Effect of Orally Administered N -Acetylcysteine on Chronic Bronchitis: A Meta-analysis Abstract Introduction The effect of N-acetylcysteine (NAC) treatment for patients with chronic bronchitis (CB) is controversial. To better understand the role of NAC in CB treatment, we performed a meta-analysis to provide a more accurate estimation of the importance of NAC treatment. Methods PubMed, Embase, and CNKI were systematically searched. The pooled relative risk (RR) and 95% confidence intervals (CI) were calculated using either fixed-effect model or random-effect model based on heterogeneity examination. Statistical analyses were performed using the STATA 12.0 and RevMan 5.2. Results A total of 11 publications with 775 patients who were taking NAC and 789 controls who were taking placebo were judged eligible regarding inclusion criteria. The pooled analysis demonstrated significant evidence that NAC reduced the frequency of CB exacerbations (RR = 0.81, 95% CI 0.69–0.93, P = 0.004). Patients treated with NAC had significant symptom improvement compared with controls (RR = 1.68, 95% CI 1.13–2.52, P = 0.01). NAC did not significantly increase the risk of adverse effects compared with placebo (RR 0.86, 95% CI 0.67–1.09, P = 0.22). Subgroup analysis was carried out to assess the stability of results. No publication bias was detected during analyses. Conclusion There is a role for NAC treatment in the management of CB by reducing symptoms and exacerbations compared with placebo, without increasing the risk of adverse effects. A regular treatment of low dosage (< 1200 mg per day) and a duration of at least 3 months seems to be effective.

Enhanced Safety Surveillance of GSK’s Quadrivalent Seasonal Influenza Vaccine in Belgium, Germany, and Spain for the 2018/19 Season: Interim Analysis Abstract Introduction Influenza is an important cause of morbidity and mortality in Europe. Prevention by annual vaccination is most effective but with yearly vaccine reformulation to match circulating virus strains, vaccine safety must be continuously monitored. The European Medicines Agency published guidance on safety monitoring of influenza vaccines. Methods An enhanced safety surveillance study of GSK’s inactivated quadrivalent influenza vaccine (IIV4) was conducted in Belgium, Germany, and Spain in influenza season 2018/19. The objective was to collect adverse event (AE) reports from subjects within 7 days of vaccination. A customized AE reporting card (AERC) with predefined AEs of interest was used to rapidly detect and evaluate potential new safety concerns. Interim results are presented here. Results Between week 40 and 52, 1060 vaccinated subjects were enrolled (31.0% Belgium, 26.2% Germany, and 42.7% Spain) covering all ages for which IIV4 is indicated (32.0% aged 6 months–17 years, 33.8% 18–65 years, and 34.2% over 65 years). Pediatric subjects  less than 9 years old (n = 139) received two doses. Following dose 1 and dose 2, 98.2% and 100%, respectively, returned the completed AERC recording any AEs. Following dose 1 and dose 2, 454 and 34 subjects, respectively, reported at least one AE (most frequently expected general and injection site symptoms and respiratory symptoms). Conclusion All reported AEs were expected as per summary product characteristics (smPC). No safety signals that impact public health or alter the benefit–risk profile of GSK’s IIV4 were identified. Subjects from all vaccinated age groups were enrolled and the use of AERCs allowed rapid monitoring and analysis of reported AEs. Trial Registration ClinicalTrials.gov identifier, NCT03688620. Funding GlaxoSmithKline Biologicals SA.

Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site Abstract The subcutaneous administration route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. However, the sensation of pain at the injection site might reduce patient adherence. Apart from a direct effect of the drug itself, several factors can influence the sensation of pain: needle features, injection site, volume injected, injection speed, osmolality, viscosity and pH of formulation, as well as the kind of excipients employed, including buffers and preservatives. Short and thin needles, conveniently lubricated and with sharp tips, are generally used to minimize pain, although the anatomic injection site (abdomen versus thigh) also affects the sensation of pain. Large subcutaneous injection volumes are associated with pain. In this sense, the maximum volume generally accepted is around 1.5 ml, although volumes of up to 3 ml are well tolerated when injected in the abdomen. Injected volumes of up to 0.5–0.8 ml are not expected to increase substantially the pain produced by the needle insertion. Ideally, injectable products should be formulated as isotonic solutions (osmolality of about 300 mOsm/kg) and no more than 600 mOs/kg have to be used in order to prevent pain. A pH close to the physiological one is recommended to minimize pain, irritation, and tissue damage. Buffers are frequently added to parenteral formulations to optimize solubility and stability by adjusting the pH; however, their strength should be kept as low as possible to avoid pain upon injection. The data available recommend the concentration of phosphate buffer be limited to 10 mM and that the concentration of citrate buffer should be lower than 7.3 mM to avoid an increased sensation of pain. In the case of preservatives, which are required in multiple-dose preparations, m-cresol seems to be more painful than benzyl alcohol and phenol. Funding: Sandoz SA.

Defining the Characteristics of Chronic Hypoparathyroidism Not Adequately Controlled on Conventional Therapy: Consensus Findings of Three European Delphi Panels Abstract Introduction European Society of Endocrinology (ESE) guidelines provide goals for hypoparathyroidism management but do not define characteristics of chronic hypoparathyroidism that is not adequately controlled. Three European country-specific Delphi panels were conducted to gain consensus on these characteristics. Methods Delphi panels were conducted in the UK, Sweden, and Portugal using similar methodology. At each round, panellists considered patients with chronic hypoparathyroidism whose disease is not adequately controlled on conventional therapy according to a matrix of four presentations of patients with chronic hypoparathyroidism: normal biochemical levels/well (group 1), abnormal biochemical levels/well (group 2), normal biochemical levels/unwell (group 3), and abnormal biochemical levels/unwell (group 4), with wellness defined by the patient’s persistent symptoms, comorbidities, and complications. For groups 2–4, panellists rated characteristics in five categories (patient characteristics, family history, comorbidities, biochemistry, and symptoms/impact on quality of life [QoL]) with respect to defining a patient as having chronic hypoparathyroidism that was not adequately controlled on conventional therapy. Consensus was achieved when more than 80% of respondents agreed. Results Among the three countries, panellists agreed that characteristics within four of the five categories (patient characteristics, comorbidities, biochemistry, and symptoms/impact on QoL) were important for defining inadequate control. Characteristics deemed important in groups 2–4 included a history of compliance problems and chronic kidney disease stages 4 and 5. In groups 2 and 4, the biochemical parameters deemed important were serum calcium, urinary calcium, and serum creatinine. In groups 3 and 4, tingling or numbness in the hands/feet and face was the only symptom deemed important in all three countries. Conclusion Delphi panels conducted in three European countries provided national consensus on key parameters of patient characteristics, biochemistry, comorbidities, and symptoms/impact on QoL that define not adequately controlled chronic hypoparathyroidism. These characteristics should be tested more widely for their applicability in clinical practice. Funding Shire International GmbH, Zug, Switzerland, a member of the Takeda group of companies.

Clinicians’ Perspectives on Cure in Adult Patients with Acute Lymphoblastic Leukemia with Minimal Residual Disease: A Delphi Study Abstract Hematologic complete remission (CR) is achievable for most adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL). However, minimal residual disease (MRD) in patients with hematologic CR is associated with increased risk of relapse, shorter survival, and poorer transplantation outcomes. This study explored the concept of cure in adults with Philadelphia chromosome-negative (Ph−) BCP-ALL by MRD status at first hematologic CR (CR1) to inform evaluation of the clinical and economic benefits of new agents, where the concept of cure is important but long-term data are not available. The study used modified Delphi methodology involving clinicians experienced in the treatment of adult ALL. Participants completed a questionnaire, which was followed by country-specific panel discussions to discuss results and identify consensus on concepts and definitions. Clinicians from France (n = 4), Germany (n = 4), and the UK (n = 5) took part. Participants described cure in terms of the probability of future relapse. Relapse-free survival (RFS) was the preferred outcome measure to describe cure for the three patient groups considered (patients with MRD at CR1; patients who become negative for MRD after further treatment; patients who continue to have MRD). Consensus was reached on definitions of cure: that cure would begin to be considered at 3 years’ RFS and/or would be highly likely at 5 years’ RFS. Participants agreed that patients with MRD should usually undergo hematopoietic stem cell transplantation to have the best chance of survival; consensus was reached that alternatives are required when transplantation is not an option. Panels agreed that patients who achieve cure have a higher mortality rate and lower health-related quality of life than the general population. This study provides quantitative and qualitative information on the concept of cure in Ph− BCP-ALL in CR by MRD status applicable to interpreting the value of new therapies. Funding: Amgen. Plain Language Summary: Plain language summary available for this article.

Correction to: Cardiovascular Risks, Bleeding Risks, and Clinical Events from 3 Phase III Trials of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis In the Original Publication the colors of Figure 2 have been switched. The correct figures are given below.

Model-Based Economic Evaluation of Ceritinib and Platinum-Based Chemotherapy as First-Line Treatments for Advanced Non-Small Cell Lung Cancer in China Abstract Introduction A trial-based assessment was completed to evaluate the cost-effectiveness of ceritinib as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with rearrangement of anaplastic lymphoma kinase. Methods Based on the disease situation of advanced NSCLC, a Markov model was constructed to estimate the costs and benefits of ceritinib and platinum-based chemotherapy. The cost information and health utilities were obtained from published literature. The incremental cost-effectiveness ratio was calculated. The stability of the model was verified by sensitivity analyses. Results The base case analysis results indicated that compared with platinum-based chemotherapy, ceritinib therapy would increase benefits in a 5-, 10- and 15-year time horizon, with extra costs of $230,661.61, $149,321.52 and $136,414.43 per quality-adjusted life-year gained, respectively. The most sensitive parameter in the model analysis was the cost of ceritinib. Probabilistic sensitivity analysis suggested that at the current price of ceritinib, the chance of ceritinib being cost-effective was 0 at the willingness-to-pay threshold of $27,142.85 per quality-adjusted life-year (three times the per capita gross domestic product of China). Conclusion As a first-line treatment for advanced NSCLC with rearrangement of anaplastic lymphoma kinase, ceritinib is unlikely to be cost-effective at the current price from the Chinese healthcare perspective. To meet the treatment demands of patients, it may be a better option to reduce the price or provide appropriate drug assistance policies.

Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors Abstract In the last few years, immunotherapy has transformed the way we treat solid tumors, including melanoma, lung, head neck, breast, renal, and bladder cancers. Durable responses and long-term survival benefit has been experienced by many cancer patients, with favorable toxicity profiles of immunotherapeutic agents relative to chemotherapy. Cures have become possible in some patients with metastatic disease. Additional approvals of immunotherapy drugs and in combination with other agents are anticipated in the near future. Multiple additional immunotherapy drugs are in earlier stages of clinical development, and their testing in additional tumor types is under way. Despite considerable early success and relatively fewer side effects, the majority of cancer patients do not respond to checkpoint inhibitors. Additionally, while the drugs are generally well tolerated, there is still the potential for significant, unpredictable and even fatal toxicity with these agents. Improved biomarkers may help to better select patients who are more likely to respond to these drugs. Two key biologically important predictive tissue biomarkers, specifically, PD-L1 and mismatch repair deficiency, have been FDA-approved in conjunction with the checkpoint inhibitor, pembrolizumab. Tumor mutation burden, another promising biomarker, is emerging in several tumor types, and may also soon receive approval. Finally, several other tissue and liquid biomarkers are emerging that could help guide single-agent immunotherapy and in combination with other agents. Of these, one promising investigational biomarker is alteration or deficiency in DNA damage response (DDR) pathways, with altered DDR observed in a broad spectrum of tumors. Here, we provide a critical overview of current, emerging, and investigational biomarkers in the context of response to immunotherapy in solid tumors.

Is Dipstick Urinalysis Screening Beneficial in Men with Lower Urinary Tract Symptoms? Abstract Introduction Dipstick urinalysis is a widely used screening tool in the evaluation of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). As limited data support the use of dipstick urinalysis, we have used data from three recently published studies to assess clinical outcomes in those who had dipstick urinalysis findings for blood, glucose, and/or leukocytes. Methods We analyzed data from three observational studies involving men interested in using over-the-counter tamsulosin: a self-selection study (SSS) and two actual-use studies of 8-week (AUS8) and 24-week (AUS24) durations. Subgroup analyses focused on pooled data from participants not using α-blockers or other prescription medication for LUTS suggestive of BPH (nonRx users) and who had urine dipstick findings. Data from participants using α-blockers (AUS8) or any prescription BPH medications (SSS and AUS24) are presented as reference. Results Overall, 2488 nonRx users underwent dipstick urinalysis and 680 (27.3%) had positive findings including traces of blood (332; 13.3%), glucose (259; 10.4%), and/or leukocytes (245; 9.8%). Among users of prescription medicines, 21.6% (37/171) in SSS, 27.4% (23/84) in AUS8, and 31.1% (47/151) in AUS24 had urine dipstick findings. The 200 dipstick-positive nonRx users in SSS underwent per protocol urological assessment: 26 (13.0%) had a newly diagnosed condition causing/contributing to urinary symptoms of which 2.9% were identified as medically important conditions. Among nonRx users with or without a dipstick finding, medically important conditions reported included prostate cancer (1.0% vs. 1.0%, respectively) and urolithiasis (1.0% vs. 0.3%, respectively). The proportion of men with dipstick urinalysis findings was similar between men who regularly visited their physician and those who did not. Conclusion Dipstick urinalysis did not markedly increase the detection of undiagnosed medically important conditions that cause/contribute to urinary symptoms, suggesting that this test may not be a very effective screening tool for men with LUTS. Funding Boehringer Ingelheim Pharmaceuticals, Inc.

Oral Corticosteroid Use for the Treatment of Chronic Eosinophilic Disease: A Patient’s and His Physician’s Experience Abstract This article, coauthored by a patient with eosinophilic granulomatosis with polyangiitis (EGPA) initially presenting as severe eosinophilic asthma and his physician-specialist, discusses the use and management of oral corticosteroid (OCS) treatment. It also considers the importance of early diagnosis of a rare disease and patient education. The patient describes his journey from progressive worsening of asthma and eventual diagnosis of EGPA to long-term OCS treatment and then participation in a clinical trial for this rare disease, involving the introduction of targeted biologic therapy with OCS tapering. The physician describes the importance of patient referral to obtain a correct diagnosis and optimal maintenance treatment, the balance between risk of adverse events associated with long-term OCS use and benefits of disease control, and various aspects of patient participation in clinical trials. Finally, the patient describes the role of continual patient education in the management of disease and OCS treatment. These considerations can apply to all chronic inflammatory diseases requiring maintenance OCS treatment. Funding: AstraZeneca.