Increasingly, cancer drugs are being approved based on surrogate measurements of efficacy. Clinically meaningful data, such as overall survival (OS) and quality of life, are often only presented in ...subsequent publications. We examined if the clinical benefit of cancer drugs, as measured by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), improves post-European Medicines Agency (EMA) approval as more data emerges.
Cancer drug indications approved by the EMA from January 2006 to December 2016 were reviewed and trials cited for efficacy were identified. Primary and subsequent publications (up to December 2019) of scorable trials were included. Changes in benefit over time were measured using ESMO-MCBS thresholds for non-curative (≥4 for substantial, =3 for intermediate and ≤2 for low benefit) and curative intent (A or B for major benefit) scoring.
Fifty-five non-curative and two curative intent trials were included. At approval, 29.1% of non-curative trials were substantial, 45.5% intermediate and 25.5% low benefit. For curative intent trials, one displayed major benefit and one displayed no major benefit. We identified 82 subsequent publications for reassessment. A change in ESMO-MCBS classification was seen in 34.5% of non-curative trials (11 raised and 8 lowered). At 3-year reassessment, 36.4% of non-curative trials were substantial, 34.5% intermediate and 29.1% low benefit. Both curative trials showed no major benefit at reassessment.
As over a third of trials changed classification, in either direction, reassessing the ESMO-MCBS score of approved cancer drugs may help to inform patients and ensure ongoing relevance of regulatory and reimbursement decisions.
•When reassessed, most cancer drugs did not exhibit substantial benefit.•Over a third of drug trials changed benefit classification at 3-year reassessment.•However, a nearly equal number of trials increased and decreased their benefit.•Thus, it may be useful to regularly reassess the benefit of approved cancer drugs.
Abstract The superelastic nature of bones requires matching biomechanical properties from the ideal artificial biomedical implants in order to provide smooth load transfer and foster the growth of ...new bone tissues. In this work, we determine the biomechanical characteristics of porous NiTi implants and investigate bone ingrowth under actual load-bearing conditions in vivo . In this systematic and comparative study, porous NiTi, porous Ti, dense NiTi, and dense Ti are implanted into 5 mm diameter holes in the distal part of the femur/tibia of rabbits for 15 weeks. The bone ingrowth and interfacial bonding strength are evaluated by histological analysis and push-out test. The porous NiTi materials bond very well to newly formed bone tissues and the highest average strength of 357 N and best ductility are achieved from the porous NiTi materials. The bonding curve obtained from the NiTi scaffold shows similar superelasticity as natural bones with a deflection of 0.30–0.85 mm thus shielding new bone tissues from large load stress. This is believed to be the reason why new bone tissues can penetrate deeply into the porous NiTi scaffold compared to the one made of porous Ti. Histological analysis reveals that new bone tissues adhere and grow well on the external surfaces as well as exposed areas on the inner pores of the NiTi scaffold. The in vitro study indicates that the surface chemical composition and topography of the porous structure leads to good cytocompatibility. Consequently, osteoblasts proliferate smoothly on the entire implant including the flat surface, embossed region, exposed area of the pores, and interconnected channels. In conjunction with the good cytocompatibility, the superelastic biomechanical properties of the porous NiTi scaffold bodes well for fast formation and ingrowth of new bones, and porous NiTi scaffolds are thus suitable for clinical applications under load-bearing conditions.
Viral shedding profile of infections caused by the pandemic H1N1 2009 influenza A virus has not been reported. The aim of this study was to determine the viral load in different body sites. Viral ...loads of pandemic H1N1 virus in respiratory specimens, stool, urine, and serum were determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Respiratory specimens from patients with seasonal influenza were used as historical controls. Initial pre-treatment viral load were compared between these two groups. Serial respiratory specimens from patients with pandemic H1N1 virus infection were obtained for analysis of viral dynamics. Twenty-two pandemic H1N1 cases and 44 seasonal influenza historical controls were included. The mean initial viral load before oseltamivir therapy was 1.84 x 10⁸ copies/ml for pandemic H1N1 virus compared with 3.28 x 10⁸ copies/ml in seasonal influenza historical controls (P = 0.085). Among patients with pandemic H1N1 virus infection, peak viral load occurred on the day of onset of symptoms, and declined gradually afterwards, with no virus being detectable in respiratory specimens by RT-PCR 8 days and by culture 5 days after the onset of symptoms respectively, except in one patient. Pandemic H1N1 virus was detected in stool and in urine from 4/9 and 1/14 patients, respectively. Viral culture was also positive from the stool sample with the highest viral load. Younger age was associated with prolonged shedding in the respiratory tract and higher viral load in the stool. Data from this quantitative analysis of viral shedding may have implications for formulating infection control measures. J. Med. Virol. 82:1-7, 2010.
Human infection caused by the avian influenza A H7N9 virus has a case-fatality rate of over 30%. Systematic study of the pathogenesis of avian H7N9 isolate and effective therapeutic strategies are ...needed.
BALB/c mice were inoculated intranasally with an H7N9 virus isolated from a chicken in a wet market epidemiologically linked to a fatal human case, (A/chicken/Zhejiang/DTID-ZJU01/2013 CK1), and with an H7N9 virus isolated from a human (A/Anhui/01/2013 AH1). The pulmonary viral loads, cytokine/chemokine profiles and histopathological changes of the infected mice were compared. The therapeutic efficacy of a non-steroidal anti-inflammatory drug (NSAID), celecoxib, was assessed.
Without prior adaptation, intranasal inoculation of 106 plaque forming units (PFUs) of CK1 caused a mortality rate of 82% (14/17) in mice. Viral nucleoprotein and RNA expression were limited to the respiratory system and no viral RNA could be detected from brain, liver and kidney tissues. CK1 caused heavy alveolar inflammatory exudation and pulmonary hemorrhage, associated with high pulmonary levels of proinflammatory cytokines. In the mouse lung cell line LA-4, CK1 also induced high levels of interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA. Administration of the antiviral zanamivir did not significantly improve survival in mice infected with CK1, but co-administration of the non-steroidal anti-inflammatory drug (NSAID) celecoxib in combination with zanamivir improved survival and lung pathology.
Our findings suggested that H7N9 viruses isolated from chicken without preceding trans-species adaptation can cause lethal mammalian pulmonary infection. The severe proinflammatory responses might be a factor contributing to the mortality. Treatment with combination of antiviral and NSAID could ameliorate pulmonary inflammation and may improve survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ontario publicly funds reference trastuzumab (Herceptin) and four biosimilar trastuzumab products for adjuvant treatment of HER2+ breast cancer. We assessed the real-world safety and effectiveness of ...biosimilar trastuzumab compared to Herceptin for adjuvant treatment of patients with HER2+ breast cancer.
This was a population-based, retrospective study comparing the safety and effectiveness of biosimilar trastuzumab and Herceptin for neoadjuvant/adjuvant treatment of HER2+ breast cancer from 2016 to 2021. Treatment patients started biosimilar trastuzumab from November 2019 to June 2021; historical comparator patients started Herceptin from June 2016 to October 2019. Safety outcomes death within 30 days of last dose of trastuzumab, direct hospitalization, emergency department visit leading to hospitalization, early treatment discontinuation, and in-patient admission for congestive heart failure were measured using logistic/negative binomial regression. Overall survival (OS) was measured using Kaplan-Meier methods and Cox proportional hazards regression. Propensity score matching was applied.
From June 2016 to 2021, 5071 patients with breast cancer were treated with neoadjuvant/adjuvant trastuzumab. The rate of direct hospitalization (RR: 0.85, 95% CI: 0.74-0.98,
-value: 0.032) was significantly lower in biosimilar compared to Herceptin patients. OS (log-rank test
= 0.98) and risk of mortality (HR: 1.29, 95% CI: 0.72-2.30,
-value = 0.39) did not significantly differ between treatment groups.
Biosimilar trastuzumab demonstrated similar safety and effectiveness to Herceptin. The findings can help improve confidence in and use of biosimilars and demonstrate the value of real-world evidence generation for supporting biosimilar implementations and reassessments.
Indices of aggressive or supportive end-of-life (EOL) care are used to evaluate health services quality. Disparities according to sex were previously described, with studies showing that male sex is ...associated with aggressive EOL care. This is a secondary analysis of 69,983 patients who died of a GI malignancy in Ontario between 2006 and 2018. Quality indices from the last 14-30 days of life and aggregate measures for aggressive and supportive EOL care were derived from administrative data. Hospitalizations, emergency department use, intensive care unit admissions, and receipt of chemotherapy were considered indices of aggressive care, while physician house call and palliative home care were considered indices of supportive care. Overall, a smaller proportion of females experienced aggressive care at EOL (14.3% vs. 19.0%, standardized difference = 0.13, where ≥0.1 is a meaningful difference). Over time, rates of aggressive care were stable, while rates of supportive care increased for both sexes. Logistic regression showed that younger females (ages 18-39) had increased odds of experiencing aggressive EOL care (OR 1.71, 95% CI 1.30-2.25), but there was no such association for males. Quality of EOL care varies according to sex, with a smaller proportion of females experiencing aggressive EOL care.
Experience from influenza pandemics suggested that convalescent plasma treatment given within 4 to 5 days of symptom onset might be beneficial. However, robust treatment data are lacking.
This is a ...multicenter, prospective, double-blind, randomized controlled trial. Convalescent plasma from patients who recovered from the 2009 pandemic influenza A(H1N1) (AH1N1) infection was fractionated to hyperimmune IV immunoglobulin (H-IVIG) by CSL Biotherapies (now BioCSL). Patients with severe A(H1N1) infection on standard antiviral treatment requiring intensive care and ventilatory support were randomized to receive H-IVIG or normal IV immunoglobulin manufactured before 2009 as control. Clinical outcome and adverse effects were compared.
Between 2010 and 2011, 35 patients were randomized to receive H-IVIG (17 patients) or IV immunoglobulin (18 patients). One defaulted patient was excluded from analysis. No adverse events related to treatment were reported. Baseline demographics and viral load before treatment were similar between the two groups. Serial respiratory viral load demonstrated that H-IVIG treatment was associated with significantly lower day 5 and 7 posttreatment viral load when compared with the control (P = .04 and P = .02, respectively). The initial serum cytokine level was significantly higher in the H-IVIG group but fell to a similar level 3 days after treatment. Subgroup multivariate analysis of the 22 patients who received treatment within 5 days of symptom onset demonstrated that H-IVIG treatment was the only factor that independently reduced mortality (OR, 0.14; 95% CI, 0.02-0.92; P = .04).
Treatment of severe A(H1N1) infection with H-IVIG within 5 days of symptom onset was associated with a lower viral load and reduced mortality.
ClinialTrials.gov; No.: NCT01617317; URL: www.clinicaltrials.gov.
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