Characterization and comparability of biosimilars: A filgrastim case of study and regulatory perspectives for Latin America

Background: Developing countries have an estimate of ten times more approved biosimilars than developed countries. This disparity demands the need of an objective regulation that incorporates health policies according to the technological and economical capabilities of each country. One of the challenges lies on the establishment of comparability principles based on a physicochemical and biological characterization that should determine the extent of additional non-clinical and clinical studies. This is particularly relevant for licensed biosimilars in developing countries, which have an extensive clinical experience since their approval as generics, in some cases more than a decade. To exemplify the current status of biosimilars in Mexico, a characterization exercise was conducted on licensed filgrastim biosimilars using pharmacopeial and extended characterization methodologies. Results: Most of the evaluated products complied with the pharmacopeial criteria and showed comparability in their Critical Quality Attributes (CQAs) towards the reference product. These results were expected in accordance with their equivalent performance during their licensing as generics. Accordingly, a rational approval and registration renewal scheme for biosimilars is proposed, that considers the proper identification of CQAs and its thoroughly evaluation using selected techniques. Conclusions: This approach provides support to diminish uncertainty of exhibiting different pharmacological profiles and narrows or even avoids the necessity of comparative clinical studies. Ultimately, this proposal is intended to improve the accessibility to high quality biosimilars in Latin America and other developing countries

Intraabdominal Pressure Targeted Positive End-expiratory Pressure during Laparoscopic Surgery: An Open-label, Nonrandomized, Crossover, Clinical Trial

Transpulmonary driving pressure (ratio of tidal volume to respiratory system compliance) increases with increased intraabdominal pressure during laparoscopic surgery. High transpulmonary driving pressure during laparoscopic surgery is associated with increased risk of postoperative pulmonary complications.Intraoperative positive end-expiratory pressure prevents atelectasis, but may also cause overdistension

Covariate-adjusted measures of discrimination for survival data

MOTIVATION: Discrimination statistics describe the ability of a survival model to assign higher risks to individuals who experience earlier events: examples are Harrell's C-index and Royston and Sauerbrei's D, which we call the D-index. Prognostic covariates whose distributions are controlled by the study design (e.g. age and sex) influence discrimination and can make it difficult to compare model discrimination between studies. Although covariate adjustment is a standard procedure for quantifying disease-risk factor associations, there are no covariate adjustment methods for discrimination statistics in censored survival data. OBJECTIVE: To develop extensions of the C-index and D-index that describe the prognostic ability of a model adjusted for one or more covariate(s). METHOD: We define a covariate-adjusted C-index and D-index for censored survival data, propose several estimators, and investigate their performance in simulation studies and in data from a large individual participant data meta-analysis, the Emerging Risk Factors Collaboration. RESULTS: The proposed methods perform well in simulations. In the Emerging Risk Factors Collaboration data, the age-adjusted C-index and D-index were substantially smaller than unadjusted values. The study-specific standard deviation of baseline age was strongly associated with the unadjusted C-index and D-index but not significantly associated with the age-adjusted indices. CONCLUSIONS: The proposed estimators improve meta-analysis comparisons, are easy to implement and give a more meaningful clinical interpretation

Risk factors for unfavourable postoperative outcome in patients with Crohn's disease undergoing right hemicolectomy or ileocaecal resection. An international audit by ESCP and S-ECCO

Aim: Patient- and disease-related factors, as well as operation technique, all have the potential to impact on postoperative outcome in Crohn's disease. The available evidence is based on small series and often displays conflicting results. The aim was to investigate the effect of preoperative and intra-operative risk factors on 30-day postoperative outcome in patients undergoing surgery for Crohn's disease. Method: This was an international prospective snapshot audit including consecutive patients undergoing right hemicolectomy or ileocaecal resection. The study analysed a subset of patients who underwent surgery for Crohn's disease. The primary outcome measure was the overall Clavien\u2013Dindo postoperative complication rate. The key secondary outcomes were anastomotic leak, reoperation, surgical site infection and length of stay in hospital. Multivariable binary logistic regression analyses were used to produce odds ratios and 95% confidence intervals. Results: In all, 375 resections in 375 patients were included. The median age was 37 and 57.1% were women. In multivariate analyses, postoperative complications were associated with preoperative parenteral nutrition (OR 2.36, 95% CI 1.10\u20134.97), urgent/expedited surgical intervention (OR 2.00, 95% CI 1.13\u20133.55) and unplanned intra-operative adverse events (OR 2.30, 95% CI 1.20\u20134.45). The postoperative length of stay in hospital was prolonged in patients who received preoperative parenteral nutrition (OR 31, 95% CI 1.08\u20131.61) and those who had urgent/expedited operations (OR 1.21, 95% CI 1.07\u20131.37). Conclusion: Preoperative parenteral nutritional support, urgent/expedited operation and unplanned intra-operative adverse events were associated with unfavourable postoperative outcome. Enhanced preoperative optimization and improved planning of operation pathways and timings may improve outcomes for patients

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.

BACKGROUND: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. METHODS: We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. FINDINGS: The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride. INTERPRETATION: These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease

Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study

To provide a global, up-to-date picture of the prevalence, treatment, and outcomes of Candida bloodstream infections in intensive care unit patients and compare Candida with bacterial bloodstream infection. DESIGN: A retrospective analysis of the Extended Prevalence of Infection in the ICU Study (EPIC II). Demographic, physiological, infection-related and therapeutic data were collected. Patients were grouped as having Candida, Gram-positive, Gram-negative, and combined Candida/bacterial bloodstream infection. Outcome data were assessed at intensive care unit and hospital discharge. SETTING: EPIC II included 1265 intensive care units in 76 countries. PATIENTS: Patients in participating intensive care units on study day. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of the 14,414 patients in EPIC II, 99 patients had Candida bloodstream infections for a prevalence of 6.9 per 1000 patients. Sixty-one patients had candidemia alone and 38 patients had combined bloodstream infections. Candida albicans (n = 70) was the predominant species. Primary therapy included monotherapy with fluconazole (n = 39), caspofungin (n = 16), and a polyene-based product (n = 12). Combination therapy was infrequently used (n = 10). Compared with patients with Gram-positive (n = 420) and Gram-negative (n = 264) bloodstream infections, patients with candidemia were more likely to have solid tumors (p < .05) and appeared to have been in an intensive care unit longer (14 days [range, 5-25 days], 8 days [range, 3-20 days], and 10 days [range, 2-23 days], respectively), but this difference was not statistically significant. Severity of illness and organ dysfunction scores were similar between groups. Patients with Candida bloodstream infections, compared with patients with Gram-positive and Gram-negative bloodstream infections, had the greatest crude intensive care unit mortality rates (42.6%, 25.3%, and 29.1%, respectively) and longer intensive care unit lengths of stay (median [interquartile range]) (33 days [18-44], 20 days [9-43], and 21 days [8-46], respectively); however, these differences were not statistically significant. CONCLUSION: Candidemia remains a significant problem in intensive care units patients. In the EPIC II population, Candida albicans was the most common organism and fluconazole remained the predominant antifungal agent used. Candida bloodstream infections are associated with high intensive care unit and hospital mortality rates and resource use

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial.

AIMS: The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). METHODS AND RESULTS: ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P &lt; 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium 656 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). CONCLUSION: This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM

Erratum to "Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2)" [Gynecol. Oncol. 144 (2017) 396-404]

Objective. Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival. Methods. The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15\u201399 years) diagnosed with ovarian cancer during 1995\u20132009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated agestandardised 5-year net survival by stage at diagnosis (localised or advanced). Results. Survival fromtype I epithelial ovarian tumours for women diagnosed during 2005\u201309 ranged from40 to 70%. Survival from type II epithelial tumours was much lower (20\u201345%). Survival fromgermcell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%). Conclusions. There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology

Erratum to "The histology of ovarian cancer: Worldwide distribution and implications for international survival comparisons (CONCORD-2)" [Gynecol. Oncol. 144 (2017) 405-413]

Objective. Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods. The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995\u20132009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included.We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results. During 2005\u20132009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions. The distribution of ovarian cancer histology varieswidely worldwide. Type I epithelial, germcell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Evaluating the incidence of pathological complete response in current international rectal cancer practice: the barriers to widespread safe deferral of surgery

This is the peer reviewed version of the following article: , which has been published in final form at https://doi.org/10.1111/codi.14361. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."Colorectal Disease © 2018 The Association of Coloproctology of Great Britain and Ireland Introduction: The mainstay of management for locally advanced rectal cancer is chemoradiotherapy followed by surgical resection. Following chemoradiotherapy, a complete response may be detected clinically and radiologically (cCR) prior to surgery or pathologically after surgery (pCR). We aim to report the overall complete pathological response (pCR) rate and the reliability of detecting a cCR by conventional pre-operative imaging. Methods: A pre-planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients treated by elective rectal resection were included. A pCR was defined as a ypT0 N0 EMVI negative primary tumour; a partial response represented any regression from baseline staging following chemoradiotherapy. The primary endpoint was the pCR rate. The secondary endpoint was agreement between post-treatment MRI restaging (yMRI) and final pathological staging. Results: Of 2572 patients undergoing rectal cancer surgery in 277 participating centres across 44 countries, 673 (26.2%) underwent chemoradiotherapy and surgery. The pCR rate was 10.3% (67/649), with a partial response in 35.9% (233/649) patients. Comparison of AJCC stage determined by post-treatment yMRI with final pathology showed understaging in 13% (55/429) and overstaging in 34% (148/429). Agreement between yMRI and final pathology for T-stage, N-stage, or AJCC status were each graded as ‘fair’ only (n = 429, Kappa 0.25, 0.26 and 0.35 respectively). Conclusion: The reported pCR rate of 10% highlights the potential for non-operative management in selected cases. The limited strength of agreement between basic conventional post-chemoradiotherapy imaging assessment techniques and pathology suggest alternative markers of response should be considered, in the context of controlled clinical trials