Incidence of heart failure following exposure to a protein kinase inhibitor, a French population-based study.

AIMS: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF. METHODS: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias. RESULTS: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis. CONCLUSIONS: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.

Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: A French population-based study on prostate cancer patients.

AIMS: Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. METHOD: Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. RESULTS: Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. CONCLUSION: Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.

Impact of the treatment of chronic myeloid leukaemia by tyrosine-kinase inhibitors on sick leaves refund: a nationwide cohort study.

BACKGROUND: The advent of chronic myeloid leukaemia (CML) tyrosine-kinase inhibitors (TKI) has led to new paradigms including occupational rehabilitation. OBJECTIVES: This study aimed to characterize the impact of CML treatment on sick leaves within the 2 years following diagnosis in working-age patients. METHODS: A cohort of all 18-60-year-old newly diagnosed CML patients initiating a TKI between January 1st 2011 and December 31st 2014 in France was identified in the French National Healthcare database (Système National des Données de Santé [SNDS]). Patients with a sick leave identified in the 24 months after TKI initiation were compared with sex and initiation date matched controls in a nested case-control design. Factors associated with sick leaves were identified through a conditional logistic regression model, providing adjusted odds-ratio (OR) with their 95% confidence interval (CI). RESULTS: Among 646 18-60-year-old patients, 268 were prescribed at least one sick leave in the study period, with 176 (27.2%) having their first sick leave prescribed after TKI initiation. The median number of sick days over the 2-years period was 115 per patient (interquartile range 25.5-384.5). In the nested case-control study (176 cases and 176 matched controls), sick leaves were more likely observed with second generation TKI (OR 4.11 [1.80-9.38]), whereas they were less likely observed in case if social deprivation (OR 0.07 [0.02-0.28]. CONCLUSION: More than 25% of working-age CML patients had at least one sick leave within 2 years of TKI initiation, with a higher impact of second generation TKI, and with a median duration of 115 days.

Lenalidomide-induced arthritis: A case report and review of literature and pharmacovigilance databases.

INTRODUCTION: Lenalidomide is an immunomodulatory agent with multiple mechanisms of action, and treatment with lenalidomide is associated with adverse events such as thrombosis and abdominal pain; nonetheless, other rarer adverse events do exist, with few knowledge from physicians and pharmacists. For such adverse events, pharmacovigilance databases are of great interest. CASE REPORT: A 71-year-old patient with no rheumatologic history, in complete remission of a mantle-cell lymphoma following rituximab, doxorubicin, vincristine, cyclophosphamide, and prednisone induction, received a maintenance treatment with rituximab and lenalidomide. After each course of lenalidomide and with no other new medication, the patient presented with fever and high inflammatory markers level, and a scapular-belt arthritis. MANAGEMENT AND OUTCOME: The patient was managed with non-steroidal anti-inflammatory drugs and colchicine, with symptomatology and inflammation improvement. After discontinuation of lenalidomide, he had no arthritis relapse; it was then concluded that the patient had a lenalidomide-induced arthritis. We interrogated the national and international (VigiBase®) pharmacovigilance databases and found that arthritis in the context of lenalidomide exposure is a rare finding, with only three reported cases in France; 0.13% of adverse events reported with lenalidomide in the international database VigiBase® were arthritis. DISCUSSION: Our case then reports an uncommon finding, of which both pharmacists and physicians should be aware due to the wide and increasing use of lenalidomide.

The pharmacology of blinatumomab: state of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Bispecific drugs (BDs) belong to the family of immunotherapies along with checkpoint inhibitors and CAR-T cells. In the field of oncology, BDs are designed to simultaneously bind a tumour antigen on the one side and an antigen present on the surface of effector cells on the other. This review summarizes the information available to date on the first marketed BiTE-format bispecific antibody, blinatumomab BLINCYTO® in acute lymphoblastic leukaemia. METHODS: A literature search was conducted in the PubMed database by including studies published in English using the term blinatumomab. Furthermore, bibliographies of selected references were also evaluated for relevant articles. Clinical trial (CT) data were retrieved from clinicaltrials.gov (ongoing trials, adverse events [AEs]) and global pharmacovigilance data were retrieved from VigiBase®. RESULTS AND DISCUSSION: Blinatumomab is a fusion protein which consists of two single-chain variable fragments arranged in tandem: the first binds the CD19 surface antigen of all B cells and the second targets the CD3 antigen of T cells. Binding of blinatumomab to B and T cells induces apoptosis of B cells after secretion of granzymes and perforins by T cells. T-cell activation results in secretion of pro-inflammatory cytokines and upregulation of activation markers and adhesion molecules on the surface of T cells. The major CTs that led to an indication show increased overall survival with blinatumomab with better efficacy in patients in haematological remission with minimal residual disease ≥10-3 . The major AEs are cytokine release syndrome, neurotoxicity and hypogammaglobulinemia. The three most frequent system organ classes in CTs are haematological, gastrointestinal and general disorders. These results are also found in VigiBase® but neurological disorders and infections appear more frequently in real life. WHAT IS NEW AND CONCLUSION: This review summarizes the current knowledge of blinatumomab in the literature. The subject of many CTs is to improve the route of administration and expand the indications for treatment.

Overall Survival Among Chemotherapy-Naive Patients With Castration-Resistant Prostate Cancer Under Abiraterone Versus Enzalutamide: A Direct Comparison Based on a 2014-2018 French Population Study (the SPEAR Cohort).

Abiraterone acetate (ABI) and enzalutamide (ENZ) are considered to be clinically relevant comparators among chemotherapy-naive patients with castration-resistant prostate cancer. No clinical trials comparing overall survival with ABI versus ENZ in a head-to-head approach have been published so far. A few observational studies with low power suggested a potential benefit of ENZ. We used the French National Health Data System to compare overall survival of new users of ABI and ENZ among chemotherapy-naive patients with castration-resistant prostate cancer in 2014-2017, followed through 2018 (the SPEAR cohort, a 2014-2018 cohort study). With an intent-to-treat approach, a survival analysis was performed, estimating hazard ratios for overall survival with the inverse probability weighted Cox model method. Among 10,308 new users, 64% were treated with ABI and 36% with ENZ. The crude mortality rate was 25.2 per 100 person-years (95% confidence interval (CI): 24.4, 26.0) for ABI and 23.7 per 100 person-years (95% CI: 22.6, 24.9) for ENZ. In the weighted analysis, ENZ was associated with better overall survival compared with ABI (hazard ratio = 0.90 (95% CI: 0.85, 0.96) with a median overall survival of 31.7 months for ABI and 34.2 months for ENZ). When restricting to 2015-2017 new users, the effect estimate shifted up to a hazard ratio of 0.93 (95% CI: 0.86, 1.01).

Small Private Online Course in Teaching Oncology-Feedback After 1 Year: What Lessons?

In response to the complexity of medical care in oncology, 2 years ago, we designed a new teaching method (SPOC, Small Private Online Course) to improve cancer treatment and its management by emphasizing the community-hospital interface. The educational objective of this study was to evaluate after 1 year if the interest for this teaching remained constant over the long term to meet both educational and financial requirements. We designed a questionnaire including 18 questions grouped in 3 main parts describing the profile of the participants, his/her own experience, and the current utilization of the SPOC. Of 1574 participants of the 2 first sessions, 182 (11.5%) completed the questionnaire after 1 year. The majority of respondents were between the ages of 31 and 60 and belonged to a paramedical group (47.81%). After 1 year, 84.6% participants were satisfied or very satisfied with the content of the SPOC, 83.6% would recommended it, and 67% would be interested in using an updated SPOC again. Only 4.9% kept some contacts with other participants and 4.9% with teachers. 31.3% considered that the SPOC had a medium impact on their professional activity, 33.5% a lot, and 2.7% completely whereas 24.7% considered that it had little impact. The evaluation at 1 year showed that this digital learning method had a global positive impact on the professional practice of the participants. This study highlighted the empowerment of participants after this kind of teaching, but the network between participants was not enhanced.

Abatacept in rheumatoid arthritis and the risk of cancer: a world observational post-marketing study.

OBJECTIVES: We aimed to investigate whether abatacept used in patients for RA was associated with an increased risk of reporting overall cancer and specific cancers, including breast, lung, lymphoma, melanoma and non-melanoma skin cancer when compared with other biologic DMARDs (bDMARDs). METHODS: We performed an observational study within VigiBase, the World Health Organization's global database of individual case safety reports, from 2007 to 2017 to compare the cases of cancer reported in RA patients exposed to abatacept with those reported in RA patients exposed to other bDMARDs. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CIs of the exposure odds among spontaneous reporting of cancers to the exposure odds among other reported adverse effects. RESULTS: We identified 15 846 adverse effects reported in RA patients who received abatacept and 290 568 adverse effects reported in RA patients treated with other bDMARDs. Compared with other bDMARDs, the use of abatacept was not associated with an increased risk of reporting cancer overall [ROR 0.98 (95% CI 0.91, 1.05)]. Analyses by specific cancer sites showed a significantly increased ROR for melanoma [1.58 (95% CI 1.17, 2.08)], but not for other specific cancer sites. CONCLUSION: Compared with other bDMARDs, exposure to abatacept in RA patients was only significantly associated with an increased risk of reporting melanoma. This increased risk is consistent with the properties of abatacept (CTLA-4 agonist) since it has an opposite action than ipilimumab, an antibody that blocks CTLA-4 and is approved for the treatment of malignant melanoma. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT03980639.

Work adjustments and employment among breast cancer survivors: a French prospective study.

PURPOSE: The objective of our study was to assess the rate of work adjustments 1 year after the diagnosis in a population of female breast cancer (BC) survivors, in the context of the French system of social protection. We also characterised these adjustments and their influence on the reduction of professional exclusion of patients 1 year after the diagnosis. METHODS: This observational, prospective study was conducted from February 2015 to April 2016 among female patients with BC. Inclusion criteria were women aged between 18 and 65 years, treated for BC and integrated into the labour market at the time of diagnosis (working or on sick leave). Exclusion criteria were metastatic BC, retired patients and refusal to participate. A 1-year follow-up was scheduled, and data collection was performed with questionnaires. RESULTS: In total, 213 patients were included between February 2015 and April 2016. One year after the diagnosis (T1), among 185 BC survivors, 78 (42.2%) patients were working. Among them, 13 patients did not interrupt their occupational activity and 65 returned to work after a period of sick leave. Sixty-four patients returned to work after the end of chemotherapy (after 6 months), and one returned to work before this therapeutic threshold. Sixty-six patients (35.7%) benefited from at least one adjustment of their work conditions to facilitate their return to work (RTW) or maintenance at work: working hours were decreased for 43 patients, and workstation changes were performed for 22 patients. An occupational health physician was involved for some patients; work adjustments were prescribed to 42 patients, 7 patients had medical restrictions for physical reasons and 4 patients had restrictions for psychological reasons. Forty-three patients benefited from part-time work prescribed for therapeutic reasons. CONCLUSIONS: Referral to occupational health physicians and work adjustments remain limited in the process of RTW or maintenance at work after BC in France, despite their positive impact.

Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance-pharmacodynamic study.

The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies.

Sustained degradation of quality of life in a subgroup of lymphoma survivors: a two-year prospective survey.

BACKGROUND: Previous studies have suggested that lymphoma survivors commonly display altered Health-Related Quality of Life (HRQoL). Because these were predominantly cross-sectional studies, the dynamic of events as well as the factors which influence HRQoL remain to be determined. METHODS: We conducted a prospective study on a cohort of 204 Hodgkin and non-Hodgkin lymphoma survivors who remained disease-free 2 years after undergoing chemotherapy (referred to the M0-M12-M24 periods). RESULTS: We found that although Physical and Mental Component Scores (PCS and MCS) of HRQoL significantly improved from M0 to M24 in the vast majority of patients (favorable group), approximately 20% of patients displayed severe alterations in HRQoL (global SF-36 scores < 50) extending over the 2-year period (unfavorable group). Low M24 PCSs were associated with Post-Traumatic Stress Disorder (PTSD), depression, cardiovascular events and neuropathy. In contrast social determinants, comorbidity and infections, as well as several other parameters related to the disease or to the treatment itself were not associated with low M24 PCSs. Low M24 MCSs were associated with a low educational level, aggressive histology, infections, cardiovascular events and PTSS. However, the most predictive risk factor for low SF-36 scores at M24 was a low SF-36 score at M12. The unfavorable group also displayed a low incidence of return to work. CONCLUSIONS: Although the HRQoL of lymphoma survivors generally improved over time, persistent and severe HRQoL alterations still affected approximately one fifth of patients, resulting in important social consequences. This specific group, which presents with identifiable risk factors, may benefit from early, targeted psycho-social support.

Are social inequalities in acute myeloid leukemia survival explained by differences in treatment utilization? Results from a French longitudinal observational study among older patients.

BACKGROUND: Evidences support social inequalities in cancer survival. Studies on hematological malignancies, and more specifically Acute Myeloid Leukemia (AML), are sparser. Our study assessed: 1/ the influence of patients' socioeconomic position on survival, 2/ the role of treatment in this relationship, and 3/ the influence of patients' socioeconomic position on treatment utilization. METHODS: This prospective multicenter study includes all patients aged 60 and older, newly diagnosed with AML, excluding promyelocytic subtypes, between 1st January 2009 to 31st December 2014 in the South-West of France. Data came from medical files. Patients' socioeconomic position was measured by an ecological deprivation index, the European Deprivation Index. We studied first, patients' socioeconomic position influence on overall survival (n = 592), second, on the use of intensive chemotherapy (n = 592), and third, on the use of low intensive treatment versus best supportive care among patients judged unfit for intensive chemotherapy (n = 405). RESULTS: We found an influence of patients' socioeconomic position on survival (highest versus lowest position HRQ5: 1.39 [1.05;1.87] that was downsized to become no more significant after adjustment for AML ontogeny (HRQ5: 1.31[0.97;1.76] and cytogenetic prognosis HRQ5: 1.30[0.97;1.75]). The treatment was strongly associated with survival. A lower proportion of intensive chemotherapy was observed among patients with lowest socioeconomic position (ORQ5: 0.41[0.19;0.90]) which did not persist after adjustment for AML ontogeny (ORQ5: 0.59[0.25;1.40]). No such influence of patients' socioeconomic position was found on the treatment allocation among patients judged unfit for intensive chemotherapy. CONCLUSIONS: Finally, these results suggest an indirect influence of patients' socioeconomic position on survival through AML initial presentation.

Oncology nurse phone calls halve the risk of reduced dose intensity of immunochemotherapy: results of the randomized FORTIS study in chronic lymphocytic leukemia.

Delivering of > 80% planned relative dose intensity (RDI) of fludarabine-cyclophosphamide-rituximab (FCR) is key to benefit from longer progression free survival (PFS) and survivals in CLL. In this randomized trial, we sought to investigate whether a telephone intervention strategy (called AMA) delivered by an oncology nurse could reduce the risk of RDI < 80% by alleviating adverse events and supporting patients' adherence. Sixty FCR patients were randomized 1:1 for AMA (stratified on Binet stage C). As per guidelines, patients received pegfilgrastim as primary prophylaxis of febrile neutropenia. At the end of therapy, RDI < 80% was reported in 31% of patients, shortening PFS (median 26 months versus not reached, P = 0.021) and OS at 3 years (100 vs 70%, P = 0.0089). Oncology nurse interventions tended to significantly reduce this event (RDI < 80%: 41.4% in non-AMA versus 20.7% in AMA patients (p = 0.09)). By adjusting our logistic regression model on published parameters exposing to RDI < 80%, we found that AMA protected significantly against the risk of reduced RDI (OR = 0.22, IC95% 0.05-0.84, p = 0.04), independently of grade 3/4 neutropenia (< 15% per cycle) and febrile neutropenia (< 5% per cycle) events. As a conclusion, we confirmed that > 20% reduction of FCR dose-intensity was detrimental for PFS/OS, but that oncology nurse interventions reduced the risk of dose concessions.

The impact of chronic myeloid leukemia on employment: the French prospective study.

Patients with chronic myeloid leukemia treated with breakpoint cluster region-Abelson tyrosine kinase inhibitors are likely to survive in excess of 20 years after diagnosis. New challenges appear as we consider life after the disease, including professional challenges and the social reintegration of patients. The purpose of this study was to determine the impact of chronic myeloid leukemia on employment within 2 years after diagnosis. This prospective, observational study included patients diagnosed with chronic myeloid leukemia and treated with a tyrosine kinase inhibitor. Two populations were defined as patients who reported modifications in their professional activity during the study (Acti-Pro+) and patients who did not report a modification (Acti-Pro-). Cancer survivors received a self-assessment questionnaire. The primary endpoint was to determine the professional status of patients. One hundred patients completed the questionnaire. Sixty-six patients out of 100 reported professional activity within 2 years after their diagnosis. During the 2 years after the diagnosis, 65.2% (95% confidence interval (CI), 53.7-76.7) of patients faced modifications in their professional activity due to chronic myeloid leukemia or adverse effects of drug treatments (group Acti-Pro+); in contrast, 34.8% of patients did not report any impact on their occupational activity (group Acti-Pro-). Among modifications to work organization, a change in the number of working hours was the most represented. Other modifications comprised changes in status or work pace. A majority of chronic myeloid leukemia patients face professional consequences of their disease and treatments. Our findings suggest that adverse drug reactions are a major factor affecting the occurrence of work modifications in this context.

Pleural adverse drugs reactions and protein kinase inhibitors: Identification of suspicious targets by disproportionality analysis from VigiBase.

AIMS: To evaluate the risk of pleural disorders (PD) associated with 33 protein kinase (PK) inhibitors (PKIs) through a disproportionality analysis and to identify which PKs and pathways are involved in PKI-induced PD. METHODS: To evaluate the risk of PD, reporting odds ratios (RORs) were calculated for 33 PKIs through data registered in the World Health Organization safety report database (VigiBase). We undertook a literature review to identify PKs that were possibly involved in PD caused by PKIs. Pearson correlation coefficients (r) between RORs and affinity data of 19 PKIs were calculated to identify the cellular target most likely to be involved in PKI-induced PD. RESULTS: A total of 235 110 individual case safety reports were extracted from the database for 33 available PKIs. Among these reports, 5001 concerned PD (2.1%). Significant and positive disproportionality for PD was found for 29 of 33 PKI included in our study with top values for dasatinib [ROR = 115.3; 95% confidence interval (CI): 110.1-120.8], bosutinib (ROR = 20.4; 95% CI: 15.8-26.4) and ponatinib (ROR = 12; 95% CI: 9.2-15.6). Correlation analyses between the product of dissociation constant and ROR highlighted possibly Lyn involvement in PD with PKI (r = 0.73, P = 0.0004). CONCLUSIONS: Our study showed that 28 of the 33 tested PKIs were associated with PD. Besides, the study highlighted the role of Lyn in PD caused by PKIs through an immune-mediated process.

Non-cancer drug consumption during the early trajectory of lymphoma survivorship.

PURPOSE: This study explored the use of non-cancer drugs in lymphoma survivors during the early trajectory (0 to 2 years) of cancer survivorship and determined the factors that influenced this consumption. METHODS: Between January and March 2014, a cross-sectional survey was conducted to assess drug consumption in adult lymphoma survivors at the Toulouse University Hospital. This study was based on a questionnaire consisting of ten open questions related to medical prescription and/or self-medication occurring within the last 3 months. RESULTS: A total of 83/103 lymphoma survivors returned the questionnaire. This study showed that 91.6% of patients were drug consumers (about twice more than the general French population). Twenty percent of patients were treated with≥5 drugs. Overall drug consumption mainly concerned analgesics, anti-inflammatory drugs and psychotropics. The presence of comorbidity, urban residence and female gender were associated with overall drug consumption. Moreover, half of survivors required at least one self-medication. Finally, only seven survivors (8.4%) reported no use of any medication. CONCLUSION: This study shows that, at least during the early trajectory of cancer survivorship, lymphoma patients are heavily treated with non-cancer drug therapy. This drug consumption profile may have serious implications in terms of safety, overall benefit and health economics.

Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling.

Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT1 receptor (AT1-R) and NE α2C-adrenergic receptor (α2C-AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the α2C-AR-AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical Gs-cAMP-PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics.

Identification of cellular targets involved in cardiac failure caused by PKI in oncology: an approach combining pharmacovigilance and pharmacodynamics.

AIMS: The aims of the present study were to evaluate the risk of cardiac failure (CF) associated with 15 anticancer protein kinase inhibitors (PKIs) through a case/noncase analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. METHODS: In order to evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the World Health Organization safety report database (VigiBase®). We realised a literature review to identify 21 protein kinases (PKs) that were possibly involved in CF caused by PKIs. Pearson correlation coefficients (r) between aRORs and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely to be involved in PKI-induced CF. RESULTS: A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase® for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib. Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively. Significant values for correlation coefficients between the product of dissociation constant (pKd) and aROR were observed for two non-receptor protein kinases: ABL1 (non-phosphorylated and phosphorylated forms) and ABL2 protein kinases, with values of r = 0.83 (P = 0.0001), r = 0.75 (P = 0.0014) and r = 0.78 (P = 0.0006), respectively. CONCLUSION: We observed a higher disproportionality for CF with dasatinib, imatinib, bosutinib, sunitinib and nilotinib than with other PKIs. In addition, the study highlighted the role of ABL tyrosine kinases in CF caused by anticancer PKIs.

Identifying cancer drug regimens in French health insurance database: An application in multiple myeloma patients.

PURPOSE: There is no consensus on how to handle complex drug combinations of cancer drugs through medico-administrative databases. Our objective was to develop an algorithm for identifying the nature and patterns of treatment lines in a cohort of newly treated multiple myeloma patients. METHODS: A cohort of multiple myeloma patients starting a first treatment line was built using both ambulatory and hospital data from regional data of the French national healthcare system database (SNIIRAM). Patients were identified from January 2011 to September 2013 using ICD-10 codes for multiple myeloma ('C90') within long-term conditions or diagnosis from hospital data. Drugs of interest for cycle identification included bortezomib, imids (thalidomide, lenalidomide), alkylating drugs (cyclophosphamide, melphalan, bendamustine, doxorubicin) and dexamethasone. An algorithm was applied to define combinations of treatment received in the first 6 months of treatment. RESULTS: Among the 236 patients included, 45% received bortezomib-melphalan-prednisone (VMP: n = 107), 22% bortezomib-thalidomide-dexamethasone (VTD/VTD-PACE: n = 52) and 21% melphalan-prednisone-thalidomide (MPT: n = 49). Other drug regimens consisted in melphalan-prednisone (MP: 7%, n = 17), lenalidomide-dexamethasone (RD) (4%, n = 9), bortezomib-cyclophosphamide-dexamethasone (VCD: n = 1) and bortezomib-bendamustine-dexamethasone (VBD: n = 1). Type of drug regimens and allocation by age class (±65 years) were in accordance with current recommendations. CONCLUSIONS: This study demonstrates the feasibility of identifying complex drug regimens in onco-haematology, using both outpatient and inpatient drug records in French health insurance databases.