Pulmonary hypertension in patients with myeloproliferative neoplasms: A large cohort of 183 patients.

BACKGROUND: Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (pH). We ought to describe the prevalence and characteristics of PH in a cohort of MPN who were screened using transthoracic echocardiography (TTE). METHODS: One hundred eighty-three newly diagnosed consecutive MPN patients were prospectively evaluated using TTE to detect PH. RESULTS: Two patients were diagnosed with chronic eosinophilic leukemia, two patients had post-essential thrombocythemia (ET) myelofibrosis (MF), two patients had post-polycythemia vera (PV) MF, 11 patients had primary myelofibrosis (PMF), 28 patients had chronic myeloid leukemia (CML), 51 patients had PV, and 87 patients had ET. TTE was used to determine PH, and PH was suspected in 16 of 183 patients as follows: four with PV, seven with ET, two with PMF, and three with CML. Two patients with ET were excluded because of global cardiac failure. Three patients underwent right heart catheterization to confirm PH. The 14 (7.7%) patients with PH had no cardiac or lung disease that directly involved MPN in PH development. CONCLUSION: In this large cohort of 183 MPN patients, TTE was used to diagnose PH, and 14 patients (7.7%) developed PH. This prevalence was lower than expected based on previously reported data, but it remains higher than in the general population.

Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone.

OBJECTIVES: Recently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life. METHODS: We conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016. RESULTS: Forty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P < .01). Twenty-six (65%) patients experimented adverse events: 8 patients (20%) underwent 12 serious AE (≥grade 3). Treatment discontinuation occurred in 2 patients (5%) because of severe AE. CONCLUSION: To our knowledge, this work provides the first evidence of the efficacy and the safety of RVD combination in patients treated in common practice.

A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation.

Autologous hematopoietic stem cell transplantation is the standard treatment for multiple myeloma and relapsed or refractory lymphomas. After autologous hematopoietic stem cell transplantation, hematologic reconstitution and infectious complications are the two most critical issues. Although many patients develop infectious complications after therapeutic intensification, it remains impossible to predict infection for each individual. The goal of this work was to determine and identify a predictive transcriptomic signature of systemic inflammatory response syndrome and/or sepsis in patients receiving autologous hematopoietic stem cell transplantation. High-throughput transcriptomic and bioinformatics analysis were performed to analyze gene expression modulation in peripheral blood mononuclear cells in 21 patients undergoing autologous hematopoietic stem cell transplantation for hematological malignancies (lymphoma or multiple myeloma). Transcriptomic analysis of peripheral blood mononuclear cells samples collected just after conditioning regimen identified an 11-gene signature (CHAT, CNN3, ANKRD42, LOC100505725, EDAR, GPAT2, ENST00000390425, MTRM8, C6orf192, LOC10289230, and XLOC-005643) that was able to early predict (at least 2-7 days before its occurrence) the development of systemic inflammatory response syndrome or sepsis. The possibility of systemic inflammatory response syndrome or sepsis occurrence early prediction (2-7 days before occurrence) opens up new therapeutic strategies based on preemptive antibiotic and/or antifungal prophylaxis adapted to the specific risk profile of each patient.

Is R-CHOP Therapy a Lymphoma Growth Factor?

This article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 × 109/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow.

Yin and yang of cytidine deaminase roles in clinical response to azacitidine in the elderly: a pharmacogenetics tale.

Azacitidine is a mainstay for treating hematological disorders. Azacitidine is metabolized by cytidine deaminase, coded by a highly polymorphic gene. Here, we present two elderly patients with opposite clinical outcomes after azacitidine treatment. First, an acute myeloid leukemia patient showed life-threatening toxicities, but outstanding complete remission, after a single round of azacitidine. Further investigations showed that this patient was cytidine deaminase 79A>C (rs2072671) homozygous with a marked deficient phenotype. Next, a chronic myelomonocytic leukemia patient displayed complete lack of response despite several cycles of azacitidine. This patient had a rapid-deaminator phenotype linked to the -31delC deletion (rs3215400). These polymorphisms lead to opposite clinical outcomes in patients with myelodysplastic syndromes treated with azacitidine, thus suggesting that determining cytidine deaminase status could help to forecast clinical outcome.

Mixed Streptococcus pneumoniae and Streptococcus pyogenes meningitis in an immunocompromised adult patient: a case report.

INTRODUCTION: Community-acquired meningitis is a monomicrobial infection caused by either viruses or bacteria in the vast majority of patients. We report here one exceptional case of a patient with mixed bacterial meningitis due to Streptococcus pneumoniae and Streptococcus pyogenes. CASE PRESENTATION: We report the case of a 68-year-old immunocompromised Caucasian man suffering from otitis and then meningitis caused by Streptococcus pneumoniae and Streptococcus pyogenes. Bacteria were undistinguishable by direct microscopic examination of the cerebrospinal fluid. He responded well to treatment with cefotaxime and dexamethasone, with no sequelae observed at the 4-month follow-up. CONCLUSIONS: This first reported case of mixed S. pneumoniae and S. pyogenes meningitis illustrates the life-threatening consequences of barotrauma in immunocompromised patients suffering from otorhinolaryngeal infections.

Eradication of T315I mutation in chronic myeloid leukemia without third-generation tyrosine kinase inhibitor: a case report.

We report the case of a patient bearing a T315I-mutant chronic myeloid leukemia resistant to nilotinib, successfully treated with omacetaxine and then with dasatinib. After 9 months of nilotinib, the patient achieved a major molecular response but relapsed 3 months later due to the T315I mutation. Because third-generation tyrosine kinase inhibitor was not available and the patient refused bone marrow transplantation, he received two cycles of omacetaxine. This treatment had been stopped after two cycles because of clinical intolerance, but a major molecular response and total disappearance of the T315I clone was obtained. Treatment with dasatinib was then started and after 34-month follow-up the patient is still in major molecular response, thus suggesting that eradication of the T315I mutation could be achieved without third-generation tyrosine kinase inhibitors.

Lethal toxicity after administration of azacytidine: implication of the cytidine deaminase-deficiency syndrome.

Azacytidine, an antimetabolite with an original epigenetic mechanism of action, increases survival in patients diagnosed with high-risk myelodysplasic syndromes or acute myeloid leukemia with less than 30% medullar blasts. Azacytidine is a pyrimidine derivative that undergoes metabolic detoxification driven by cytidine deaminase (CDA), a liver enzyme whose gene is prone to genetic polymorphism, leading to erratic activity among patients. Clinical reports have shown that patients with the poor metabolizer (PM) phenotype are likely to experience early severe or lethal toxicities when treated with nucleosidic analogs such as gemcitabine or cytarabine. No clinical data have been available thus far on the relationships between CDA PM status and toxicities in azacytidine-treated patients. Here, we measured CDA activity in a case of severe toxicities with fatal outcome in a patient undergoing standard azacytidine treatment. Results showed that the patient was PM (i.e. residual activity reduced by 63%), thus suggesting that an impaired detoxification step could have given rise to the lethal toxicities observed. This case report calls for further prospective studies investigating the exact role that CDA status plays in the clinical outcome of patients treated with azacytidine.

100% human monoclonal antibodies in oncology: hype or breakthrough?

Targeted therapies have dramatically modified treatment strategies in oncology since the early 2000's, especially for treating digestive cancers. These new biotherapies such as anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) monoclonal antibodies have given oncologists new opportunities to use innovative treatment schedules or combinations with cytotoxics. Consequently, significant improvements in response rates, with trends to longer progression-free survival and/or overall survival have been achieved in patients with metastatic colorectal cancer (mCRC). Panitumumab is a novel, 100% human, anti-EGFR1 (HER1) antibody that has been approved in late 2007 for use as monotherapy in mCRC patients resistant to standard chemotherapy, provided that their tumor express EGFR and display wild-type K-Ras status. Panitumumab has been recently further approved in combination with chemotherapy in mCRC patients. However, owing to the fact that its mechanism of action for targeting EGFR is similar to that of chimeric cetuximab, picturing the specificities in pharmacological and pharmacokinetic properties of this 100% human antibody could help the oncologists to better define their strategies at the bedside.

Optimize administration protocol of capecitabine plus docetaxel combination in metastatic breast cancer patients.

Combining several cytotoxics is the current mainstay for treating breast cancer patients. The combination between capecitabine and docetaxel was found to be more efficient than capecitabine or docetaxel when both were used as single agents. However, the administration protocol for this combination has been empirically chosen from single-agent trials. Based on already available population analysis, we propose here to optimize the administration protocol of this association so as to enhance efficacy while limiting treatment-related toxicity. Efficacy parameters evaluated from population analysis using a disturbed tumor growth model and safety characteristics from the available databases evidenced that: 1) Docetaxel is more efficient than capecitabine at the start of the treatment, but becomes less efficient next because of acquisition of resistance; 2) Over a long period of time, capecitabine is better tolerated than docetaxel. These characteristics allowed the following recommendations for an optimized modality of combination: 1) The treatment has to be started at the maximum tolerated dose for docetaxel; this dose should be individualized right from the start of the second cycle of treatment; 2) In parallel, capecitabine has to be started at a dose lower than its maximum tolerated dose. 3) When docetaxel becomes less efficient than capecitabine because of resistance, docetaxel dose has to be reduced but not discontinued. 4) If adverse events show during the treatment, it is recommended to reduce docetaxel, rather than capecitabine dosage. Combining modeling and statistical analysis of clinical data permit to optimize combination treatments. This procedure could be extended to others treatments involving combination of several cytotoxics.

Physicochemical properties and cellular toxicity of (poly)aminoalkoxysilanes-functionalized ZnO quantum dots.

Luminescent ZnO nanocrystals were synthesized by basic hydrolysis of Zn(OAc)(2) in the presence of oleic acid and then functionalized with (poly)aminotrimethoxysilanes in the presence of tetramethylammonium hydroxide to render the QDs water-dispersible. The highest photoluminescence quantum yield (17%) was achieved using N(1)-(2-aminoethyl)-N(2)-[3-(trimethoxysilyl)propyl]-1,2-ethanediamine as surface ligand. Transmission electron microscopy and powder x-ray diffraction showed highly crystalline materials with a ZnO nanoparticle diameter of about 4 nm. The cytotoxicity of the different siloxane-capped ZnO QDs towards growing Escherichia coli bacterial cells was evaluated in MOPS-minimal medium. Although concentrations of 5 mM in QDs caused a complete growth arrest in E. coli, siloxane-capped ZnO QDs appeared weakly toxic at lower doses (0.5 or 1 mM). The concentration of bioavailable Zn (2+) ions leaked from ZnO QDs was evaluated using the biosensor bacteria Cupriavidus metallidurans AE1433. The results obtained clearly demonstrate that concentrations of bioavailable Zn(2+) are too low to explain the inhibitory effects of the ZnO QDs against bacteria cells at 1 mM and that the siloxane shell prevents ZnO QDs from dissolution contrary to uncapped ZnO nanoparticles. Because of their low cytotoxicity, good biocompatibility, low cost and large number of functional amine end groups, which makes them easy to tailor for end-user purposes, siloxane-capped ZnO QDs offer a high potential as fluorescent probes and as biosensors.

CDA deficiency as a possible culprit for life-threatening toxicities after cytarabine plus 6-mercaptopurine therapy: pharmacogenetic investigations.

We describe here the case of a 7-year old girl with lymphoma who developed life-threatening toxicities upon cytarabine plus mercaptopurine. Surprisingly, initial investigations on canonical thiopurine methyltransferase genetic polymorphism proved to be negative. We focused next on deregulations affecting the CDA gene implicated in the liver disposition of cytarabine. This patient was homozygous for both the 79A>C and the -31delC polymorphisms on the CDA gene and promoter, two genotypes with reported opposite effects on CDA phenotype. To determine the CDA status of this patient, additional functional testing was performed and eventually demonstrated that this patient was a poor metabolizer. This case demonstrates that besides affecting thiopurine methyltransferase, dysregulations with CDA should be screened to anticipate toxicities with the cytarabine plus mercaptopurine combination.

5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases.

PURPOSE: 5-Fluorouracil (5-FU) is a mainstay for treating various solid tumours in adults, including digestive and head and neck cancers. 5-FU-related toxicities usually include haematological, digestive and cutaneous features. Additionally, 5-FU has been described as being potentially neurotoxic in patients, but these side effects are quite rare in clinical practice. Here, we report two cases of sudden and unpredictable drug-induced neurotoxicities that occurred in patients undergoing their first course of 5-FU-based chemotherapy. PATIENTS AND METHODS: None of these patients had any previous neurological disorder history, and both were treated following standard regimen (LV-5-FU2 and TPF for patient 1 and 2, respectively). Neurotoxicity included drowsiness, acute confusion plus dysarthria for the first patient and seizure, confusion and signs of metabolic encephalopathy for the second one. In addition, typical 5-FU-related severe toxicities (e.g. neutropenia and mucosities) were observed. Both patients slowly recovered from these neurological toxicities under supportive treatment. It was assumed that overexposure to 5-FU could explain the severe toxicities encountered. To test this hypothesis, we retrospectively evaluated the dihydropyrimidine dehydrogenase (DPD) activity of these patients on a phenotypic basis. RESULTS: Evaluation of the uracil-to-di-hydrouracil (U/UH2) ratio in plasma revealed a profound DPD deficiency syndrome in both patients. CONCLUSION: These cases suggest that 5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features. It implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of DPD deficiency before starting any 5-FU-containing chemotherapy so as to prevent such side effects in the future.

Integrating pharmacogenetics into gemcitabine dosing--time for a change?

Increasing the efficacy of anticancer agents and avoiding toxic effects is a critical issue in clinical oncology. Identifying biomarkers that predict clinical outcome would ensure improved patient care. Gemcitabine is widely used to treat various solid tumors as a single agent or in combination with other drugs. The therapeutic index of gemcitabine is narrow, and abnormal pharmacokinetics leading to changes in plasma exposure is a major cause of adverse effects. A number of biomarkers have been proposed to predict efficacy of gemcitabine, focusing on molecular determinants of response identified at the tumor level. Genetic and functional deregulations that affect the disposition of a drug could be the reason for life-threatening adverse effects or treatment failure. In particular, deregulation of cytidine deaminase, the enzyme responsible for detoxification of most nucleotide analogs, should be examined. Identifying and validating biomarkers for pharmacogenetic testing before administration of gemcitabine is a step towards personalized medicine.

DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.

BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 ± 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 ± 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.