First case of proven invasive pulmonary infection due to Trichoderma longibrachiatum in a neutropenic patient with acute leukemia.

Trichoderma species are saprophytic filamentous fungi that can be found all over the word. These fungi show increasing medical importance as opportunistic human pathogens, particularly in immunocompromised patients. Invasive infections due to Trichoderma are rare and definitive diagnosis is complex to achieve because of the lack of specific diagnosis tools. We report in this work the first proven case of invasive pulmonary infection due to T. longibrachiatum in a 69-year-old white male with hematologic malignancy. The patient was successfully treated initially with voriconazole alone followed by a combination of voriconazole and caspofungine.

[Retrospective study of 25 cases of pulmonary mucormycosis in acute leukaemia]. / Mucormycoses pulmonaires au cours des traitements de leucémies aiguës. Analyse rétrospective d'une série de 25 patients.

INTRODUCTION: In acute leukaemia (AL), the occurrence of pulmonary mucormycosis (PM), the incidence of which is increasing, as a result of chemotherapy induced marrow aplasia, remains a life threatening complication. METHODS: Analysis of clinical, biological and thoracic CT characteristics of patients with PM developing during the treatment of AL between 2000 and 2015. Day 0 (D0) was defined as the day with first CT evidence of PM. RESULTS: Among 1193 patients, 25 cases of PM were recorded during 2099 episodes of bone marrow aplasia. At time of diagnosis of PM, 24/25 patients had been neutropenic for a median of 12 days. None of the patients had diabetes mellitus. On initial CT (D0), the lesion was solitary in 20/25 cases and a reversed halo sign (RHS) was observed in 23/25 cases. From D1 to D7, D8 to D15 and after D15, RHS was seen in 100 %, 75 % and 27 % of cases, respectively. A tissue biopsy was positive in 17/18 cases. The detection of circulating Mucorales DNA in serum was positive in 23/24 patients and in 97/188 serum specimens between D-9 and D9. Bronchoalveolar lavage contributed to diagnosis in only 3/21 cases. The antifungal treatment was mainly based on liposomal amphotericin B combined with, or followed by, posaconazole. A pulmonary surgical resection was performed in 9/25 cases. At 3 months, 76 % of patients were alive and median overall survival was 14 months. CONCLUSION: In AL, early use of CT could improve the prognosis of PM. The presence of a RHS on CT suggests PM and is an indication for prompt antifungal treatment.

Expressed fusion gene landscape and its impact in multiple myeloma.

Multiple myeloma is a plasma cell malignancy characterized by recurrent IgH translocations and well described genomic heterogeneity. Although transcriptome profiles in multiple myeloma has been described, landscape of expressed fusion genes and their clinical impact remains unknown. To provide a comprehensive and detailed fusion gene cartography and suggest new mechanisms of tumorigenesis in multiple myeloma, we performed RNA sequencing in a cohort of 255 newly diagnosed and homogeneously treated multiple myeloma patients with long follow-up. Here, we report that patients have on average 5.5 expressed fusion genes. Kappa and lambda light chains and IgH genes are main partners in a third of all fusion genes. We also identify recurrent fusion genes that significantly impact both progression-free and overall survival and may act as drivers of the disease. Lastly, we find a correlation between the number of fusions, the age of patients and the clinical outcome, strongly suggesting that genomic instability drives prognosis of the disease.

Impact of pharmaceutical intervention on quality of life and coping strategies in patients with haematological malignancies.

OBJECTIVES: We conducted a prospective study approved by the local ethics committee to determine the impact of a pharmaceutical intervention (PI) on pain, fatigue, quality of life (QoL) and coping strategies in patients with HMs starting chemotherapy sessions. MATERIAL AND METHODS: Patients received either usual care (UC)+PI (PI group) or UC alone (UC group). They had to complete 2 questionnaires, QLQ-C30 and MAC 21, at 3 different time points: before starting the 1st chemotherapy session (T1), during the intercure (T2) and the day before starting the 2nd chemotherapy session (T3). To determine predictive factors of pain, fatigue, QoL and coping scores at T3, a multivariate ANOVA was used. QoL and coping scores were analysed longitudinally using a linear mixed model. RESULTS: Sixty-eight patients were included in the PI (n=34) or UC groups (n=34). Ninety-two percent of the patients returned all the questionnaires. At inclusion, QoL was significantly better in the PI group (P=0.047). At T3, the group had no influence on pain, fatigue, nor coping scores but a trend towards a better QoL was observed in the PI group (P=0.090). Longitudinally, the PI group did not present significantly better scores on pain, fatigue but both a trend toward better Qol scores and lower anxious preoccupations scores. CONCLUSION: A PI at the beginning of chemotherapy sessions did not have any significant impact on pain and fatigue but a trend towards better Qol scores and lower anxious preoccupations scores.

Autologous stem cell transplantation for patients aged 60 years or older with refractory or relapsed classical Hodgkin's lymphoma: a retrospective analysis from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC).

This report retrospectively analyzed the outcome of 91 patients aged 60 years or older with refractory/relapsed (R/R) classical Hodgkin's lymphoma (cHL) who underwent autologous stem cell transplantation (ASCT) between 1992 and 2013 and were reported to the French Society of Bone Marrow Transplantation and Cell Therapies registry. The median age at transplant was 63 years. The majority of patients exhibited disease chemosensitivity to salvage treatment (57 complete responses, 30 partial responses, 1 progressive disease and 3 unknown). The most frequent conditioning regimen consisted of BCNU, cytarabine, etoposide, melphalan (BEAM) chemotherapy (93%). With a median follow-up of 54 months, 5-year estimates of overall survival (OS) and progression free survival (PFS) for the entire group were 67 and 54%, respectively. Despite the missing data, in univariate analysis, the number of salvage chemotherapy lines (1-2 versus ⩾3) significantly influenced the OS, unlike the other prognostic factors (stage III-IV at relapse, disease status before ASCT and negative positron emission tomography (PET) scan) encountered in younger patients. In spite of its limitations, this retrospective study with a long-term follow-up suggests that ASCT is a valid treatment option for chemosensitive R/R cHL in selected elderly patients, with an acceptable rate of toxicity.

Emergency and elective pulmonary surgical resection in haematological patients with invasive fungal infections: a report of 50 cases in a single centre.

Invasive fungal infections (IFI) remain life-threatening complications in haematological patients. The aim of the study was to present the experience of a single centre in the surgical treatment of pulmonary IFI. Between 1992 and 2014, 50 haematological patients with IFI underwent pulmonary resection. In 27 cases it was an emergency procedure to avoid haemoptysis (if the lesion threatened pulmonary vessels). The remaining 23 patients underwent elective surgery before new chemotherapy or stem-cell transplantation. Among these patients (median age: 54 years; range: 5-70 years), 92% had acute leukaemia and 68% were on haematological first-line therapy (receiving induction or consolidation chemotherapies). Invasive pulmonary aspergillosis and pulmonary mucormycosis were diagnosed in 37 and 12 patients, respectively. One patient had IFI due to Trichoderma longibrachiatum. All of the patients received antifungal agents. In the month preceding IFI diagnosis, 94% of patients had been neutropenic. At the time of surgery, 30% of patients were still neutropenic and 54% required platelet transfusions. Lobectomy or segmentectomy were performed in 80% and 20% of cases, respectively. Mortality at 30 and 90 days post-surgery was 6% and 10%, respectively. After surgery, median overall survival was 21 months; median overall survival was similar between patients with emergency or elective surgery and between the types of IFI (invasive pulmonary aspergillosis or pulmonary mucormycosis). However, overall survival was far better in haematological first-line patients or in those achieving a haematological complete response than in other patients (p <0.001). In pulmonary IFI, lung resection could be an effective complement to medical treatment in selected haematological patients.

A retrospective study of the prescribing and outcomes of tyrosine kinase inhibitors in chronic myeloid leukaemia over a period of more than 10 years.

WHAT IS KNOWN AND OBJECTIVE: Since their introduction, tyrosine kinase inhibitors (TKIs) have been increasingly used in clinical practice. We describe the prescribing and the clinical and biological consequences of two such inhibitors, imatinib and erlotinib, in patients with chronic myeloid leukaemia (CML) in a practice setting over a period of more than 10 years. METHODS: All patients who received at least one TKI for chronic phase CML between 2001 and 2012 in our university hospital were included in the study. RESULTS AND DISCUSSION: Of the 139 patients, with a median age of 57 years, who were surveyed, imatinib and nilotinib were prescribed as the first TKI in 131 (94%) and 8 (6%) patients, respectively. With a median follow-up of 6 years, 342 treatment modifications were observed: 113 (33%) increased doses, 109 (32%) decreased doses, 89 (26%) TKI changes, 14 (4%) definitive discontinuations, 13 (4%) temporary discontinuations and 4 (1%) additions of IFN-α. The main reasons for the 342 treatment modifications were adverse events (n = 112, 33%), long-term optimal response (n = 58, 17%) and failure (n = 57, 17%). Eighty-five (61%), 31 (22%), 18 (13%) and 5 (4%) patients had no, 1, 2 and 3 TKI changes, respectively. Imatinib was the most prescribed TKI (75%). Adverse events resulting in treatment modifications occurred in 18% of patients for imatinib, 49% for nilotinib and 41% for dasatinib (P < 0·001). Median time to TKI change whatever the reason was >50 months (not achieved) for imatinib, 22 months for nilotinib and 27 months for dasatinib (log-rank test, P < 0·001). WHAT IS NEW AND CONCLUSION: Imatinib was the most prescribed TKI both in the first and in subsequent therapeutic lines for chronic phase CML. Our study showed a very good efficacy-safety profile for imatinib at a median follow-up of 6 years in an unselected French population.

[A rare cause of pulmonary opacities: Lung localization of Waldenström's macroglobulinemia]. / Une cause rare d'opacités alvéolaires : maladie de Waldenström à localisation pulmonaire.

INTRODUCTION: Pulmonary localized forms of Waldenström's macroglobulinemia are rare. CASE REPORT: We report the observation of a 71-year-old woman with chronic cough and persisting alveolar opacities after several courses of antibiotics. Physical examination was unremarkable. Protein electrophoresis identified a monoclonal IgM in the serum. The lymphocyte immunophenotyping from the bronchoalveolar lavage was consistent with a B-cell lymphoma and Waldenström's macroglobulinemia was confirmed by the bone marrow biopsy. Chemotherapy with a combination of rituximab, fludarabine and cyclophosphamide improved the patient's symptoms and caused the pulmonary opacities to resolve. We discuss the various clinical and radiological pulmonary manifestations of this slowly progressive hematological condition. CONCLUSION: Pulmonary manifestations of Waldenström's macroglobulinemia result in various clinical and radiological patterns. A serum protein electrophoresis should be performed in cases of pleuropulmonary opacities persisting despite antibiotics.

Generic vancomycin products: Analysis of serum concentrations in patients with acute myeloid leukemia.

UNLABELLED: Concerns have recently emerged about the quality of generic vancomycin products. Our aim is to analyze serum vancomycin concentrations measured 48 hours after the start of an empirical treatment regimen in patients with acute myeloid leukemia (AML) who received one of the two generic vancomycin products available in France. PATIENTS AND METHODS: Seventy-nine AML patients treated with vancomycin during two study periods were included in the study. Our vancomycin dosing regimen was based on the patients' total body weight adjusted for renal clearance. RESULTS: A total of 93 serum vancomycin concentrations were collected: 31 in period 1 and 62 in period 2. In bivariate analysis, the mean serum vancomycin concentrations were not significantly different (19.9 ± 11.2 mg/L in period 1 vs 18.9 ± 6.0 mg/L in period 2, P=0.64). In the final generalized estimating equations model, serum vancomycin concentrations correlated statistically with a positive coefficient for age (P<0.001) and with negative coefficients for male sex (P=0.001) and hemoglobin level (P=0.021). CONCLUSION: Serum vancomycin concentrations measured 48 hours after the start of an empirical treatment were not influenced by the nature of the generic product but correlated with age, sex and hemoglobin level in AML patients.

The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?

BACKGROUND: Pulmonary mucormycosis (PM) is a life-threatening fungal infection with an increasing incidence among patients with acute leukemia. In some immunocompromised hosts, the reversed halo sign (RHS) has been described on the pulmonary computed tomographic (CT) scan of patients with mucormycosis. METHODS: This study reports a single-center experience with PM exclusively in patients with acute leukemia. Clinical records, laboratory results, and CT scans were retrospectively analyzed to evaluate the clinical usefulness of the RHS for the early identification and treatment of PM, with regard to outcomes in these patients. RESULTS: Between 2003 and 2012, 16 cases of proven PM were diagnosed among 752 consecutive patients receiving chemotherapy for acute myeloblastic or lymphoblastic leukemia. At the time PM was diagnosed, all patients but one were neutropenic. The study of sequential thoracic CT scans showed that during the first week of the disease, the RHS was observed in 15 of 16 patients (94%). Initially, other radiologic findings (multiple nodules and pleural effusion) were less frequent, but appeared later in the course of the disease (6% and 12% before vs 64% and 55% after the first week). After the diagnosis of PM, median overall survival was 25 weeks (range, 3-193 weeks), and 6 patients (38%) died before day 90. CONCLUSIONS: In the particular setting of neutropenic leukemia patients with pulmonary infection, the presence of the RHS on CT was a strong indicator of PM. It could allow the early initiation of appropriate therapy and thus improve the outcome.

Potentiation of carbon monoxide-induced relaxation of rat aorta by YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole].

The hypothesis that endogenous carbon monoxide (CO), produced during the oxidation of heme catalyzed by heme oxygenase (HO), plays a role similar to that of nitric oxide (NO) in the regulation of cardiovascular tone has been criticized because of the low potency of CO compared with NO in relaxing blood vessels and stimulating soluble guanylyl cyclase (sGC). This criticism has been muted by the demonstration that, in the presence of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole], CO has similar potency to NO in stimulating sGC activity. In this study, we determined that YC-1 potentiated CO-induced relaxation of rat aortic strips (RtAS) by approximately ten-fold. Furthermore, CO-induced relaxation of RtAS was shown to be mediated through stimulation of sGC because vasorelaxation was inhibited by ODQ (1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one), a selective sGC inhibitor, in the absence and presence of YC-1. A gas chromatographic-headspace method was used to measure CO concentration in Krebs' solution following the addition of CO-saturated saline solution to the tissue bath, in order to provide an accurate determination of RtAS exposure to CO. The tissue bath concentration of CO was shown to be approximately one-half of that calculated to be present. We conclude that should an endogenous compound exist with properties similar to that of YC-1, then the potency of CO as a vasorelaxant in the presence of this factor would be increased. As a consequence, CO could play a role in the regulation of cardiovascular tone, comparable to that of NO.

Selective inhibition of heme oxygenase, without inhibition of nitric oxide synthase or soluble guanylyl cyclase, by metalloporphyrins at low concentrations.

Studies on the physiological role of heme oxygenase (HO) require an inhibitor that will selectively inhibit HO activity without inhibiting the activity of either nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). The objective of this study was to test a series of metalloporphyrins that have previously been shown to inhibit HO activity, for their ability to inhibit HO without inhibiting NOS or sGC activities. Measurement of activity of HO in rat brain microsomes and NOS in rat brain cytosol was made for samples incubated with metalloporphyrins (0.15-50 microM), including zinc protoporphyrin IX, zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG), chromium mesoporphyrin IX (CrMP), tin protoporphyrin IX, and zinc N-methylprotoporphyrin IX. CrMP and ZnBG were found to be the most selective inhibitors of HO activity (i.e., caused the greatest inhibition of HO activity, 89 and 80%, respectively, without inhibition of NOS activity). Based on these results, sGC activity in rat lung cytosol incubated with CrMP or ZnBG (0.15-15 microM) was measured. ZnBG did not affect basal sGC activity but did potentiate S-nitroso-N-acetylpenicillamine (SNAP)-induced sGC activity. CrMP did not affect either basal or SNAP-induced activity. It was concluded that of the five metalloporphyrins studied, CrMP, at a concentration of 5 microM, was a selective inhibitor of HO activity and was the most useful metalloporphyrin for the conditions tested. Thus, CrMP would appear to be a valuable chemical probe in elucidating the physiological role of HO.