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Abstract: Philadelphia chromosome (Ph)–like acute lymphoblastic leukemia (ALL) is a subtype of Ph-negative ALL that molecularly resembles Ph-positive ALL. It shares the adverse prognosis of Ph-positive ALL, but lacks the BCR-ABL1 fusion oncogene. Instead, Ph-like ALL is associated with alternative mutations in signaling pathways. We describe a case of Ph-like ALL that harbored 2 genomic alterations, which activated signaling, an NRASGly12Asp mutation, and an ETV6-NTRK3 rearrangement. Initially, the NRAS mutation was detected at high frequency, whereas the gene fusion was only detectable with a targeted next-generation sequencing-based fusion assay, but not by fluorescence in situ hybridization analysis. The disease failed to respond to multiagent chemotherapy but investigational CD19-directed chimeric antigen receptor T-cell therapy resulted in a complete remission. However, the leukemia relapsed after 6 weeks. Intriguingly, the NRAS mutation was extinguished during the chimeric antigen receptor T-cell therapy and did not contribute to the relapse, which was instead associated with a rise in ETV6-NTRK3. The relapsed leukemia progressed with further chemo- and immunotherapy but was controlled for 6 weeks with substantial leukemic cytoreduction using the TRK inhibitor larotrectinib. Unfortunately, recovery of normal hematopoiesis was only marginal and the patient eventually succumbed to infections. These results demonstrate that larotrectinib has clinical activity in ETV6-NTRK3-associated Ph-like ALL.

Abstract: Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders associated with progression to leukemia and poor survival. Clonal hematopoiesis in people without an MDS diagnosis carries an increased risk of cardiovascular death. Many clonally restricted mutations are shared between patients with MDS and those with non-MDS clonal hematopoiesis; therefore, we evaluated the risk of cardiovascular death among patients with MDS. We evaluated adults with MDS in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute and compared them with the general population living in the same states. We grouped histological subtypes of MDS into lower-, intermediate-, and higher-risk disease. The primary outcomes were overall survival and primary cause of death (COD) as reported to state registries. A total of 21 372 patients with MDS between 2001 and 2011 died during follow-up with a known COD. The rate of death due to cardiovascular disease (CVD) was 4613 per 100 000 person-years, compared with 2091 in the age- and-sex-adjusted US population (standardized mortality ratio, 2.21). At 24 months, the cumulative incidence of death attributed to MDS or leukemia was 23% vs 8% for CVD. Among those alive at 60 months, 27% eventually died of CVD compared with 29% from MDS or leukemia; those with lower-risk disease who survived >60 months had more deaths attributed to cardiovascular causes (30%; 95% confidence interval [CI], 26.7-33.2%) than MDS itself (24%; 95% CI, 21.4-27.5%). Patients with MDS are more likely to die of cardiovascular causes than the general population. Modifying cardiovascular risk factors, especially among those with lower-risk disease, may be warranted for MDS-related clinical care.

Background: Humoral immune responses during heart transplantation may result in antibody-mediated rejection (AMR), which is now taken into account on endomyocardial biopsy (EMB) specimens and ranked according to the pathologic AMR (pAMR) grades of the International Society for Heart and Lung Transplantation classification. This classification might benefit from new immunohistological markers and validation by others biomarkers, namely donor-specific antibodies (DSA)., Methods: From the 293 protocol EMBs performed in 113 patients in our institution during a 1-year period for this prospective study, 280 EMB specimens were available with both histology and immunohistochemistry. C4d and labeling of intravascular cells by cluster of differentiation (CD) 68 were performed on paraffin sections. Available sera (n = 150) concomitant of EMB specimens were tested for the presence of DSA. All of the pAMR+ EMB specimens, along with a set of randomized pAMR0 EMB specimens, were immunolabeled for mammalian target of rapamycin (mTOR) effectors, phosphorylated 70 S6-kinase (p70S6K) and phosphorylated S6 ribosomal protein (pS6RP)., Results: AMR was diagnosed in 37 EMB specimens (13.2%): 1 pAMR1(I+), 27 pAMR1(H+), and 9 pAMR2. The proportion of DSA-positive EMB varied according to the pAMR grade, with pAMR0, pAMR1(H+), and pAMR2 EMB presenting 17.6%, 77.3%, and 100% of DSA-positivity, respectively. Among the 30 pAMR+ specimens with available DSA testing and the 30 pAMR0 randomized specimens, mTOR pathway immunohistochemistry showed endothelial cell positivity for p70S6K in 17 pAMR+ EMB specimens (56.7%) and in 1 pAMR0 EMB specimen (3.3%). pS6RP was detected in 8 pAMR+ EMB specimens (26.7%) and in 1 pAMR0 EMB specimen (3.3%)., Conclusions: p70S6K and pS6RP immunohistochemistry afford new markers of AMR on EMB specimens because their expression is correlated with microcirculation inflammation and DSA. The correlation of DSA with pAMR grade suggests that this grading system is valid., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

Voriconazole is an anti-fungal agent active against Aspergillus infection that is used for prophylaxis and curative treatment in lung transplant patients. We present nine cases of painful neuromuscular disorders, an unusual and rare side effect of high-dose voriconazole in association with tacrolimus.

We report a case of unilateral pulmonary edema due to the decompensation of an asymptomatic ipsilateral pulmonary venous stenosis by a contralateral pulmonary embolism. Emergency surgery included pulmonary embolectomy and refashioning of the stenotic pulmonary venous anastomosis.

Acute renal insufficiency (ARI) is a frequent complication of nonrenal solid organ transplantation and may be responsible for an unfavorable outcome, particularly if dialysis is required. The etiology of post-transplantation ARI is poorly understood, with only isolated clinical cases being reported, most imputed to drug toxicity. We report here, the first three observations of irreversible ARI associated with acute oxalate nephropathy (AON) in the course of nonrenal organ transplants: a lung transplant and a lung-liver transplant in two patients with mucoviscidosis, and a cardiac transplant. The diagnosis of AON was made histologically. In all three cases, the ARI supervened after prolonged consumption of antibiotics capable of interfering with the colonic flora, and leading to enteric hyperoxaluria. The recognition of AON as a cause of post-transplantation, ARI underlines hyperoxaluria and digestive hyperabsorption of oxalate as specific risk factors for AON and should permit better posttransplant care of these patients.

Background: Previous reports, all concerning pulsatile devices, have indicated an increased risk of development of circulating antileukocyte antigen (HLA; human leukocyte antigen) antibodies during ventricular assist device (VAD) support. We investigated sensitization in patients implanted with the DeBakey VAD (MicroMed Technology, Inc, Houston, TX) axial flow pump as a bridge to heart transplantation., Methods: Inclusion criteria for this prospective study were the following. Patients implanted with the DeBakey VAD axial flow pump, without HLA antibodies prior to implantation, with a duration of support of at least one month. The HLA antibody testing for IgG and IgM class I and II antibodies was performed weekly during support, using both a complement dependant cytotoxicity assay and an enzyme-linked immunosorbent assay (ELISA). Retrospective cross match was performed for all patients transplanted. The occurrence of graft rejection was determined by regular endomyocardial biopsies after heart transplantation, graded according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines. Additionally, the transfusion history was reviewed for all patients., Results: Fourteen patients were included representing 1,220 cumulative patient-days of support (mean duration time on support, 87 days). No patient developed detectable IgG antibodies to class I or II. One patient had a positive ELISA, corresponding to nonsignificant (6/30) class I IgM antibodies at 3 weeks postimplantation. Ten patients underwent successful heart transplantation, representing 156 cumulative months. No retrospective cross match was positive. The percentage of significant acute rejection episodes (ISHLT grade 3A or more) was 6% and 4.3% in the first 6 months and from 6 to 12 months, respectively. No vascular rejection was noted. The posttransplantation survival rate was 87% at 6 months and 75% at 1 year, respectively., Conclusions: Patients implanted with the DeBakey VAD axial flow pump as a bridge to heart transplantation do not appear to be exposed to an increased risk of sensitization.

Background: The knowledge of long-term changes in the transplanted heart is still incomplete. Among these changes that could potentially have an adverse effect on long-term cardiac function, myocardial fibrosis is of great concern. The aim of this study was to investigate the possible influence of acute or chronic rejection on the development of myocardial fibrosis in cardiac allografts., Methods: We used light microscopic computer-assisted morphometry of collagen density in 200 right ventricular endomyocardial biopsy specimens taken routinely in 21 heart transplant recipients during a mean follow-up period of 36 months (range, 12 to 84). The 21 patients were divided into two groups according to the presence of chronic rejection assessed by coronary angiography. The first group consisted of 11 patients with no chronic rejection; the second group consisted of 10 patients with chronic rejection. Both groups were divided into four subgroups according to the highest grade of acute rejection reached during the follow-up period (subgroup 1, no acute rejection or grade 1A; subgroup 2, grade 1B; subgroup 3, grades 3A or 3B; subgroup 4, grade 4). Patients of both groups were selected on the basis of similarity patterns in clinical characteristics and mean follow-up time., Results: Patients with no chronic rejection had relatively little variation in serial determinations of myocardial collagen density. During the prechronic and chronic phases in patients with chronic rejection, we found no overall increase in myocardial collagen density. In both the chronic rejection and no chronic rejection groups there was no consistent relationship between myocardial collagen density and severity of acute rejection. In both groups there were occasional strikingly elevated myocardial collagen density values that were well above the other serial determinations. These elevated values of collagen density were mainly a result of scars, the sequellae of prior myocyte damage, because neither interstitial nor perivascular fibrosis could be detected., Conclusion: During this long-term follow-up study of endomyocardial biopsy samples, we found no significant association between either acute or chronic rejection and the later increase in myocardial collagen density.

Background and Methods: We investigated extracorporeal photochemotherapy--which consists of the collection of blood mononuclear cells by means of a cell separator, their exposure to ultraviolet A light in the presence of a photoactivatable molecule such as 8-methoxypsoralen, and their intravenous reinjection into the patient--for the treatment of an acute lung rejection episode in a severely infected patient, assuming that its mechanism of action is an immunomodulation rather than an actual immunosuppression., Results: Three weeks after the simultaneous beginning of antiinfectious and extracorporeal photochemotherapy treatments, the patient improved clinically. Acute lung rejection was no longer detectable histologically 4 weeks after the beginning of extracorporeal photochemotherapy. Twenty-two months after the beginning of extracorporeal photochemotherapy (47 months after transplantation), the patient was living a normal life., Conclusions: We believe this treatment may be considered for further studies not only in acute lung rejection therapy when intensive immunosuppression is contraindicated but also as a means of rejection prevention.

Objective: Treatment of transplant rejection with muromonab CD3 (Orthoclone OKT3) may result in haemodynamic instability and pulmonary oedema, which would question its prophylactic use. The aim of this study was to the evaluate haemodynamic and respiratory tolerance of prophylactic treatment of cardiac rejection with OKT3., Study Design: Prospective clinical study., Patients: Twelve patients, whose pulmonary arterial resistances before transplantation were less than 400 dyn.s.cm-5, with haemodynamic and respiratory stability during the 4 hours before OKT3 administration., Method: Patients under preventive haemodynamic support with isoprenaline 0.05 micrograms.kg-1.min-1 and dopamine 3 micrograms.kg-1.min-1. Immunosuppressive treatment with azathioprine 5 mg.kg-1 at d0 and 3 mg.kg-1 at d1 and d2 and with methylprednisolone 720 mg at d0 and 240 mg at d1 and d2. OKT3, 5 mg administered i.v. at d0, d1, d2. Respiratory and haemodynamic variables were recorded prior to (T0), 30 min (T1) and 360 min (T2) after injection of OKT3., Result: Neither clinical nor radiological changes were observed after the OKT3 injections. At d0, T2, the heart rate increased and PaO2 and SaO2 decreased. At d1 and d2, T1, PaO2 decreased, and QS2QT at T1 d2 increased by nearly 3%., Conclusion: OKT3 does not result in major circulatory and haematosis changes, provided patients are selected, especially free of pretransplantation pulmonary hypertension. Prior to the treatment with OKT3, they should be in a satisfactory haemodynamic and respiratory status and receive high doses of corticosteroids.

The increase of organ transplantations during the last decades conjointly with the prescription of heavy immunosuppressive drugs, has led to an increased incidence of new invasive aspergillosis (IA). This study is a report of the Broussais Hospital experience from 1968 to 1993 on kidney, heart and heart and lungs transplantations. It concerns 21 IA cases. Incidence was 0.5% for kidney, 4.5% for heart and 18% for heart and lungs transplantations. The most important risk factors were the increase of immunosuppressive therapy (66% of the cases), neutropenia (19%), and renovation of the hospital wards (36%). Lung was the most frequent site of infection (95% of the cases), clinical symptoms were no significant. Diagnosis procedures were realised on biopsy (23%) and on bronchoalveolar lavage (66%). Usual amphotericin B treatment was disappointing: mortality rate of 77%, the liposomal preparation of the drug seemed to be more efficient: mortality rate of 50%. Itraconazole appeared to be used in succession with a careful adaptation of posology. Prophylactic amphotericin B in a local way (sprays and aerosols) led to a good efficiency jointly with the patient isolation during constructions in the hospital area.

Between 1984 and 1991 a total of 200 patients underwent heart transplantation in our unit. The records of 121 patients who were followed up for more than 1 year were reviewed for peripheral vascular abnormalities, which were found in 12 (9.9%). Most of these patients underwent transplantation for ischemic heart disease, and peripheral vascular disease preceded the heart transplantation in 80%. Although surgical risks are low in this setting, particular caution should be exercised to prevent septic complications in the femoral triangle. Among the risk factors studied, only elevated blood cholesterol was frequently found in the vascular patients before or after transplantation. Peripheral vascular involvement in heart transplant patients corresponds to the natural course of atheroma rather than to an accelerated process of atherosclerosis.

Cytomegalovirus (CMV) infection is a major cause of morbidity and death in heart transplant recipients. Cardiac graft involvement in CMV infection is a matter of controversy, considering its frequency and its relationship with acute or chronic rejection. Four heart transplant patients were selected because of a severe CMV infection (systemic, gastrointestinal, ophthalmic, and neurologic involvement). Immunoglobulin M and increased immunoglobulin G CMV antibodies developed. Twenty-two routine endomyocardial biopsies (EMB; mean: 5.5 EMB per patient; range, 3 to 9) from these patients were selected covering the period of CMV infection. Grading of rejection showed 12 biopsies with "no evidence of rejection (grade 0)," nine biopsies with "mild acute rejection (grade 1B)," and one biopsy with "moderate acute rejection (grade 3A)." One EMB exhibited a single CMV inclusion in an endothelial cell detectable by light microscopy. The EMB were assessed for CMV infection using in situ hybridization (ISH) for the detection of CMV genome with a biotinylated CMV probe and immunohistochemistry (IHC) for the detection of CMV immediate-early antigen with the monoclonal antibody E13. ISH and IHC detected a single CMV-infected cell, respectively, in one and two EMB from two patients. The patient with a CMV inclusion determined by light microscopy was also positive with both techniques. Positive ISH and IHC were always in enlarged inclusion-bearing cells, which were easily observable with routine staining. One EMB had mild acute rejection, and the other one had no rejection.(ABSTRACT TRUNCATED AT 250 WORDS)