Drug-Induced Liver Injury in the Elderly: Consensus Statements and Recommendations from the IQ-DILI Initiative.

The elderly demographic is the fastest-growing segment of the world's population and is projected to exceed 1.5 billion people by 2050. With multimorbidity, polypharmacy, susceptibility to drug-drug interactions, and frailty as distinct risk factors, elderly patients are especially vulnerable to developing potentially life-threatening safety events such as serious forms of drug-induced liver injury (DILI). It has been a longstanding shortcoming that elderly individuals are often a vulnerable population underrepresented in clinical trials. As such, an improved understanding of DILI in the elderly is a high-priority, unmet need. This challenge is underscored by recent documents put forward by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) that encourage data collection in the elderly and recommend improved practices that will facilitate a more inclusive approach. To establish what is already known about DILI in the elderly and pinpoint key gaps of knowledge in this arena, a working definition of "elderly" is required that accounts for both chronologic and biologic ages and varying states of frailty. In addition, it is critical to characterize the biological role of aging on liver function, as well as the different epidemiological factors such as polypharmacy and inappropriate prescribing that are common practices. While data may not show that elderly people are more susceptible to DILI, DILI due to specific drugs might be more common in this population. Improved characterization of DILI in the elderly may enhance diagnostic and prognostic capabilities and improve the way in which liver safety is monitored during clinical trials. This summary of the published literature provides a framework to understand and evaluate the risk of DILI in the elderly. Consensus statements and recommendations can help to optimize medical care and catalyze collaborations between academic clinicians, drug manufacturers, and regulatory scientists to enable the generation of high-quality research data relevant to the elderly population.

Safety and efficacy of BAY 94-9027, an extended-half-life factor VIII, during surgery in patients with severe hemophilia A: Results of the PROTECT VIII clinical trial.

INTRODUCTION: Ensuring hemostasis during invasive procedures is a challenge in patients with severe hemophilia A. This analysis evaluated efficacy and safety of BAY 94-9027, an extended-half-life recombinant factor VIII (FVIII), in the surgical setting. MATERIALS AND METHODS: Patients participating in an open-label BAY 94-9027 clinical trial who underwent major surgery were included in the analysis. Investigator/surgeon assessment of hemostasis during surgery was the primary outcome. In addition, information about FVIII use, FVIII levels during perioperative period, bleeding complications and FVIII inhibitor development were collected. RESULTS: Data were analyzed for 26 major surgeries (orthopedic, n = 21) in 20 patients aged 13-61 years. BAY 94-9027 provided effective hemostasis during all procedures. FVIII levels 6-8 h post preoperative infusion and prior to the first follow-up infusion were in the range expected to maintain protection in the major surgery setting. The median time from preoperative infusion to the first follow-up infusion (the first infusion administered after the preoperative infusion) was 12.33 (3.6-49.9) h. No intraoperative bleeding complications occurred, and no new inhibitors developed following any surgery. CONCLUSIONS: The results of the study demonstrate that BAY 94-9027 was efficacious and well tolerated in the treatment of patients undergoing major surgeries. Advantages of BAY 94-9027 include the potential for less frequent infusion and reduced factor consumption, which should simplify the management of patients during major surgery.

2-[18F]-fluoro-2-desoxy-D-glucose positron emission tomography initial staging impacts on survival in Hodgkin lymphoma.

AIM: To assess the prognostic value and risk classification improvement of metabolic staging (MS) with Initial 2-[18F]-fluoro-2-desoxy-D-glucose positron emission tomography (FDG-PET) in initial staging of Hodgkin's Lymphoma (HL) patients to predict 5 years overall survival (5y-OS) and event free survival (EFS). METHODS: A total of 275 patients were included in this retrospective study, 155 patients were staged with conventional anatomical staging (AS), and 120 also submitted to MS (FDG-PET). Prognostic analysis compared 5y-OS and 5y-EFS of patients staged with AS and MS. Risk-adjusted models incorporated clinical risk factors, computed tomography and FDG-PET staging. RESULTS: During the follow up of 267 evaluated patients, 220 (122 AS and 98 MS) achieved complete remission after first-line therapy (median follow-up: 70 ± 29 mo), treatment failure occurred in 79 patients and 34 died. The 5y-EFS for early vs advanced disease in AS patients was 79.3% and 66.7%, and 85.6% and 53.6% in MS patients, respectively (P < 0.01). The 5y-OS for early and advanced disease with AS was 91.3% and 81.5%, and 97.5% and 80.7% for patients staged with MS, respectively. Cox proportional hazards analysis demonstrated that FDG-PET added significant prognostic information and improved risk prediction (P = 0.02). CONCLUSION: Initial staging FDG-PET could be used as an accurate and independent predictor of OS and EFS in HL, with impact in 5y-EFS and OS.

Consistency of FDG-PET accuracy and cost-effectiveness in initial staging of patients with Hodgkin lymphoma across jurisdictions.

INTRODUCTION: Two hundred ten patients with newly diagnosed Hodgkin's lymphoma (HL) were consecutively enrolled in this prospective trial to evaluate the cost-effectiveness of fluorine-18 ((18)F)-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scan in initial staging of patients with HL. METHODS: All 210 patients were staged with conventional clinical staging (CCS) methods, including computed tomography (CT), bone marrow biopsy (BMB), and laboratory tests. Patients were also submitted to metabolic staging (MS) with whole-body FDG-PET scan before the beginning of treatment. A standard of reference for staging was determined with all staging procedures, histologic examination, and follow-up examinations. The accuracy of the CCS was compared with the MS. Local unit costs of procedures and tests were evaluated. Incremental cost-effectiveness ratio (ICER) was calculated for both strategies. RESULTS: In the 210 patients with HL, the sensitivity for initial staging of FDG-PET was higher than that of CT and BMB in initial staging (97.9% vs. 87.3%; P < .001 and 94.2% vs. 71.4%, P < 0.003, respectively). The incorporation of FDG-PET in the staging procedure upstaged disease in 50 (24%) patients and downstaged disease in 17 (8%) patients. Changes in treatment would be seen in 32 (15%) patients. Cumulative cost for staging procedures was $3751/patient for CCS compared to $5081 for CCS + PET and $4588 for PET/CT. The ICER of PET/CT strategy was $16,215 per patient with modified treatment. PET/CT costs at the beginning and end of treatment would increase total costs of HL staging and first-line treatment by only 2%. CONCLUSION: FDG-PET is more accurate than CT and BMB in HL staging. Given observed probabilities, FDG-PET is highly cost-effective in the public health care program in Brazil.

18F-FDG PET after 2 cycles of ABVD predicts event-free survival in early and advanced Hodgkin lymphoma.

UNLABELLED: Our objective was to assess the prognostic value of (18)F-FDG PET after 2 cycles of chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in Hodgkin lymphoma (HL) patients overall and in subgroups of patients with early and advanced stages and with low and high risks according to the International Prognostic Score (IPS). METHODS: One hundred fifteen patients with newly diagnosed HL were prospectively included in the study. All underwent standard ABVD therapy followed by consolidation radiotherapy in cases of bulky disease. After 2 cycles of ABVD, the patients were evaluated with PET (PET2). Prognostic analysis compared the 3-y event-free survival (EFS) rate to the PET2 results, clinical data, and IPS. RESULTS: Of the 104 evaluated patients, 93 achieved complete remission after first-line therapy. During a median follow-up of 36 mo, relapse or disease progression was seen in 22 patients. Treatment failure was seen in 16 of the 30 PET2-positive patients and in only 6 of the 74 PET2-negative patients. PET2 was the only significant prognostic factor. The 3-y EFS was 53.4% for PET2-positive patients and 90.5% for PET2-negative ones (P < 0.001). When patients were categorized according to low or high IPS risk and according to early or advanced stage of disease, PET2 was also significantly associated with treatment outcome. CONCLUSION: PET2 is an accurate and independent predictor of EFS in HL. A negative interim (18)F-FDG PET result is highly predictive of treatment success in overall HL patients, as well as in subgroups with early or advanced-stage disease and with low or high IPS risk.

Cost effectiveness of positron emission tomography in patients with Hodgkin's lymphoma in unconfirmed complete remission or partial remission after first-line therapy.

PURPOSE: To assess the cost effectiveness of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with Hodgkin's lymphoma (HL) with unconfirmed complete remission (CRu) or partial remission (PR) after first-line treatment. PATIENTS AND METHODS: One hundred thirty patients with HL were prospectively studied. After treatment, all patients with CRu/PR were evaluated with FDG-PET. In addition, PET-negative patients were evaluated with standard follow-up, and PET-positive patients were evaluated with biopsies of the positive lesions. Local unit costs of procedures and tests were evaluated. Cost effectiveness was determined by evaluating projected annual economic impact of strategies without and with FDG-PET on HL management. RESULTS: After treatment, CRu/PR was observed in 50 (40.0%) of the 127 patients; the sensitivity, specificity, and positive and negative predictive values of FDG-PET were 100%, 92.0%, 92.3%, and 100%, respectively (accuracy of 95.9%). Local restaging costs without PET were $350,050 compared with $283,262 with PET, a 19% decrease. The incremental cost-effectiveness ratio is -$3,268 to detect one true case. PET costs represented 1% of total costs of HL treatment. Simulated costs in the 974 patients registered in the 2008 Brazilian public health care database showed that the strategy including restaging PET would have a total program cost of $56,498,314, which is $516,942 less than without restaging PET, resulting in a 1% cost saving. CONCLUSION: FDG-PET demonstrated 95.9% accuracy in restaging for patients with HL with CRu/PR after first-line therapy. Given the observed probabilities, FDG-PET is highly cost effective and would reduce costs for the public health care program in Brazil.

Gemcitabina e ifosfamida no tratamento do linfoma de Hodgkin refratário ou recidivado após múltiplas terapias: [carta ao editor] / Gemcitabine and ifosfamide in the treatment of Hodgkin's lymphoma refractory to or relapsed after multiple therapies: [letter to the editor]

Patients with Hodgkin's lymphoma relapsed after or refractory to multiple therapies (rHL) have a dismal prognosis. Monotherapy with gemcitabine can promote an overall response rate of about 40 percent in these patients and its association with alkylating agents can provide better results. We retrospectively evaluated 17 rHL cases. All were treated with the combination of gemcitabine (1.0 g/m²; D1 and D8) and ifosfamide (1.0 g/m²; D1 to D5) in a 21-day cycle. Treatment response was evaluated according to the Cotswolds criteria. Toxicity was evaluated according to WHO criteria. The median age of all patients was 34 years (18-53). Nine of them (53 percent) were men and eight (47 percent) had Stage III/IV. The median number of previous treatments was 2 (2-3); two patients had already been treated with autologous stem cell transplant. Overall response rate to the combined regimen was 62.5 percent (95 percent CI = 38.8 percent - 86.2 percent) and the median progression-free survival was 15 months (95 percent CI = 4 - 24 months). Fifty-six cycles were evaluated for toxicity. The most frequent toxicities observed by cycle were: hepatic Grade I/II in 48.2 percent of the cycles and Grade III/IV in 1.8 percent; anemia Grade I/II in 45 percent; neutropenia Grade I/II in 36 percent and Grade III/IV 16 percent. Grade III/IV renal toxicity on any degree of haematuria were not observed. Combined therapy with Gemcitabine and Ifosfamide promoted responses in more than half of the evaluated patients with an acceptable toxicity profile.

Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis.

The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3',5-triiodothyronine (T3), the disruption of which (Dio2(-/-)) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2(-/-) BAT sympathetic stimulation approximately 10-fold (normal approximately 4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor gamma coactivator 1, increased well above the levels detected in the cold-exposed wild-type animals. The sustained Dio2(-/-) BAT adrenergic hyperresponse suppressed the three- to fourfold stimulation of BAT lipogenesis normally seen after 24-48 h in the cold. Pharmacological suppression of lipogenesis with betabeta'-methyl-substituted alpha-omega-dicarboxylic acids of C14-C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2(-/-) mice.