Pattern of Care and Outcomes of Adolescent and Young Adults with Lymphoma Treated in the Rhône-Alpes Region.

Background: Management of adolescent and young adults (AYAs) cancer is very heterogeneous. In the case of lymphomas, outcomes are mostly favorable but there is still room for improvement. Design: We retrospectively collected the pattern of care of all institutional 13- to 25-year-old AYAs patients with classical Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) diagnosed in the Rhône-Alpes region between the years 2000 and 2005. Management, including adherence to Clinical Practice Guidelines (CPGs), and long-term survival were analyzed by comparing adult units (AU) and pediatric units (PU). Results: 278 patients were included: 198 treated for HL (median age of 19 years), 80 treated for NHL (median age of 20 years). Among them, 74% were managed in AU and 26% in PU. The median time between diagnosis and starting treatment was significantly lower in PU than in AU. Sixty-five patients (23%) were included in clinical trials, mostly in AU. Five-year overall survival was 96% for HL [14 deaths, median follow-up 91 months (9-180)] and 90% for NHL [nine deaths, median follow-up 80 months (3-180)]. Secondary cancers occurred for 2% (n = 3) of HL patients and for none in NHL. Other major late complications included cardiovascular accidents in two patients and fatal pulmonary fibrosis in one patient. Major differences in chemotherapy and radiotherapy use are emphasized. Global management conformed to CPGs by 56%. Conclusions: Important differences between adult and pediatric management were reported, without any impact on survival. A few patients can be included in clinical trials: Homogeneity in management could improve specific care for AYAs.

Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?

BACKGROUND: Colonoscopy with pan-chromoendoscopy (CE) is superior to standard colonoscopy in detecting neoplasia in patients with IBD. Performing random biopsies in unsuspicious mucosa after CE remains controversial. METHODS: Consecutive patients with IBD who underwent surveillance colonoscopy using CE were prospectively included. The standardised procedure used CE, performed targeted biopsies or endoscopic resection on suspicious lesions and then quadrant random biopsies every 10 cm. A panel of five expert pathologists reviewed histological slides with dysplasia. Logistic regression model was used to evidence the factors associated with neoplasia in any or in random biopsies. RESULTS: 1000 colonoscopes were performed in 1000 patients (495 UC, 505 Crohn's colitis). In 82 patients, neoplasia was detected from targeted biopsies or removed lesions, and among them dysplasia was detected also by random biopsies in 7 patients. Importantly, in 12 additional patients dysplasia was only detected by random biopsies. Overall, 140 neoplastic sites were found in 94 patients, 112 (80%) from targeted biopsies or removed lesions and 28 (20%) by random biopsies. The yield of neoplasia by random biopsies only was 0.2% per-biopsy (68/31 865), 1.2% per-colonoscopy (12/1000) but 12.8% per-patient with neoplasia (12/94). Dysplasia detected by random biopsies was associated with a personal history of neoplasia, a tubular appearing colon and the presence of primary sclerosing cholangitis (PSC). CONCLUSIONS: Despite their low yield, random biopsies should be performed in association with CE in patients with IBD with a personal history of neoplasia, concomitant PSC or a tubular colon during colonoscopy. TRIAL REGISTRATION NUMBER: IRB 001508, Paris 7 University.

Exome sequencing identifies recurrent BCOR alterations and the absence of KLF2, TNFAIP3 and MYD88 mutations in splenic diffuse red pulp small B-cell lymphoma.

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other related splenic B-cell lymphomas with frequent leukemic involvement or other lymphoproliferative disorders remains undetermined. We performed whole-exome sequencing to explore the genetic landscape of ten cases of splenic diffuse red pulp lymphoma using paired tumor and normal samples. A selection of 109 somatic mutations was then evaluated in a cohort including 42 samples of splenic diffuse red pulp lymphoma and compared to those identified in 46 samples of splenic marginal zone lymphoma and eight samples of hairy-cell leukemia. Recurrent mutations or losses in BCOR (the gene encoding the BCL6 corepressor) - frameshift (n=3), nonsense (n=2), splicing site (n=1), and copy number loss (n=4) - were identified in 10/42 samples of splenic diffuse red pulp lymphoma (24%), whereas only one frameshift mutation was identified in 46 cases of splenic marginal zone lymphoma (2%). Inversely, KLF2, TNFAIP3 and MYD88, common mutations in splenic marginal zone lymphoma, were rare (one KLF2 mutant in 42 samples; 2%) or absent (TNFAIP3 and MYD88) in splenic diffuse red pulp lymphoma. These findings define an original genetic profile of splenic diffuse red pulp lymphoma and suggest that the mechanisms of pathogenesis of this lymphoma are distinct from those of splenic marginal zone lymphoma and hairy-cell leukemia.

Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network.

Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.

Splenic diffuse red pulp lymphoma has a distinct pattern of somatic mutations amongst B-cell malignancies.

Splenic Diffuse Red Pulp Lymphoma (SDRPL) has been recently introduced as a provisional entity but differential diagnosis with other splenic lymphomas is needed to be clarified since the therapeutic approaches are distinct. Recently described recurrent mutations or CD180 expression appear useful for differential diagnosis. We completed our previous description in a larger cohort including 53 patients selected on the presence of characteristic villous cells in peripheral blood (PB) and a specific immunophenotype. Immunoglobulin heavy variable (IGHV), BRAF, MYD88, and NOTCH2 mutations were determined and CD180 and BRAF expressions were assessed. Most cases (79%) were IGHV mutated with an overrepresentation of IGHV3-23 (19%) and IGHV4-34 (21%). MYD88 L265P and NOTCH2 mutations were observed in one case each, whereas no BRAF V600E mutation or expression was found. All cases demonstrated a high CD180 expression. Those results strengthen the concept that SDRPL does emerge as a new lymphoma entity distinct from the other splenic lymphomas with circulating lymphocytes.

Primary cardiac lymphoma: diagnosis, treatment and outcome in a modern series.

Primary cardiac lymphoma (PCL) represents a rare subset of extranodal lymphomas for which the primary lesion arises from the heart and/or the pericardium. Fundamental characteristics of PCL remain uncertain, regarding optimal diagnosis strategy, pathological features, treatments, as well as prognostic factors. This is a single-institution retrospective study of patients with histologically proven lymphoma, presenting with exclusive or predominant myocardial invasion at time of diagnosis. Thirteen patients were included, all of whom had symptoms related to cardiac tumour location with chronic chest pain in six (46%), dyspnea in seven (54%) and arythmia in three (23%). Sub-acute and acute congestive heart failure were noticed in respectively nine (70%) and one (9%). PCL was identified at transthoracic echocardiography and computed tomography scan in 80 and 100% of patients, respectively. Most frequent location was the right atrium in 10 (77%) patients. Pericardial effusion was identified in 10 (77%). Pathological diagnosis-diffuse large B-cell lymphoma in 12 cases and Burkitt in 1 case-was made on cardiac surgical biopsies in 9 cases and by intravascular procedure in 2 cases. All patients received first-line chemotherapy, with a complete response rate of 62%. Recurrences occurred in 55% of patients, mostly at extracardiac extranodal sites. Our data confirm that PCL harbours specific clinical and anatomical features. The aggressiveness of PCL mainly results from the possible onset of acute cardiac events. Further molecular characterization may help to further individualize PCL among diffuse and intrathoracic lymphomas. Copyright © 2016 John Wiley & Sons, Ltd.

Array-CGH predicts prognosis in plasma cell post-transplantation lymphoproliferative disorders.

Plasma-cell post-transplantation lymphoproliferative disorder (PC-PTLD) is a rare monomorphic PTLD entity divided into plasma cell myeloma (PCM) and plasmacytoma-like lesion (PLL) PTLD. To date, there are no exhaustive published cytogenetic data on PC-PTLD. We report array-based comparative genomic hybridization (aCGH) of 10 cases of PCM and PLL-PTLD. Patients had received kidney (n = 6), heart (n = 2), lung (n = 1) or bone marrow (n = 1) transplantation. There were six men and median age at time of PTLD was 56.5 years (3-74). We identified two different cytological features, plasmacytic and plasmablastic, among six PLL and three PCM PTLD. Eight cases were associated with EBV. First line treatment was heterogeneous: rituximab alone (n = 5), CHOP-like (n = 3) and multiple myeloma-like (n = 1). One patient died before any treatment. After a median follow-up of 19.5 months (0-150), five patients died (four from PTLD) and five were alive without evidence of disease. By aCGH, 5/10 demonstrated a complex profile. The most frequent abnormalities were +7q (5/10), +16q (5/10), +17q (5/10), +17p (4/10), +5q (4/10), t7 (4/10), t9 (3/10), del1p (3/10). No del17p13 (TP53) were observed. Del1p32.3 (CDKN2C) was observed in 2 cases. On univariate prognostic analysis, a complex aCGH was associated with a shorter OS. Thus, cytogenetic abnormalities seem to be closely related to those reported in multiple myeloma or diffuse large B cell lymphoma. Complex aCGH constitutes an unfavorable prognostic marker and aCGH should be integrated in the evaluation of patients with PLL/PCM-PTLD. © 2016 Wiley Periodicals, Inc.

In Situ Hepatitis C NS3 Protein Detection Is Associated with High Grade Features in Hepatitis C-Associated B-Cell Non-Hodgkin Lymphomas.

Hepatitis C Virus (HCV) infection is associated with the B-cell non-Hodgkin lymphomas (NHL), preferentially marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL). While chronic antigenic stimulation is a main determinant of lymphomagenesis in marginal zone lymphomas (MZL), a putative role of HCV infection of B-cells is supported by in vitro studies. We performed a pathological study within the "ANRS HC-13 LymphoC" observational study focusing on in situ expression of the oncogenic HCV non structural 3 (NS3) protein. Lympho-C study enrolled 116 HCV-positive patients with B-NHL of which 86 histological samples were collected for centralized review. Main histological subtypes were DLBCL (36%) and MZL (34%). Almost half of DLBCL (12/26) were transformed from underlying small B-cell lymphomas. NS3 immunostaining was found positive in 17 of 37 tested samples (46%). There was a striking association between NS3 detection and presence of high grade lymphoma features: 12 out of 14 DLBCL were NS3+ compared to only 4 out of 14 MZL (p = 0.006). Moreover, 2 among the 4 NS3+ MZL were enriched in large cells. Remarkably, this study supports a new mechanism of transformation with a direct oncogenic role of HCV proteins in the occurrence of high-grade B lymphomas.

Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network.

PURPOSE: Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. PATIENTS AND METHODS: Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. RESULTS: The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. CONCLUSION: Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.

Multiparameter Phase I trials: a tool for model-based development of targeted agent combinations--example of EVESOR trial.

Optimal development of targeted drug combinations is one of the future challenges to be addressed. Computerization and mathematical models able to describe biological phenomena and to simulate the effects of changes in experimental conditions may help find solutions to this issue. We propose the concept of 'multiparameter trials', where biological, radiological and clinical data required for modeling purpose are collected and illustrated by the ongoing academic EVESOR trial. The objective of the model-based work would be the determination of the optimized doses and dosing schedules of everolimus and sorafenib, offering the maximization of the predicted modeled benefit/toxicity ratio in patients with solid tumors. It may embody the 'proof of concept' of model-based drug development of anticancer agent combinations.

High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma.

We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients treated first line with immunochemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age, 56 years) was analyzed by multiplex ligation-dependent probe amplification and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments. As expected, MYC (18%) was the more frequently gained, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%), and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A, TP53, and CDKN1B were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (hazard ratio, 2.3; P = .007, MIPI-adjusted) and TP53 deletions (hazard ratio, 2.4; P = .007), reflected in a dismal outcome with simultaneous deletions (median OS, 1.8 years) compared with single deletions (median OS, 4.3 and 5.1 years) or without these deletions (median OS, 7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A and TP53 deletions were independent of the Ki-67 index. Despite immunochemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. This trial was registered at www.clinicaltrials.gov as #NCT00209222.

Endoscopic and histologic characteristics of serrated lesions.

In recent years, a second pathway for colonic carcinogenesis, distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp, characterised by a serrated appearance of the crypts: hyperplastic polyps (HP), sessile serrated adenomas (SSA) or lesions, and traditional serrated adenomas. Each lesion has its own genetic, as well as macroscopic and microscopic morphological features. Because of their flat aspect, their detection is easier with chromoendoscopy (carmin indigo or narrow-band imaging). However, as we show in this review, the distinction between SSA and HP is quite difficult. It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia. These different types of lesion are described in detail in the present review in general population, in polyposis and in inflammatory bowel diseases patients. This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.

Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study.

Hepatitis C virus (HCV) infection increases the risk of B-cell non-Hodgkin lymphomas (B-NHL). Antiviral treatment (AT) can induce hematological responses in patients with marginal zone lymphomas (MZL). The ANRS HC-13 Lympho-C study aimed at a better understanding of the impact of AT on HCV associated B-NHL. This multicentric study enrolled 116 HCV-positive patients with B-NHL between 2006 and 2012. Cytological and histological samples were collected for centralized review. At lymphoma diagnosis, median age was 61 years and gender ratio M/F was 1. Cytohistological distribution was marginal zone lymphoma (MZL) n = 45 (39%), diffuse large B-cell lymphoma (DLBCL) n = 45 (39%), and other types n = 26 (22%). MZL patients had more frequent detection of rheumatoid factor (68% vs. 35%; P = 0.001) and more frequently mixed cryoglobulinemia (74% vs. 44%; P = 0.021) than patients with DLBCL. Among patients receiving AT, a sustained virologic response was achieved in 23 of 38 (61%) patients with MZL and in 9 of 17 (53%) with DLBCL (P = 0.42). Three-year overall survival (OS) and progression-free survival were 78% 95%CI [63-88] and 64% [48-76], respectively, without difference between cytohistological groups. Outcome analysis showed a favorable association between OS and AT in all patients (P = 0.05) and in the subgroup of MZL patients only (P = 0.04). Our data support that AT improves the outcomes of HCV-associated NHLs. The impact of new AT regimen with protease inhibitor needs to be investigated in this setting. [clinicalTrials.gov Identification number NCT01545544]

Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B.

PURPOSE: To determine whether any tumor biomarkers could account for the survival advantage observed in the LNH 03-2B trial among patients with diffuse large B-cell lymphoma (DLBCL) and low-intermediate risk according to the International Prognostic Index when treated with dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) compared with standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). PATIENTS AND METHODS: Using immunohistochemistry, expression of CD10, BCL6, MUM1, MYC, and BCL2 and coexpression of MYC/BCL2 were examined. The interaction effects between each biomarker and treatment arm on survival were studied in a restricted model and a full model incorporating clinical parameters. RESULTS: Among the 379 patients analyzed in the trial, 229 tumors were evaluable for germinal center B-cell-like (GCB)/non-GCB subclassification according to the Hans algorithm. Among all the biomarkers, only the interaction between the Hans algorithm and the treatment arm was significant for progression-free survival (PFS) and overall survival (OS) in univariable (PFS, P = .04; OS, P = .01) and multivariable (PFS, P = .03; OS, P = .01) analyses. Non-GCB tumors predicted worse PFS (hazard ratio [HR], 3.21; 95% CI, 1.29 to 8.00; P = .01) and OS (HR, 6.09; 95% CI, 1.37 to 27.03; P = .02) among patients treated with R-CHOP compared with patients who received R-ACVBP, whereas there were no significant survival differences between these regimens among patients with GCB tumors. CONCLUSION: The survival benefit related to R-ACVBP over R-CHOP is at least partly linked to improved survival among patients with non-GCB DLBCL. Therefore, the Hans algorithm could be considered a theragnostic biomarker for selecting young patients with DLBCL who can benefit from an intensified R-ACVBP immunochemotherapy regimen.

Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).

Hepatomegaly and fever at the time of neutrophil recovery revealing L-asparaginase toxicity in the treatment of acute lymphoblastic leukemia.

PATIENT: Male, 52 FINAL DIAGNOSIS: L-asparaginase associated steatohepatitis and pulmonary Pneumocystis Symptoms: Cholestasis • hepatomegaly MEDICATION: Corticosteroids • atovaquone • antioxidant therapy Clinical Procedure: Liver biopsy Specialty: Hematology • Infectious Disease • Hepatology. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: L-asparaginase (L-aspa) is an important component of chemotherapy in acute lymphoblastic leukemia (ALL). Main adverse effects of L-aspa include allergic reactions, pancreatitis, thrombosis, and liver disturbances. L-aspa-associated steatohepatitis may be a life-threatening disorder but has very rarely been reported in the literature. CASE REPORT: ALL was diagnosed in a 52-year-old man with a history of cardiovascular disease and obesity. Chemotherapy combining daunorubicin, vincristine, cyclophosphamide, and L-aspa was initiated. At the time of neutrophil recovery, the patient developed hepatomegaly in the context of fever and cough. On day 25, after 6 injections of L-aspa, liver function tests showed elevated alkaline phosphatase and transaminases levels. Although pulmonary Pneumocystis was concomitantly diagnosed, biological hepatic disturbances were attributed to L-aspa-associated toxicity. A liver biopsy revealed severe diffuse micro- and macrovesicular steatosis affecting more than 50% of hepatocytes. Other causes of liver dysfunction were eliminated. L-aspa and other hepatotoxic treatments were stopped, and treatment with antioxidant therapy, atovaquone, and corticosteroids was initiated. The clinical outcome was rapidly favorable. CONCLUSIONS: This case illustrates the necessity of carefully monitoring liver function test results in patients receiving L-aspa. In case of major increase of hepatic enzymes, a hepatic biopsy should rapidly be performed to exclude differential diagnosis in patients with prolonged neutropenia. L-aspa should be stopped and further administration definitively avoided. In the present case, the early administration of systemic corticosteroids as treatment of the concomitant Pneumocystis with hypoxemia could have participated to the favorable clinical evolution.