Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.

Cancer Res Treat. 2017 Aug 29;:

Authors: Kim TM, Lee KW, Oh DY, Lee JS, Im SA, Kim DW, Han SW, Kim YJ, Kim TY, Kim JH, Han H, Kim WH, Bang YJ

Abstract
Purpose: Poziotinib, a pan-HER tyrosine kinase inhibitor (TKI), has shown potent activity against wild type of epidermal growth factor receptor (EGFR) family kinases including EGFR, HER-2 and HER-4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety and antitumor activity against advanced solid tumors.
Materials and Methods: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort.
Results: A total of 75 patients were enrolled in the 2 studies. The most common drug-related treatment-emergent adverse events were diarrhea, rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were Grade 3 diarrhea in the intermittent schedule and Grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24mg/day in the intermittent dosing schedule and 18mg/day in the continuous dosing schedule. Eight (16%) and twenty-four (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer).
Conclusions: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

PMID: 28859471 [PubMed - as supplied by publisher]

Morbidity in Pregnant Women Associated with Unverified Penicillin Allergies, Antibiotic Use, and Group B Streptococcus Infections.

Perm J. 2017;21:

Authors: Desai SH, Kaplan MS, Chen Q, Macy EM

Abstract
CONTEXT: The morbidity potentially associated with unverified penicillin allergy in pregnant women, with and without group B streptococcus (GBS) infections, is unknown. Penicillin allergy testing is safe during pregnancy but is done infrequently.
OBJECTIVE: To determine morbidity associated with antibiotic use in a large cohort of pregnant women, with and without an unverified history of penicillin allergy, and with and without GBS.
DESIGN: Retrospective. All pregnant women who delivered live infants in Kaiser Permanente Southern California between January 1, 2009, and December 31, 2014, were identified.
MAIN OUTCOME MEASURES: Penicillin allergy status at delivery, delivery method, maternal and infant hospital utilization, peripartum antibiotic exposures, new antibiotic-associated adverse drug reactions, and new Clostridium difficile infections.
RESULTS: There were 170,379 unique women who had 201,316 pregnancies during the study period. There were 16,084 pregnancies in women with an active, but unverified, penicillin allergy at delivery. There were 42,524 pregnancies in GBS-positive women, and 3500 also had a penicillin allergy. Women with a penicillin allergy, with or without GBS, had significantly (about 10%) higher cesarean section rates and spent significantly more (about 0.1) days in the hospital after delivery. Among GBS-positive women, those with an unverified penicillin allergy were exposed to significantly more cefazolin, clindamycin, vancomycin, and gentamicin and had significantly higher rates of adverse drug reactions associated with all antibiotic use.
CONCLUSIONS: Unverified penicillin allergy is associated with more hospital utilization and additional morbidity. Penicillin allergy testing of pregnant women with a history of penicillin allergy may help reduce these unwanted outcomes.

PMID: 28333608 [PubMed - indexed for MEDLINE]

Context as a drug: some consequences of placebo research for primary care.

Scand J Prim Health Care. 2016 Dec;34(4):428-433

Authors: Lucassen P, Olesen F

Abstract
OBJECTIVE: On the basis of emerging research evidence, this review aims to discuss the importance of the context surrounding the doctor-patient encounter for the success of treatment.
DESIGN AND SETTING: Discussion paper based on placebo-nocebo and pain studies conducted in the western world.
MAIN OUTCOME MEASURES: Literature-based theory about impact of communication elements on seriousness of symptoms in clinical practice.
RESULTS: The therapeutic outcome seems to be impacted by rituals around a clinical encounter and by the doctor patient communication and relation. A warm, friendly and empathic attitude is crucial in the first contact with the practice and during the consultation as it influences the patient's perceived outcome. It is important to raise positive expectations when discussing the prognosis, conducting treatment and prescribing medications as the effect may be reduced if the physician expresses doubt about the effectiveness of the medication. Additionally, overly focus on side effects in the doctor-patient conversation about proposed treatments seems to influence the magnitude of perceived side effects in the patient. Thus, shared decision-making might be a desirable tool for ensuring better expectations in the patient and successful symptom relief.
CONCLUSIONS: The context of the doctor-patient interplay matters. Placebo-nocebo research provides strong evidence for this link. The therapeutic context induces biomedical processes in the patient's brain that may enhance or reduce the effects of chosen interventions. The context thus works as a drug, with real effects and side effects. KEY POINTS Increased awareness of the context drug may help GPs alleviate symptoms and better motivate patients for treatment. Treatment is affected by multiple types of context, as also confirmed by placebo-nocebo research. The therapeutic context influences the biomedical processes, which may enhance or reduce intervention effects on symptoms. The impact of context should be considered in daily general practice as it may serve as a drug, with real effects and side effects.

PMID: 27978780 [PubMed - indexed for MEDLINE]

Does dual HER-2 blockade treatment increase the risk of severe toxicities of special interests in breast cancer patients: A meta-analysis of randomized controlled trials.

Oncotarget. 2017 Mar 21;8(12):19923-19933

Authors: Hao S, Tian W, Gao B, Jiang Y, Zhang X, Zhang S, Guo L, Zhao J, Zhang G, Hu C, Yan J, Luo D

Abstract
Although dual HER-2 blockade treatment could offer greater clinical efficacy in breast cancer, the risk of severe toxicities of special interest related to this combined regimen in breast cancer remained unknown. We systematically searched public databases (MEDLINE, EMBASE, Cochrane library) to identify relevant studies that comparing anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) with dual HER-2 blockade treatment (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) in breast cancer. A total of 11,941 breast cancer patients from 9 trials were included for analysis. Meta-analysis showed that dual HER2 blockade treatment significantly increased the risk of severe diarrhea (OR 2.52, p<0.001) and treatment discontinuation (OR 1.52, p=0.014), but not for severe rash (OR 1.06, p=0.81), liver toxicities (OR 1.16, p=0.28), CHF (OR 1.46, p=0.09), LVEF decline (OR 1.09, p=0.40) and FAEs (OR 0.97, p=0.91). Similar results were observed in sub-group analysis according to anti-HER2 regimens in terms of severe diarrhea and treatment discontinuation. Additionally, trastuzumab plus lapatinib significantly increased the risk of LVEF decline in comparison with lapatinib alone (OR 1.48, p=0.002). Our analysis indicated that dual anti-HER2 blockade treatment significantly increased the risk of developing severe diarrhea and treatment discontinuation in comparison with anti-HER2 monotherapy. These were no evidence of an increased risk of fatal adverse events with dual-HER2 blockade treatment.

PMID: 28199966 [PubMed - indexed for MEDLINE]

Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient.

BMC Cancer. 2017 Aug 29;17(1):586

Authors: De Weerdt A, Dendooven A, Snoeckx A, Pen J, Lammens M, Jorens PG

Abstract
BACKGROUND: The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged.
CASE PRESENTATION: We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy.
CONCLUSIONS: We found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.

PMID: 28851379 [PubMed - in process]

Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: a multicenter randomized controlled trial.

BMC Cancer. 2017 Aug 29;17(1):581

Authors: Hata Y, Kiribayashi T, Kishi K, Nagashima M, Nakayama T, Ikeda S, Kadokura M, Ozeki Y, Otsuka H, Murakami Y, Takagi K, Iyoda A

Abstract
BACKGROUND: We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non-small cell lung cancer patients.
METHODS: Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival.
RESULTS: From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1-3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94).
CONCLUSIONS: The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1-3 elevation of bilirubin.
TRIAL REGISTRATION: This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

PMID: 28851314 [PubMed - in process]

Blood Pressure, Antihypertensive Polypharmacy, Frailty, and Risk for Serious Fall Injuries Among Older Treated Adults With Hypertension.

Hypertension. 2017 Aug;70(2):259-266

Authors: Bromfield SG, Ngameni CA, Colantonio LD, Bowling CB, Shimbo D, Reynolds K, Safford MM, Banach M, Toth PP, Muntner P

Abstract
Antihypertensive medication and low systolic blood pressure (BP) and diastolic BP have been associated with an increased falls risk in some studies. Many older adults have indicators of frailty, which may increase their risk for falls. We contrasted the association of systolic BP, diastolic BP, number of antihypertensive medication classes taken, and indicators of frailty with risk for serious fall injuries among 5236 REGARDS study (Reasons for Geographic and Racial Difference in Stroke) participants ≥65 years taking antihypertensive medication at baseline with Medicare fee-for-service coverage. Systolic BP and diastolic BP were measured, and antihypertensive medication classes being taken assessed through a pill bottle review during a study visit. Indicators of frailty included low body mass index, cognitive impairment, depressive symptoms, exhaustion, impaired mobility, and history of falls. Serious fall injuries were defined as fall-related fractures, brain injuries, or joint dislocations using Medicare claims through December 31, 2014. Over a median of 6.4 years, 802 (15.3%) participants had a serious fall injury. The multivariable-adjusted hazard ratio for a serious fall injury among participants with 1, 2, or ≥3 indicators of frailty versus no frailty indicators was 1.18 (95% confidence interval, 0.99-1.40), 1.49 (95% confidence interval, 1.19-1.87), and 2.04 (95% confidence interval, 1.56-2.67), respectively. Systolic BP, diastolic BP, and number of antihypertensive medication classes being taken at baseline were not associated with risk for serious fall injuries after multivariable adjustment. In conclusion, indicators of frailty, but not BP or number of antihypertensive medication classes, were associated with increased risk for serious fall injuries among older adults taking antihypertensive medication.

PMID: 28652459 [PubMed - indexed for MEDLINE]

Optimizing Symptoms and Management of Febrile Neutropenia among Cancer Patients: Current Status and Future Directions.

Curr Oncol Rep. 2017 Mar;19(3):20

Authors: Wang XJ, Chan A

Abstract
Febrile neutropenia (FN) is a common and serious complication among cancer patients undergoing myelosuppressive chemotherapy. FN should be treated as a medical emergency because it can lead to life-threatening complications if appropriate treatment is not initiated immediately. This study provides a critical review on the current management of FN and identifies possible directions to optimize FN management.

PMID: 28271398 [PubMed - indexed for MEDLINE]

Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa.

Clin Vaccine Immunol. 2017 02;24(2):

Authors: Loxton AG, Knaul JK, Grode L, Gutschmidt A, Meller C, Eisele B, Johnstone H, van der Spuy G, Maertzdorf J, Kaufmann SH, Hesseling AC, Walzl G, Cotton MF, VPM Study Group

Abstract
Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 (n = 36) or BCG Danish strain (n = 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8(+) IL-17(+) T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.).

PMID: 27974398 [PubMed - indexed for MEDLINE]

Non-cytochrome P450-mediated bioactivation and its toxicological relevance.

Drug Metab Rev. 2016 Nov;48(4):473-501

Authors: Gan J, Ma S, Zhang D

Abstract
The bioactivation of drugs is often associated with toxicological outcomes; however, for most cases, the causal relationship between bioactivation and toxicity is not well established despite extensive research that attempts to elucidate the mechanisms leading to the formation of chemically reactive species, presumably the initial step towards adverse reactions. Due to rapid advancement in the research of cytochrome P450s (CYPs) and the prevalence of CYP involvement in the metabolic clearance of pharmaceuticals, CYP-mediated bioactivation is widely investigated and reviewed, while non-CYP-mediated bioactivation has not been emphasized. The widespread use of metabolic stability screening in drug discovery, however, has led to the identification of new chemical entities that rely on non-CYP enzymes for clearance, and the number of drugs that undergo metabolism via these enzymes has increased. Non-CYP enzymes can be divided into four general categories according to their enzymatic function, namely, oxidative, reductive, conjugative and hydrolytic. The aim of this review is to complement the existing literature on CYP-mediated metabolism by focusing on bioactivation mediated non-CYP enzymes and provide representative examples in each category.

PMID: 27533622 [PubMed - indexed for MEDLINE]

Safety of Recombinant Fusion Protein ESAT6-CFP10 as a Skin Test Reagent for Tuberculosis Diagnosis: an Open-Label, Randomized, Single-Center Phase I Clinical Trial.

Clin Vaccine Immunol. 2016 Sep;23(9):767-73

Authors: Li F, Xu M, Zhou L, Xiong Y, Xia L, Fan X, Gu J, Pu J, Lu S, Wang G

Abstract
This trial was conducted to explore the safety of recombinant fusion protein ESAT6-CFP10 as a skin test reagent for the diagnosis of Mycobacterium tuberculosis infection. Twenty-four healthy adult volunteers were recruited and randomized into four groups (groups A to D) to study four increasing doses of ESAT6-CFP10. All subjects in each dose group received an intradermal injection of reagent (0.1 ml) via the Mantoux technique. Then, the vital signs of all subjects were monitored, and skin reactions around injection sites and adverse events were recorded at different detection time points after the skin test. No serious adverse events were observed in this study. A total of 3 subjects had unexpected events. One subject in group A developed subcutaneous hemorrhage 24 h after the skin test, one subject in group B was found with red spots 15 min after the skin test, and another subject in group A showed abnormity during a chest X-ray after the skin test without affecting her health. One of three adverse events (red spots) was probably related to the recombinant ESAT6-CFP10 reagent. A single dose of 1, 5, 10, or 20 μg/ml of recombinant ESAT6-CFP10 as a skin test reagent for M. tuberculosis infection diagnosis is well tolerated and safe in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT01999231.).

PMID: 27413070 [PubMed - indexed for MEDLINE]

Pharmacokinetics of Co-Formulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate After Switch From Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Healthy Subjects.

J Acquir Immune Defic Syndr. 2016 Jul 01;72(3):281-8

Authors: Ramanathan S, Custodio JM, Wei X, Wang H, Fordyce M, Dave A, Ling KH, Szwarcberg J, Kearney BP

Abstract
BACKGROUND: Elvitegravir (EVG), a HIV integrase inhibitor, is metabolized primarily by CYP3A, and secondarily by UGT1A1/3; Efavirenz (EFV), a HIV non-nucleoside reverse transcriptase inhibitor, is metabolized by Cytochrome P450 (CYP) 2B6 and induces CYP3A and uridine diphosphate glucuronosyltransferase (UGT) with residual effects post discontinuation because of long T1/2 (40-55 hours). This study evaluated the pharmacokinetics after switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF).
METHODS: Healthy subjects (n = 32 including n = 8 CYP2B6 poor metabolizers) received EVG/COBI/FTC/TDF (150/150/200/300 mg) on days 1-7, and after a washout, received EFV/FTC/TDF (600/200/300 mg) on days 15-28 and switched to EVG/COBI/FTC/TDF (150/150/200/300 mg) for 5 weeks (days 29-62). Pharmacokinetic assessments occurred on days 7, 28, 35, and 42; trough samples (Ctrough) were collected periodically until day 63. Safety was assessed throughout the study.
RESULTS: Twenty-nine subjects completed with 3 adverse events leading to discontinuation; no grade ≥3 adverse events were reported. Post-EFV/FTC/TDF, mean EVG area under concentration (AUCtau) was 37% and 29% lower and mean Ctrough ∼3- and ∼5-fold above IC95, respectively, on days 35 and 42, and 7-8-fold above IC95 by 5 weeks. COBI AUCtau returned to normal by day 42. EVG glucuronide, GS-9200, AUCtau was higher (46% and 32% on days 35 and 42, respectively) postswitch. CYP2B6 poor metabolizers displayed higher EFV AUCtau and Cmax (125% and 91%, respectively) versus non-poor metabolizers, and lower EVG and COBI exposures. EFV Ctrough was >IC90 (10 ng/mL) in all subjects postswitch. FTC and tenofovir (TFV) exposures were unaffected.
CONCLUSIONS: After EFV/FTC/TDF to EVG/COBI/FTC/TDF switch, EVG and/or EFV exposures were in an active range. These findings support further evaluation of switching regimens in HIV-1 patients.

PMID: 26885802 [PubMed - indexed for MEDLINE]

Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicin-induced small intestinal damage in mice.

PLoS One. 2017;12(3):e0173429

Authors: Carr JS, King S, Dekaney CM

Abstract
BACKGROUND & AIMS: While enteric bacteria have been shown to play a critical role in other forms of intestinal damage, their role in mediating the response to the chemotherapeutic drug Doxorubicin (Doxo) is unclear. In this study, we used a mouse model of intestinal bacterial depletion to evaluate the role enteric bacteria play in mediating Doxo-induced small intestinal damage and, more specifically, in mediating chemokine expression and leukocyte infiltration following Doxo treatment. An understanding of this pathway may allow for development of intervention strategies to reduce chemotherapy-induced small intestinal damage.
METHODS: Mice were treated with (Abx) or without (NoAbx) oral antibiotics in drinking water for four weeks and then with Doxo. Jejunal tissues were collected at various time points following Doxo treatment and stained and analyzed for apoptosis, crypt damage and restitution, and macrophage and neutrophil number. In addition, RNA expression of inflammatory markers (TNFα, IL1-β, IL-10) and cytokines (CCL2, CC7, KC) was assessed by qRT-PCR.
RESULTS: In NoAbx mice Doxo-induced damage was associated with rapid induction of apoptosis in jejunal crypt epithelium and an increase weight loss and crypt loss. In addition, we observed an increase in immune-modulating chemokines CCL2, CCL7 and KC and infiltration of macrophages and neutrophils. In contrast, while still positive for induction of apoptosis following Doxo treatment, Abx mice showed neither the overall weight loss nor crypt loss seen in NoAbx mice nor the increased chemokine expression and leukocyte infiltration.
CONCLUSION: Enteric bacteria play a critical role in Doxo-induced small intestinal damage and are associated with an increase in immune-modulating chemokines and cells. Manipulation of enteric bacteria or the damage pathway may allow for prevention or treatment of chemotherapy-induced small intestinal damage.

PMID: 28257503 [PubMed - indexed for MEDLINE]

Safety of measles-containing vaccines in post-marketing surveillance in Anhui, China.

PLoS One. 2017;12(2):e0172108

Authors: Meng FY, Sun Y, Shen YG, Pan HF, Tang JH, Wang BB, Wu CH, Ye DQ

Abstract
The safety of measles vaccination is of great interest and importance to public health practice and the general society. We have analyzed the adverse events following immunization (AEFIs) of currently used measles-containing vaccines (including live attenuated measles vaccine, live attenuated measles and rubella combined vaccine, live attenuated measles and mumps combined vaccine, live attenuated Measles, Mumps and Rubella Combined Vaccine) in Anhui Province, China. From 2009 to 2014, 9.9 million doses of measles-containing vaccines were administrated and 1893 AEFIs were found (191.4 per million doses), of which, 33 serious AEFIs (3.3 per million vaccine doses) were reported. 59.4% (1124 cases) were male cases, and 85.1% (1611 cases) occurred in persons aged < 1 year. 93.3% (1766 cases) occurred at the first dose of vaccination and 95.9% (1815 cases) were found within 3 days after vaccination. This study presents up-to-date data and suggests that the measles-containing vaccines used in Anhui Province of China are safe.

PMID: 28192490 [PubMed - indexed for MEDLINE]

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Utilization of iPSC-derived human neurons for high-throughput drug-induced peripheral neuropathy screening.

Toxicol In Vitro. 2017 Aug 23;:

Authors: Rana P, Luerman G, Hess D, Rubitski E, Adkins K, Somps C

Abstract
As the number of cancer survivors continues to grow, awareness of long-term toxicities and impact on quality of life after chemotherapy treatment in cancer survivors has intensified. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of modern chemotherapy. Animal models are used to study peripheral neuropathy and predict human risk; however, such models are labor-intensive and limited translatability between species has become a major challenge. Moreover, the mechanisms underlying CIPN have not been precisely determined and few human neuronal models to study CIPN exist. Here, we have developed a high-throughput drug-induced neurotoxicity screening model using human iPSC-derived peripheral-like neurons to study the effect of chemotherapy agents on neuronal health and morphology using high content imaging measurements (neurite length and neuronal cell viability). We utilized this model to test various classes of chemotherapeutic agents with known clinical liability to cause peripheral neuropathy such as platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, and anti-angiogenic compounds. The model was sensitive to compounds that cause interference in microtubule dynamics, especially the taxane, epothilone, and vinca alkaloids. Conversely, the model was not sensitive to platinum and anti-angiogenic chemotherapeutics; compounds that are not reported to act directly on neuronal processes. In summary, we believe this model has utility for high-throughput screening and prediction of human risk for CIPN for novel chemotherapeutics.

PMID: 28843493 [PubMed - as supplied by publisher]

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia.

Lung Cancer. 2017 Sep;111:1-5

Authors: Fujimoto D, Morimoto T, Ito J, Sato Y, Ito M, Teraoka S, Otsuka K, Nagata K, Nakagawa A, Tomii K

Abstract
INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP.
METHODS: Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity ≥80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3mg/kg biweekly.
RESULTS: Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response.
CONCLUSIONS: Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037).

PMID: 28838377 [PubMed - in process]

[Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs)].

Dtsch Med Wochenschr. 2017 Aug;142(16):e100-e107

Authors: Freudenmann RW, Freudenmann N, Zurowski B, Schönfeldt-Lecuona C, Maier L, Schmieder RE, Lange-Asschenfeldt C, Gahr M

Abstract
Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies.

PMID: 28645134 [PubMed - indexed for MEDLINE]

Nicotine Withdrawal, Relapse of Mental Illness, or Medication Side-Effect? Implementing a Monitoring Tool for People With Mental Illness Into Quitline Counseling.

J Dual Diagn. 2017 Jan-Mar;13(1):60-66

Authors: Segan CJ, Baker AL, Turner A, Williams JM

Abstract
BACKGROUND: Smokers with mental illness and their health care providers are often concerned that smoking cessation will worsen mental health. Smokers with mental illness tend to be more nicotine-dependent and experience more severe symptoms of nicotine withdrawal, some of which are difficult to distinguish from psychiatric symptoms. In addition, smoking cessation can increase the blood levels and hence side effects of some psychotropic medications. Improved monitoring of nicotine withdrawal and medication side effects may help distinguish temporary withdrawal symptoms from psychiatric symptoms and facilitate targeted treatment to help smokers with mental illness manage the acute phase of nicotine withdrawal.
OBJECTIVE: The aim of this research was to examine the acceptability and feasibility to quitline counselors of implementing structured assessments of nicotine withdrawal and common medication side effects in people with mental illness who are quitting smoking using a telephone smoking cessation service.
METHODS: Monitoring involves administering (once pre-cessation and at each contact post-cessation) (1) the Minnesota Nicotine Withdrawal Scale, assessing eight symptoms: anger, anxiety, depression, cravings, difficulty concentrating, increased appetite, insomnia, and restlessness and (2) an adverse side effects checklist of 5 to 10 symptoms, for example, dry mouth and increased thirst. Following a 1-day update training in mental health, quitline counselors were asked to offer these assessments to callers disclosing mental illness in addition to usual counseling. Group interviews with counselors were conducted 2 months later to examine implementation barriers and benefits.
RESULTS: Barriers included awkwardness in integrating a new structured practice into counseling, difficulty in limiting some callers to only the content of new items, and initial anxieties about how to respond to changes in some symptoms. Benefits included the ability to provide objective feedback on changes in symptoms, as this identified early benefits of quitting, provided reassurance for clients, and provided an opportunity for early intervention where symptoms worsened.
CONCLUSIONS: Structured monitoring of withdrawal symptoms and medication side effects was able to be integrated into the quitline's counseling and was valued by counselors and clients. Given evidence of its benefits in this limited pilot study, we recommend it be considered for larger-scale adoption by quitlines.

PMID: 28067594 [PubMed - indexed for MEDLINE]

A Systematic Review and Network Meta-Analysis to Evaluate the Comparative Efficacy of Interventions for Unfit Patients with Chronic Lymphocytic Leukemia.

Adv Ther. 2016 Oct;33(10):1814-1830

Authors: Städler N, Shang A, Bosch F, Briggs A, Goede V, Berthier A, Renaudin C, Leblond V

Abstract
INTRODUCTION: Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in 'unfit' (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.
METHODS: For inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL.
RESULTS: In unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints).
CONCLUSION: G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.
FUNDING: F. Hoffmann-La Roche Ltd.

PMID: 27535291 [PubMed - indexed for MEDLINE]