followed by the administration of the three cytokines from January 1994-2000. A backup marrow, albeit infiltrated by tumor cells, had been collected earlier and stored in all. A total of 30 patients (91%) recovered normal hematopoiesis. In total, 32 patients (97%) recovered neutrophils (>500/microl) at a median of 19 days and 30 patients (91%) recovered platelets (>20,000/microl) at a median of 26 days. Age, richness of backup graft and blood-hemoglobin level at intensification had an impact on the time for hematopoietic recovery (P=0.014, P=0.014, P=0.048). The median follow-up was 62 months. Five patients died from toxicity related to the procedure. Eight patients relapsed and died. A total of 20 patients (61%) are alive, 16 (49%) in complete remission. A 5-year disease-free survival was 52+/-9%, relapse incidence 35+/-16%, mortality due to the procedure 12+/-12% and overall survival 61+/-10%. The BEAM regimen is not myeloablative. The BEAM+3CK procedure is a feasible therapeutic option that has shown efficacy in poor risk NHL patients who were not eligible for autografting because of persisting marrow/blood tumor contamination, or poor hemopoietic progenitor harvesting. It is unclear today whether some of these patients would have cleared their marrow/peripheral blood with the additional use of anti-CD20 treatment, thereby making the classical approach (BEAM followed by the infusion of a clean autograft) feasible.

Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias.

Chronic myeloid leukemia in blast crisis (BC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) are associated with extremely poor outcome. Allogeneic transplantation during BC or active leukemia is most often unsuccessful due to high-rates of both treatment-related complications and relapse. Long-term results are significantly better if a second chronic phase or remission can be achieved prior to transplantation. Similarly, DLI given for the treatment of post-transplant relapse is more successful when given during a second remission. In this study we report our results with a previously unreported approach consisting of short-term treatment with imatinib mesylate (formerly, STI571) to induce or maintain remission, followed by allogeneic transplantation or DLI and the impact on transplantation/DLI outcome. Sixteen patients were treated either in preparation for transplantation (n = 12), for DLI (n = 1), or for both (n = 3). Ten had CML in BC; seven myeloid and three lymphoid BC. Six patients had Ph(+) ALL. The donors were matched unrelated (n = 9), matched siblings (n = 5) or haplo-identical (n = 2). Eleven of 15 patients given imatinib pre-transplant were transplanted in complete hematologic response. Engraftment and GVHD rates were not different from expected. Seven patients had grade II-III hepatic toxicity after transplantation. After a median follow-up of 10 months (range, 3-16 months) six remain alive, two after further therapy. The 1-year survival rate was 25%. Four patients were given imatinib prior to DLI, all had complete response. Two remain in remission >6 months from relapse. In conclusion, treatment with imatinib allows transplantation in a more favorable status or maintaining remission with low toxicity until transplantation is feasible. Pre-transplant imatinib seems safe and not associated with excess post-transplant complications. Imatinib may have substantial activity in combination with DLI. Further study of a larger group of patients is required to assess the impact on long-term outcome and the role of post-transplant imatinib in controlling residual disease.

Chimerism testing and detection of minimal residual disease after allogeneic hematopoietic transplantation using the bioView (Duet) combined morphological and cytogenetical analysis.

Recurrent disease remains a major obstacle to cure after allogeneic transplantation. Various methods have been developed to detect minimal residual disease (MRD) after transplantation to identify patients at risk for relapse. Chimerism tests differentiate recipient and donor cells and are used to identify MRD when there are no other disease-specific markers. The detection of MRD does not always correlate with relapse risk. Chimerism testing may also identify normal hematopoietic cells or other cells not contributing to relapse. In this study we report our initial experience with a novel system that provides combined morphological and cytogenetical analysis on the same cells. This system allows rapid automatic scanning of a large number of cells, thus increasing the sensitivity of detection of small recipient population. The clinical significance of MRD detection is improved by identifying the morphology of recipient cells. Identification of recipient characteristics within blasts predicts overt relapse in leukemia patients and precedes it by a few weeks to months. Identification within mature hematopoietic cells may not be closely associated with relapse. The system also allows chimerism testing after sex-mismatched transplants, within cellular subsets, with no need for sorting of cells. The system merits further study in larger scale trials.

Acute liver failure as initial manifestation of low-grade non-Hodgkin's lymphoma transformation into large-cell lymphoma.

Acute liver failure as an initial manifestation of primary non-Hodgkin's lymphoma is a rare phenomenon with a grim prognosis. We report for the first time on a patient with a history of follicular lymphoma in complete remission, presenting fulminant liver failure due to massive liver infiltration by transformed lymphoma cells and portal vein thrombosis, as an initial manifestation of transformation into large-cell lymphoma.

Reconstitution of self-reactive antibody repertoires of autologous plasma IgM in patients with non-Hodgkin's lymphoma following myeloablative therapy.

In healthy individuals, natural self-reactive antibody repertoires are restricted to a limited subset of autoantigens that is selected early in development and that remains invariant between individuals through aging. In the present study, we addressed the question of whether self-reactive antibody repertoires of plasma IgM change during high-dose chemotherapy (HDCT) with autologous blood stem cell support and whether antibody repertoires generated during immune reconstitution are similar to those present under physiological conditions. We followed the development of antibody repertoires in patients undergoing HDCT for the treatment of B-cell non-Hodgkin's lymphoma (NHL). Antibody repertoires were investigated by quantitative immunoblotting on whole tissue extracts as sources of self-antigens and by multiparametric statistical analysis of the data. We demonstrate that self-reactive antibody repertoires of plasma IgM of NHL patients prior to HDCT differ from those of healthy individuals, that they change during recovery of immune functions, and that antibody repertoires similar to those of healthy individuals are generated during immune reconstitution. We conclude that the mechanisms responsible for the selection of self-reactive repertoires of autologous plasma IgM during immune reconstitution after HDCT may follow those present under physiological conditions and that immune reconstitution may include a shift from altered toward normal patterns of self-reactivity.

Transient hepatopulmonary syndrome in a patient with acute hepatitis A.

The hepatopulmonary syndrome is defined as the triad of liver disease, hypoxaemia and intrapulmonary vascular dilatation. This syndrome has been described in patients with liver cirrhosis, noncirrhotic portal hypertension, and fulminant hepatic failure, however, there are no previous descriptions of hepatopulmonary syndrome in patients with acute nonfulminant viral hepatitis. We report a 47-year-old, previously healthy man that presented with acute hepatitis A, and developed progressive dyspnoea, platypnoea and orthodeoxia with no evidence of parenchymal or thromboembolic lung disease. PaO2 on room air was 58 mmHg, O2 saturation was 88% and alveolar-arterial O2 gradient was 62%. During his hospitalization serum albumin level decreased to 3.1 g/dl and prothrombin time was prolonged to 16.8 s, however, he remained alert with no signs of hepatic encephalopathy. Contrast echocardiography revealed left heart chamber opacification 3-4 cardiac cycles after the opacification of the right heart chamber, consistent with hepatopulmonary syndrome. During the following days there was a gradual improvement in the patient's condition, with resolution of his dyspnoea and gradual increase of PaO2. Repeat contrast echocardiography and PaO2 determinations, 3 weeks later, were normal. On long-term follow-up the patient remained asymptomatic with normal liver function tests and normal O2 saturation. This report indicates that hepatopulmonary syndrome may be a transient manifestation of acute hepatitis A in the absence of fulminant liver failure.

Infective endocarditis in renal transplant recipients.

Because of the increasing number of renal transplantations performed and the rarity of reported cases of infective endocarditis in these patients, we studied the clinical characteristics of this infection in this population. We report on two cases from our experience and review reported cases of infective endocarditis in renal transplant recipients retrieved from the MEDLINE system. In addition, we reviewed a large series of infective endocarditis looking for patients with renal transplants. In addition to our 2 cases, 12 previously reported cases were found. The mean time from transplantation to diagnosis of infective endocarditis was 3.5 years (range 2 months to 15 years). Causative organisms included fungi, Staphylococcus aureus (3 cases each), Corynebacterium sp. (2 cases), Streptococcus viridans, VRE, Brucella sp., Clostridium sp., Nocardia sp. and Erysipelothrix sp. (one case each). Skin manifestations of endocarditis and/or splenomegaly were not reported in these patients. Septic emboli and mycotic aneurysms were relatively common. The overall mortality rate was 50% (7 of 14 patients died). Infective endocarditis seems to be rare in renal transplant recipients. The few reported cases are characterized by unusual causative micro-organisms and atypical clinical presentation. Further studies are needed to delineate the magnitude and scope of this association.