[Show abstract][Hide abstract] ABSTRACT: Invasive aspergillosis is a devastating infection with attributable mortality of 40% despite antifungal therapy. In animal models of aspergillosis, deficiency of mannose-binding lectin (MBL), a pattern recognition receptor that activates complement, is a susceptibility factor. MBL deficiency occurs in 20%-30% of the population. We hypothesized that MBL deficiency may be a susceptibility factor for invasive aspergillosis in humans.
Serum MBL concentrations were measured by enzyme-linked immunosorbent assay in 65 patients with proven or probable acute invasive aspergillosis and 78 febrile immunocompromised control subjects. MBL concentrations and the frequency of MBL deficiency were compared.
The median serum MBL level was significantly lower in patients with aspergillosis than in control subjects (281 ng/mL vs 835 ng/mL; P = .007). MBL deficiency (MBL concentration, <500 ng/mL) was significantly more common in patients with aspergillosis than control subjects (62% vs 32%; P < .001). Frequency of MBL deficiency was similar among patients with aspergillosis irrespective of response to antifungal therapy (P = .10).
This study is the first, to our knowledge, to show an association between MBL deficiency and acute invasive aspergillosis in humans. Further study is required to investigate the causal nature of this association and to define whether diagnosis of MBL deficiency may identify immunocompromised patients at increased risk of invasive aspergillosis.
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of mature B-cell neoplasms (MBCN) remains difficult in a number of cases, especially leukemic phases of non-Hodgkin lymphoma, for which discriminating criteria or biomarker are often lacking. To identify new surface biomarkers, we developed an original proteomic approach based on mass spectrometry analysis of plasma membrane microparticles derived from chronic B-cell lymphoproliferations of single patients: chronic lymphocytic leukemia (CLL), small cell lymphoma (SLL) and mantle cell lymphoma (MCL). A straightforward selection process for proteomic-based candidate biomarker identification was further constructed in order to propose potentially useful and relevant biomarkers. Comparison of the lists of the proteins identified in each pathology combined to highly stringent MS validation criteria for protein identification allowed to propose CD148, a membrane receptor with phosphatase activity, as a discriminating biomarker candidate. Flow cytometry analyses, performed on 158 patients and 30 controls, showed that an anti-CD148 antibody stained significantly higher MCL than CLL and SLL circulating cells (p<0.0001), which validates CD148 overexpression in MCL. Our results indicate that a medium or high CD148 expression level may exclude the diagnosis of CLL and high CD148 expression levels (CD148 MFI equal or superior to 2 times the value obtained with CLL/SLL) allows MCL diagnosis to be suspected with 91% specificity (versus CLL and SLL) and 78% sensitivity. This study is one of the first where proteomic strategies allowed to identify a potentially useful biomarker.
Journal of Proteome Research 09/2009; · 5.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease.
In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.
Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.
Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
Journal of Clinical Oncology 09/2009; 27(23):3822-9. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CASE DESCRIPTION: A French Caucasian man aged 39 with HIV infection was treated with abacavir/lamivudine and ritonavir/lopinavir. The patient (normal renal and liver functions) was diagnosed with a Burkitt lymphoma for which he was treated with cyclophosphamide day 1 to 5; doxorubicin day 1; methotrexate day 10; and vincristine day 1 and 8. At day 12, he suffered from abdominal pain associated with constipation. Paralytic ileus was diagnosed by study imaging. Ileus lasted 10 days necessitating parenteral feeding. Later on, a further cycle of chemotherapy with etoposide replacing vincristine was given and was well tolerated. CONCLUSION: We speculate that an interaction between ritonavir/lopinavir and vincristine was responsible for this severe toxicity. Vincristine is transported by P-gp and is metabolized via CYP3A5. Ritonavir is a potent CYP3A5 isoenzyme and P-gp inhibitor. Lopinavir is also a P-gp inhibitor. Ritonavir and lopinavir might have delayed vincristine elimination. Clinicians should be aware of this possible interaction.
International Journal of Clinical Pharmacy 09/2009; 31(6):619-21. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The exact timing of the evolution of lesion volumes of invasive pulmonary aspergillosis (IPA) on CT scan images could be helpful in the management of hematological patients but has never been evaluated in a prospective study. We analyzed the CT scan data from the prospective Combistrat trial.
Volumes of aspergillosis lesions from 30 patients (including 24 acute myeloid leukaemia) with probable (n=26) or proven (n=4) IPA according to the EORTC-MSG modified criteria, were measured prospectively on the thoracic CT scans at the enrolment in the study on day 0 (D0), D7, D14 and end of treatment (EOT).
For the overall population, the volume of pulmonary aspergillosis lesions increased significantly from D0 to D7 (1.6 fold; p=0.003). Then this volume decreased significantly from D7 to D14 (1.36 fold at D14 with p=0.003 for D14 vs. D7, but with p=0.56 for D14 vs. D0). At EOT (= D17, median value), the volume of lesions was significantly lower than D14 (0.76 fold the initial volume; p<0.001) but it was not significantly different when compared to D0 (p=0.11).
The results of this prospective study suggest that the sequential analysis of CT scan in neutropenic patients with IPA depicts more precisely the evolution of lesion volumes than comparison to baseline images. Moreover, the systematic use of chest CT appears to be a useful tool for diagnosis and outcome evaluation of IPA in clinical trials.
European journal of radiology 08/2009; 74(3):e172-5. · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE) with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT.
Four hundred and seventy-six patients <60 years old with newly diagnosed CD20+ DLBCL were randomised to induction with ACE or ACVBP. Three hundred and thirty responders received HDT followed by ASCT. After ASCT, 269 patients were re-randomised to receive either maintenance rituximab or observation alone. Randomisation was stratified by the quality of response to ASCT. The primary end point of this study was event-free survival (EFS).
At a median of 4 years' follow-up from the second randomisation, there was a trend (P = 0.1) towards increased EFS for patients who received rituximab compared with observation.
The type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months' follow-up.
Annals of Oncology 07/2009; 20(12):1985-92. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.
Current Drug Metabolism 06/2009; 10(4):395-409. · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen.
Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy.
A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, -4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, -5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups.
Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day.
[Show abstract][Hide abstract] ABSTRACT: Invasive aspergillosis is associated with high death rates. Factors associated with increased mortality have not yet been identified in a large population of patients with various underlying conditions.
We retrospectively reviewed 385 cases of suspected or documented aspergillosis that occurred during a 9-year period. We identified 289 episodes that fulfilled the criteria for possible, probable, or proven invasive aspergillosis according to the international definition criteria and that was treated with an anti-Aspergillus active antifungal drug. Clinical and microbiological variables were analyzed for their effects on overall and attributable mortality. Significant variables in univariate analysis were introduced into a multivariate Cox model.
Twelve-week overall and disease-specific survival rates were 52.2% (95% confidence interval, 46.5%-57.9%) and 59.8% (95% confidence interval, 54.0%-65.4%), respectively. Receipt of allogeneic hematopoietic stem cell or solid-organ transplant, progression of underlying malignancy, prior respiratory disease, receipt of corticosteroid therapy, renal impairment, low monocyte counts, disseminated aspergillosis, diffuse pulmonary lesions, pleural effusion, and proven or probable (as opposed to possible) aspergillosis are predictors of increased overall mortality. Similar factors are also predictors of increased attributable mortality, with the following exceptions: pleural effusion and low monocyte counts have no impact, whereas neutropenia is associated with a higher attributable mortality.
Identification of predictors of death helps in the identification of patients who could benefit from more-aggressive therapeutic strategies. Initiation of therapy at the stage of possible infection improves outcome, and this finding calls for the development of efficient preemptive strategies to fill the gap between empirical and directed therapy.
[Show abstract][Hide abstract] ABSTRACT: Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.
[Show abstract][Hide abstract] ABSTRACT: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies.
After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved.
The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only.
These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
[Show abstract][Hide abstract] ABSTRACT: Assessment of response to invasive aspergillosis (IA) therapy has been challenging in treatment trials.
The causes of death over 12 weeks were categorized prospectively by a blinded data review committee using a priori defined criteria in participants in a randomized comparative trial of voriconazole versus amphotericin B as first-line therapy of proven or probable IA.
Death occurred in 98 of 277 patients during the 12-week course of study. Seventy-three of the 98 deaths (74%) occurred in the first 6 weeks; 25 deaths occurred during the second 6 weeks. Of the 73 deaths during the first 6 weeks, 50 (68%) were judged to be attributable to IA. Of the 25 deaths during the second 6 weeks, only 6 (24%) were judged to be attributable to IA. Fifty of the 56 deaths (89%) attributable to IA occurred during the first 6 weeks.
These data suggest that most deaths due to IA occur during the first 6 weeks after the start of therapy and 6 weeks may be a better interval to judge the effectiveness of antifungal therapy because most deaths after 6 weeks are due to causes related to the underlying disease and its treatment rather than due to IA. Attributable mortality when assessed using a priori definitions and conducted in a blinded manner by a central data review committee can be useful in the assessment of IA therapy.
Cancer 06/2008; 112(10):2309-12. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polycythemia vera (PV) is a clonal stem cell disorder characterized by an excessive erythrocyte production. At diagnosis, a normal karyotype is found in < or =80% of cases, but an abnormal karyotype frequently develops with evolution. Trisomy 9 and gains on 9p are some of the most frequent cytogenetic abnormalities, together with trisomy 8 and del(20q) in both PV and idiopathic myelofibrosis. We report the case of a 54-year-old man whose disease was classified as an acute myeloid transformation of PV. Cytogenetic and multicolor fluorescence in situ hybridization (FISH) analysis detected several chromosomal abnormalities that included an amplification of 9p. Complementary FISH analysis established amplification of the 9p22 approximately p24.3 region including several known genes: MLLT3 (alias AF9), JMJD2C (alias GASC1), JAK2, and SMARCA2 (alias BRM). JAK2(V617F) mutation status was quantitatively assessed by allele-specific quantitative polymerase chain reaction. Although crossing points analysis showed JAK2(V617F) mutated alleles at 52%, it is still impossible to describe conclusively the mutational status of the amplified JAK2 gene within the sole homogeneously staining region, because total genomic DNA was extracted for the analysis and not only DNA from cells with the homogeneously staining region. Gains on 9p being among the most common anomalies in PV, amplification of a gene or genes on this region may play a crucial role in the pathogenesis or evolution of PV.
Cancer Genetics and Cytogenetics 02/2008; 180(1):51-5. · 1.93 Impact Factor