Thromboprophylaxis with enoxaparin and direct oral anticoagulants in major orthopedic surgery and acutely ill medical patients: a meta-analysis.

Intern Emerg Med. 2017 Dec;12(8):1291-1305

Authors: Cimminiello C, Prandoni P, Agnelli G, Di Minno G, Polo Friz H, Scaglione F, Boracchi P, Marano G, Harenberg J

Abstract
Subjects undergoing major orthopedic surgery and acutely ill hospitalized medical patients represent a population at medium-high risk for venous thromboembolism (VTE). They are treated with low molecular weight heparin (LMWH) and direct oral anticoagulants [DOACs] for VTE prevention. We conducted a meta-analysis of phase III randomized clinical trials evaluating LMWH enoxaparin versus DOACs for prophylaxis of VTE by combining studies including patients undergoing elective total hip and knee replacement surgery, and acutely ill hospitalized medical subjects. Studies were searched using PubMed, MEDLINE, and EMBASE databases until December 2016. Differences in clinical outcomes for efficacy and safety endpoints between treatment groups were expressed as risk differences with 95% confidence intervals (95% CI), using random effects regression models. Fourteen RCTs were considered (60,467 subjects). Overall mortality, symptomatic deep venous thrombosis, non-fatal pulmonary embolism (PE) major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) are not different between treatment regimens. Treatment with LMWH enoxaparin is associated with a lower risk of fatal PE plus VTE-related death compared therapy with DOACs (RD = 0.040%, 95% CI 0.001-0.080%, p = 0.0434). Subgroup analysis shows an incidence of MB (RD = 0.181%, 95% CI 0.029-0.332%, p = 0.0033) and CRNMB (RD = 0.546%, 95% CI 0.009-1.082%, p = 0.0462) in patients treated with 40 mg OD enoxaparin compared to DOACs. In major orthopedic surgery and acutely ill hospitalized medical patients, DOACs do not offer clear advantages in terms of clinical efficacy compared to enoxaparin. The advantage of the latter in terms of major and CRNMB, when used at a dose of 40 mg, is statistically significant, but small in terms of clinical relevance.

PMID: 28756546 [PubMed - indexed for MEDLINE]

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America.

J Med Virol. 2017 Sep;89(9):1590-1596

Authors: Mendizabal M, Haddad L, Gallardo PE, Ferrada A, Soza AA, Adrover R, Aravena E, Roblero JP, Prieto J, Vujacich C, Romero G, Muñoz A, Anders M, Hernández N, Coccozella D, Gruz F, Reggiardo MV, Ruf AE, Varón A, Cartier M, Pérez Ravier R, Ridruejo E, Peralta M, Poncino D, Vorobioff J, Aballay Soteras G, Silva MO

Abstract
Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real-clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real-world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child-Pugh B at baseline and one patient died due to multi-organ failure. Follow up HCV-RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child-Pugh A cirrhosis in non-European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child-Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.

PMID: 28370222 [PubMed - indexed for MEDLINE]

Systemic lupus erythematosus.

Nat Rev Dis Primers. 2016 06 16;2:16039

Authors: Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G, Hughes G

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

PMID: 27306639 [PubMed - indexed for MEDLINE]

Combined application of tenuigenin and β-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease.

Drug Des Devel Ther. 2018;12:455-462

Authors: Chang W, Teng J

Abstract
Background: Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD.
Patients and methods: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received β-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5-20 mg/d. Patients in the control group only received memantine 5-20 mg/d. The Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Activities of Daily Living (ADL) were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks.
Results: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001), lower average ADL score (p=0.00002), and lower average CDR score (p=0.030). Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60-74-years-old male patients with moderate AD.
Conclusion: These results demonstrated that the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored.

PMID: 29551889 [PubMed - in process]

The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.

J Ocul Pharmacol Ther. 2017 Dec;33(10):718-734

Authors: Eaton JS, Miller PE, Bentley E, Thomasy SM, Murphy CJ

Abstract
PURPOSE: To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development.
METHODS: Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science.
RESULTS: The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species.
CONCLUSIONS: The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development.

PMID: 29239680 [PubMed - indexed for MEDLINE]

A single center, open label study of intradermal administration of an inactivated purified chick embryo cell culture rabies virus vaccine in adults.

Vaccine. 2017 Aug 03;35(34):4315-4320

Authors: Recuenco S, Warnock E, Osinubi MOV, Rupprecht CE

Abstract
In the USA, rabies vaccines (RVs) are licensed for intramuscular (IM) use only, although RVs are licensed for use by the intradermal (ID) route in many other countries. Recent limitations in supplies of RV in the USA reopened discussions on the more efficient use of available biologics, including utilization of more stringent risk assessments, and potential ID RV administration. A clinical trial was designed to compare the immunogenic and adverse effects of a purified chicken embryo cell (PCEC) RV administered ID or IM. Enrollment was designed in four arms, ID Pre-Exposure Prophylaxis (Pre-EP), IM Pre-EP, ID Booster, and IM Booster vaccination. Enrollment included 130 adult volunteers. The arms with IM administration received vaccine according to the current ACIP recommendations: Pre-EP, three 1mL (2.5 I.U.) RV doses, each on day 0, 7, and 21; or a routine Booster, one 1ml dose. The ID groups received the same schedule, but doses administered were in a volume of 0.1mL (0.25 I.U.). The rate of increase in rabies virus neutralizing antibody titers 14-21days after vaccination were similar in the ID and correspondent IM groups. The GMT values for ID vaccination were slightly lower than those for IM vaccination, for both naïve and booster groups, and these differences were statistically significant by t-test. Fourteen days after completing vaccination, all individuals developed RV neutralizing antibody titers over the minimum arbitrary value obtained with the rapid fluorescent focus inhibition test (RFFIT). Antibodies were over the set threshold until the end of the trial, 160days after completed vaccination. No serious adverse reactions were reported. Most frequent adverse reactions were erythema, induration and tenderness, localized at the site of injection. Multi use of 1mL rabies vaccine vials for ID doses of 0.1 was demonstrated to be both safe and inmunogenic.

PMID: 28688782 [PubMed - indexed for MEDLINE]

The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies.

Immunotherapy. 2017 Jun;9(7):579-587

Authors: Ciccarese C, Iacovelli R, Bria E, Modena A, Massari F, Brunelli M, Fantinel E, Bimbatti D, Zamboni GA, Artibani W, Tortora G

Abstract
AIM: Monoclonal antibodies (mAbs) directed against PD-1/PD-L1 have recently entered the therapeutic algorithm of several solid tumors. Among treatment-related adverse events pulmonary toxicity (PT) is of particular interest. We assess the incidence and relative risk (RR) of PT in patients treated with anti-PD1/PD-L1 mAbs.
RESULTS: 11 articles were selected. The incidence of any- and high-grade PT was low (2.9 and 1.0%, respectively). Compared with standard therapies, anti-PD-1 mAbs do not significantly increase the risk of both any-grade (RR: 2.65; p = 0.06) and high-grade PT (RR: 1.40; p = 0.25). Of note, the RR: of developing any-grade (RR: 3.13; p < 0.0001) and high-grade (RR: 2.42; p = 0.03) PT significantly increased when excluding the Checkmate-025 trial, with everolimus as control therapy. No differences were identified between the type of mAbs, the tumor type and treatment duration for both any-grade and high-grade PT.

PMID: 28595514 [PubMed - indexed for MEDLINE]

Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in Non-Small Cell Lung Cancer.

J Immunother. 2017 Jul/Aug;40(6):249-251

Authors: Leonardi GC, Oxnard GR, Haas A, Lang JP, Williams JS, Awad MM

Abstract
Programmed cell death protein 1 pathway inhibitors are now routinely administered to patients with non-small cell lung cancer, and prompt recognition of immune-related adverse events is critical to managing serious drug toxicities. Here, we describe a 66-year-old man with no known history of diabetes who presented with diabetic ketoacidosis after receiving 3 doses of pembrolizumab for lung adenocarcinoma. Autoimmune diabetes is a rare but potentially life-threatening complication of programmed cell death protein 1 inhibitors.

PMID: 28557813 [PubMed - indexed for MEDLINE]

Inflammatory Myopathy and Axonal Neuropathy in a Patient With Melanoma Following Pembrolizumab Treatment.

J Immunother. 2017 Jul/Aug;40(6):221-223

Authors: Diamantopoulos PT, Tsatsou K, Benopoulou O, Anastasopoulou A, Gogas H

Abstract
Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.

PMID: 28498142 [PubMed - indexed for MEDLINE]

[Stroke prophylaxis in atrial fibrillation : When, how and for whom?]

Herz. 2017 Jun;42(4):373-379

Authors: Maurer T, Sohns C

Abstract
In patients suffering from atrial fibrillation (AF), modern antithrombotic therapy and anticoagulation strategies should be individualized based on shared decision making including patient preferences and the absolute and relative risks of stroke and bleeding. Estimation of the individual risk for stroke is still based on the CHA2DS2-VASc score. Based on the most recent guidelines for the management of AF, oral anticoagulation therapy should be considered for men with a CHA2DS2-VASc score ≥1 and women with a score ≥2, balancing the expected stroke reduction, risk of bleeding and patient preference. Both vitamin K antagonists and novel oral anticoagulants (NOAC) are effective for the prevention of stroke in AF. In AF patients treated with NOAC, kidney function should be regularly monitored to refine risk estimation and to enable dose adaptation. As an alternative to oral anticoagulation therapy, left atrial appendage occlusion may be considered for stroke prevention in patients with AF and contraindications for long-term anticoagulant treatment. This article provides a review of the indications and contraindications of modern stroke prophylaxis and discusses the approach to frequent clinical scenarios, such as treatment of patients with an acute coronary syndrome, coronary stent intervention or catheter ablation of AF.

PMID: 28439617 [PubMed - indexed for MEDLINE]

Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

Curr HIV Res. 2017;15(3):216-224

Authors: Gallant J, Moyle G, Berenguer J, Shalit P, Cao H, Liu YP, Myers J, Rosenblatt L, Yang L, Szwarcberg J

Abstract
OBJECTIVES: Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV-infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naïve adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF), at Weeks 48 and 144, with high rates of virologic success for both regimens (85.2% and 87.4%, respectively, at Week 48; and 72.1% and 74.1% at Week 144), and with comparable safety and tolerability. Here, we describe virologic response and treatment discontinuation by a wider range of subgroups than previously presented.
METHODS: Subgroup analyses by baseline CD4 count (≤200, 201-350, &gt;350 cells/mm3), baseline HIV-1 RNA level (≤100,000, &gt;100,000 copies/mL), race, sex, and age (&lt;40, ≥40 years) evaluated ATV+COBI versus ATV+RTV univariate odds ratios (ORs) for virologic success (viral load &lt;50 copies/mL, intention-to-treat US Food and Drug Administration Snapshot algorithm) and discontinuation due to adverse events (AEs) at Weeks 48 and 144. Of 692 patients randomized, 344 received ATV+COBI and 348 ATV+RTV.
RESULTS: ATV+COBI versus ATV+RTV ORs for virologic success did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.90; 95% confidence interval [CI]: 0.64, 1.26) or within subgroups, except in females, for whom ATV+COBI was favored at Week 144 (OR 2.36; 95% CI: 1.02, 5.47). However, there were more discontinuations due to withdrawal of consent and pregnancies in females receiving ATV+RTV versus ATV+COBI. ORs for discontinuation due to AEs did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.98; 95% CI: 0.61, 1.58) or within subgroups.
CONCLUSION: These findings indicate that both ATV+COBI and ATV+RTV, each with FTC/TDF, are effective and well-tolerated treatment options across a wide demographic range of HIV-infected patients.

PMID: 27774892 [PubMed - indexed for MEDLINE]

Efficacy and safety of apatinib in patients with previously treated metastatic colorectal cancer: a real-world retrospective study.

Sci Rep. 2018 Mar 15;8(1):4602

Authors: Gou M, Si H, Zhang Y, Qian N, Wang Z, Shi W, Dai G

Abstract
No definitive treatment strategy has been established for patients with metastatic colorectal cancer (mCRC) who experienced progression after three or more lines of chemotherapy. A total of 36 mCRC patients were enrolled in this retrospective study who received apatinib therapy under non-clinical trial setting after progression in People's liberation army general Hospital from March 2015 and August 2017. Progression free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR) and treatment-related adverse events (AEs) were reviewed and evaluated. Five patients achieved partial response (PR), and 25 achieved stable disease (SD), and 6 achieved progression disease (PD), illustrating a DCR of 83.3% and an ORR of 13.9%. Median PFS was 3.82 m and median OS was not reached. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 adverse event incidence of 27.8%. The most common grade 3/4 adverse events were hypertension (n = 4, 11.1%), liver function damage (n = 3, 8.3%) and hand-foot syndrome (n = 2, 5.6%). No drug-related death occurred. Apatinib therapy provides a reasonable option with an acceptable safety profile for Chinese mCRC patients failed to prior chemotherapy.

PMID: 29545575 [PubMed - in process]

Prevalence and Management of Symptoms Associated With Statin Therapy in Community Practice: Insights From the PALM (Patient and Provider Assessment of Lipid Management) Registry.

Circ Cardiovasc Qual Outcomes. 2018 Mar;11(3):e004249

Authors: Navar AM, Peterson ED, Li S, Robinson JG, Roger VL, Goldberg AC, Virani S, Wilson PWF, Nanna MG, Lee LV, Elassal J, Wang TY

PMID: 29545393 [PubMed - in process]

Sequence symmetry analysis in pharmacovigilance and pharmacoepidemiologic studies.

Eur J Epidemiol. 2017 Jul;32(7):567-582

Authors: Lai EC, Pratt N, Hsieh CY, Lin SJ, Pottegård A, Roughead EE, Kao Yang YH, Hallas J

Abstract
Sequence symmetry analysis (SSA) is a method for detecting adverse drug events by utilizing computerized claims data. The method has been increasingly used to investigate safety concerns of medications and as a pharmacovigilance tool to identify unsuspected side effects. Validation studies have indicated that SSA has moderate sensitivity and high specificity and has robust performance. In this review we present the conceptual framework of SSA and discuss advantages and potential pitfalls of the method in practice. SSA is based on analyzing the sequences of medications; if one medication (drug B) is more often initiated after another medication (drug A) than before, it may be an indication of an adverse effect of drug A. The main advantage of the method is that it requires a minimal dataset and is computationally efficient. By design, SSA controls time-constant confounders. However, the validity of SSA may be affected by time-varying confounders, as well as by time trends in the occurrence of exposure or outcome events. Trend effects may be adjusted by modeling the expected sequence ratio in the absence of a true association. There is a potential for false positive or negative results and careful consideration should be given to potential sources of bias when interpreting the results of SSA studies.

PMID: 28698923 [PubMed - indexed for MEDLINE]

Phase II Study of Modified Carboplatin Plus Weekly Nab-Paclitaxel in Elderly Patients with Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1301.

Oncologist. 2017 Jun;22(6):640-e59

Authors: Miyauchi E, Inoue A, Usui K, Sugawara S, Maemondo M, Saito H, Fujita Y, Kato T, Suzuki T, Harada T, Watanabe H, Nakagawa T, Ichinose M

Abstract
LESSONS LEARNED: Weekly nanoparticle albumin-bound-paclitaxel (75 mg/m2) in combination with carboplatin (area under the curve 6 mg/mL/min) in elderly patients with previously untreated, advanced non-small cell lung cancer showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity.This modified regimen offers potential for the treatment of elderly patients.
BACKGROUND: The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC.
METHODS: Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.
RESULTS: Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33-67) and 94% (95% CI: 85-100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8-8.0) and 17.5 months (95% CI: 11.9-23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed.
CONCLUSION: Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC.

PMID: 28526722 [PubMed - indexed for MEDLINE]

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis.

Oncologist. 2017 Jun;22(6):709-718

Authors: Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, Suijkerbuijk KPM, Azevedo S, Li H, Reshef D, Avila A, Reardon DA

Abstract
BACKGROUND: Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management.
METHODS: We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.
RESULTS: In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal.
CONCLUSION: Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.
IMPLICATIONS FOR PRACTICE: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

PMID: 28495807 [PubMed - indexed for MEDLINE]

Phase I Dose-Escalation Study of Ramucirumab in Chinese Patients with Advanced Solid Tumors.

Oncologist. 2017 Jun;22(6):638-e56

Authors: Cao J, Ji D, Chen Z, Shen W, Wang J, Li B, Chi H, Long A, Gao L, Li J

Abstract
LESSONS LEARNED: Ramucirumab was well tolerated in Chinese patients with advanced solid tumors, and adverse events were manageable in this study.Pharmacokinetics characteristics in Chinese patients were similar to those in other populations. Immunogenicity was not detected.No efficacy conclusion could be drawn, and further randomized studies are warranted.
BACKGROUND: This single-arm, nonrandomized, open-label, dose-escalation, phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of ramucirumab in Chinese patients with advanced solid tumors that were resistant to standard therapy or no standard therapy was available.
METHODS: Dose escalation was a 3 + 3 design, with expansion in Cohorts 2 and 3 for PK. Ramucirumab was given intravenously at three different dosages: 6 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 8 mg/kg every 2 weeks. Safety analyses included all patients. PK, immunogenicity, and antitumor activity were also assessed.
RESULTS: Among 28 patients treated, 2 experienced dose-limiting toxicity, possibly related to ramucirumab. No maximum tolerated dose was determined. All patients experienced at least one treatment-emergent adverse event. Grade ≥3 adverse event was reported for 53.6% (n = 15) of patients. PK analyses indicated that ramucirumab had low clearance, small volume of distribution, and long half-life in Chinese patients, as in other populations. Immunogenicity was not detected. No patient had complete/partial response, and 64.3% (n = 18) had stable disease with a median duration of 5.55 months (95% confidence interval: 3.38-7.13 months).
CONCLUSION: Ramucirumab appeared to be well tolerated in Chinese patients with advanced solid tumors. PK characteristics in Chinese patients were similar to those in other populations.

PMID: 28465370 [PubMed - indexed for MEDLINE]

Everolimus Plus Exemestane in Advanced Breast Cancer: Safety Results of the BALLET Study on Patients Previously Treated Without and with Chemotherapy in the Metastatic Setting.

Oncologist. 2017 Jun;22(6):648-654

Authors: Generali D, Montemurro F, Bordonaro R, Mafodda A, Romito S, Michelotti A, Piovano P, Ionta MT, Bighin C, Sartori D, Frassoldati A, Cazzaniga ME, Riccardi F, Testore F, Vici P, Barone CA, Schirone A, Piacentini F, Nolè F, Molino A, Latini L, Simoncini EL, Roila F, Cognetti F, Nuzzo F, Foglietta J, Minisini AM, Goffredo F, Portera G, Ascione G, Mariani G

Abstract
BACKGROUND: The BALLET study was an open-label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%).
PATIENTS AND METHODS: One thousand one hundred and fifty-one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%).
RESULTS: One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus-related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus-related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting.
CONCLUSION: Real-life data of the Italian patients BALLET-related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane.
IMPLICATIONS FOR PRACTICE: With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from one line to another. Thus, it is important to assess even the potential of cumulative and additive toxic effects among the drugs. Previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The continuous monitoring of the safety signals of this drug combination from general clinical practice is important, in particular for stomatitis.

PMID: 28432226 [PubMed - indexed for MEDLINE]

Safety issues of compounds acting on adenosinergic signalling.

J Pharm Pharmacol. 2017 Jul;69(7):790-806

Authors: Schmidt J, Ferk P

Abstract
OBJECTIVES: Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting.
KEY FINDINGS: Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic.
SUMMARY: Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.

PMID: 28397249 [PubMed - indexed for MEDLINE]

Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.

Clin Cancer Res. 2017 Jun 01;23(11):2730-2741

Authors: Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG, Terwisscha van Scheltinga AGT, Jansen L, de Vries J, Lub-de Hooge MN, Schröder CP, Jorritsma-Smit A, Linssen MD, de Boer E, van der Vegt B, Nagengast WB, Elias SG, Oliveira S, Witkamp AJ, Mali WPTM, Van der Wall E, van Diest PJ, de Vries EGE, Ntziachristos V, van Dam GM

Abstract
Purpose: To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730-41. ©2016 AACR.

PMID: 28119364 [PubMed - indexed for MEDLINE]