Stéphane Courby

Therapeutic impact and diagnostic performance of multiplex PCR in patients with malignancies and suspected sepsis.

OBJECTIVES New molecular methods allow rapid pathogen detection in patients with sepsis, but their impact on treatment decisions remains to be established. We evaluated the therapeutic usefulness of multiplex PCR testing in patients with cancer and sepsis. METHODS 110 patients with cancer and sepsis were included prospectively and underwent LightCycler® SeptiFast (LC-SF) multiplex PCR testing in addition to standard tests. Two independent panels of experts assessed the diagnosis in each patient based on medical record data; only one panel had the LC-SF results. The final diagnosis established by a third panel was the reference standard. RESULTS The final diagnosis was documented sepsis in 50 patients (55 microorganisms), undocumented sepsis in 54, and non-infectious disease in 6. LC-SF detected 17/32 pathogens recovered from blood cultures (BC) and 11/23 pathogens not recovered from BC; 12 microorganisms were detected neither by BC nor by LC-SF. LC-SF produced false-positive results in 10 cases. The LC-SF results would have significantly improved treatment in 11 (10%) patients and prompted immediate antimicrobial therapy not given initially in 3 patients. CONCLUSIONS In cancer patients with suspected sepsis, LC-SF detected 11/55 (20%) true pathogens not recovered from BCs and would have improved the initial management in 11/110 (10%) patients.

Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

BACKGROUND There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

Paraneoplastic Acute Diffuse Encephalitis Revealing Hodgkin's Disease

Paraneoplastic neurological syndromes are associated with various cancers. Cerebellar and limbic paraneoplastic manifestations are known to be associated with Hodgkins disease (HD), but reports of diffuse encephalitis associated with HD are very rare. We report a case of acute severe diffuse encephalitis revealing a HD. Clinical presentation, cerebro-spinal fluid modifications and magnetic resonance imagery data are described. The treatment associated specific chemotherapy and plasma exchange. The neurological status improved dramatically within the first days of treatment, with parallel neoplasm regression. This case stresses the fact that encephalopathy can be the first sign of an undiagnosed extra-cerebral neoplasm.

High response rate and acceptable toxicity of a combination of rituximab, vinorelbine, ifosfamide, mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse: results of the R-NIMP GOELAMS study

The optimal management of relapsed diffuse large B‐cell lymphoma (DLBCL) is not standardized. The Groupe Ouest Est des Leucémies et aAutres Maladies du Sang developed a combination of vinorelbine, ifosfamide, mitoxantrone and prednisone (NIMP) for the treatment of relapsed DLBCL, and assessed its efficacy and safety in association with rituximab (R). This multicentric phase II study included 50 patients with DLBCL in first relapse, aged 18–75 years. Patients received rituximab 375 mg/m² day 1, ifosfamide 1000 mg/m² days 1–5, vinorelbine 25 mg/m² days 1 and 15, mitoxantrone 10 mg/m² day 1, and prednisone 1 mg/kg days 1–5, every 28 days for three cycles. Responding patients underwent autologous transplantation or received three additional R‐NIMP cycles. All patients were evaluable for toxicity and 49 for response. Centralized pathology review confirmed DLBCL in all cases. Toxicities were mainly haematological with infectious events needing hospitalization in nine cases. Two toxic deaths were observed. After three cycles, 22 patients (44%) achieved complete response/unconfirmed complete response, 11 achieved partial response (24%), 2 had stable disease and 13 progressed. The non‐germinal centre B immunophenotype was associated with shorter progression‐free survival. in conclusion, the R‐NIMP regimen displayed significant activity in relapsed DLBCL, with acceptable toxicity and should be considered a candidate for combination with new agents.

Two New α-Thalassemia Point Mutations that are Undetectable by Biochemical Techniques

We report two new point mutations causing α-thalassemia (α-thal) that could not be characterized by conventional biochemical studies. The first mutation is a single base substitution at codon 123 of the α1-globin gene [α123(H6)Ala→Pro, GCC>CCC (α1)] and leads to the substitution of a proline residue in the H helix. The resulting unstable hemoglobin (Hb) variant has been named Hb Voreppe. The second is a frameshift of the α2 gene due to a deletion (−C), either of the third base of codon 112 or of the first base of codon 113, that causes a premature stop codon at position 132.

Érythropoïétine (EPO) et anémie en soins palliatifs chez le patient atteint de cancer

Resume Au cours des affections cancereuses, qu’il s’agisse de tumeurs solides ou d’hemopathies malignes, l’apparition d’une anemie est retrouvee chez un a deux tiers des patients. En phase palliative, l’incidence de l’anemie encore plus importante est souvent meconnue, negligee ou insuffisamment prise en charge alors qu’il existe un lien certain entre le taux d’hemoglobine et la qualite de vie du patient. Le cout juge eleve des erythropoietines (EPO) a longtemps ete mis en avant pour ne recourir qu’aux transfusions lorsqu’il n’y a plus de traitement etiologique possible de cette anemie. Cependant, les EPO se revelent etre davantage « cout-efficaces » comparativement aux transfusions. Il faut tenir compte du maintien plus stable dans le temps du resultat du traitement par EPO, du benefice superieur en termes de qualite de vie et de la reduction du recours aux transfusions. Ainsi, les recommandations internationales preconisent, en cas d’anemie en rapport avec un cancer chez des patients qui ne recoivent ni chimiotherapie ni radiotherapie, le traitement par une EPO a un seuil d’hemoglobine de 9-11 g/dl. En soins palliatifs, le probleme est d’evaluer la qualite de vie des patients en faisant la part de ce qui revient a l’anemie et aux autres facteurs d’inconfort et surtout, de pouvoir evaluer l’esperance de vie du patient afin de savoir s’il aura le temps de beneficier de ce traitement. En pratique, une esperance de vie de 3 mois ou plus et une alteration de la qualite de vie nous paraissent etre les criteres de depart pour l’utilisation d’une EPO dans ce contexte.

Multifocal polyclonal Epstein-Barr virus-associated B-cell lymphoproliferative disorder secondary to azathioprine therapy successfully treated with rituximab.

We describe the case of a woman with Crohn disease treated with azathioprine (AZA) who developed a multisystemic Epstein–Barr virus (EBV)-related polyclonal B-cell lymphoproliferative disorder. A 34-year-old woman was referred to our institution because of fever, dyspnea, and soft subcutaneous forehead swelling. She had been treated with AZA (175 mg/day) for 5 years for Crohn disease (diagnosed at the age of 10). Chest X-ray and computed tomography (CT) scan (Figure 1) demonstrated multiple, bilateral nodular condensations surrounded by areas of ground-glass opacity. The nodules ranged from 1 to 10 cm in diameter. A 2-cm hypodense mass was also found in the left kidney. Head CT scan showed a subcutaneous infiltration of the left part of the forehead without bone involvement. Blood cell count showed a mild lymphopenia. We performed a CT-guided transthoracic biopsy of one of the lung nodules and a surgical biopsy of the forehead infiltration. Pathologic examination of both samples revealed diffuse polymorphic lymphoid proliferation with angiocentric features and large areas of coagulative necrosis. The infiltrate consisted of numerous small CD3þT-cells and a minor population of large CD20þ, CD79aþ immunoblast-like B-cells preferentially located at the periphery of vascular structures. These atypical B-cells were IRF4/MUM1 positive and showed a high Ki67/MIB-1 proliferative index. In situ hybridization with EBER (EBV-encoded RNA) probes demonstrated EBV infection in the majority of B-cells. Immunohistochemistry revealed a latency III profile, and these cells expressed LMP1 and EBNA2 antigens. Molecular analysis of immunoglobulin heavy chain and T-cell receptor-gamma chain gene rearrangements did not reveal any clonal populations. The patient was seropositive for past EBV infection (no anti-VCA IgM); plasma viral load was 11 650 (4.07 log) copies/mL. The patient was diagnosed with iatrogenic polyclonal EBV-positive B-cell lymphoproliferative disorder close to a grade 2 lymphomatoid granulomatosis (LYG). Steroids (prednisolone 1 mg/kg/day) were given first because of the intense fever and other general symptoms, and AZA was discontinued. By analogy with the treatment of CD20 positive EBV-related post-transplantation disorders, 375 mg/m body surface area of the anti-CD20 chimeric monoclonal antibody rituximab was administered intravenously once weekly for 4 weeks. A dramatic reduction in the lung masses was observed. The EBV genome was not detectable in the plasma after the fourth dose. Six months later, the patient was asymptomatic with unchanged residual pulmonary nodules. EBV predominantly infects epithelial cells and B-lymphocytes. EBV infection of B-lymphocytes is associated with a potent activation and proliferation process, ending only when a cytotoxic T-lymphocyte