Significance of emerging clinical oncology endpoints in support of overall survival

Despite a better understanding of the pathophysiology and development of newer therapeutic options, cancer remains an area with several unmet needs. Although overall survival (OS) remains a gold standard endpoint for all cancer therapies, it poses challenges such as the requirement of a long?term follow?up, a higher number of patients, and a higher financial burden. Therefore, surrogate endpoints such as progression?free survival, time to progression, duration of response, and objective response rate are being investigated and used in oncology studies. Patient?related outcomes that measure the patient抯 overall health, quality of life, and satisfaction in the long term are crucial surrogate endpoints considered for drug approval. Surrogate endpoints shorten oncology clinical studies and accelerate the evaluation and implementation of newer therapies. Emerging surrogate endpoints such as biomarkers, immune?related response criteria, minimal residual disease, and pathological complete response are increasingly being considered in oncology trials. Validation of surrogate endpoints enables their substitution for OS and gain market approval. The selection of surrogate endpoints for an oncology trial depends on cancer type and stage, the purpose of treatment, and expected duration of survival for the relevant disease. With the advent of individualized approach and complex study designs, the field of oncology is currently undergoing a paradigm shift. The use of newer surrogate endpoints will aid in accelerating the drug development process, making patient care for oncology more accessible

A practical guide to understanding, using and including patient reported outcomes in clinical trials in ovarian cancer / 부인종양

Health related quality of life (HRQOL) is a key priority for patients with ovarian cancer as there is significant morbidity associated with the disease and the treatment. It is therefore essential to include measures of HRQOL and patient reported outcomes (PROs) in all clinical trials and ideally report them in the initial manuscript. The results of these analyses help interpret the primary trial endpoints which are typically progression free survival and overall survival from the perspective of the patients, but can also assist with regulatory approval of new drugs and inform future patients regarding the potential benefits and downsides of the treatment as well as help support clinical recommendations. Including PROs in clinical trials allows patient-defined clinical benefits to be assessed in parallel to traditional survival outcomes to provide a more holistic overview and aid in the interpretation of the trial results. Given the importance of these instruments in clinical trials, greater effort is required to improve the appropriate inclusion, quality of analyses and reporting of PROs. It is also essential that all clinicians understand the intricacies of the selection, implementation and interpretation of these measures of HRQOL and PRO's and how important their contribution is to clinical trials as well as clinical practice. This review is a practical guide for clinicians to gain a better understanding of PROs and how they can be incorporated into ovarian cancer trials.

Endpoints for evaluating drug-induced liver injury in vitro and their application in detection systems / 中国药理学与毒理学杂志

Drug-induced liver injury (DILI) is a major cause of acute liver failure in clinic.Numerous emerging cell-based models and high-throughput screening technologies are being applied to hepato?toxicity evaluation in vitro.Before applying these emerging technologies and approaches,it is important to determine which endpoints should be included in the testing system to improve the predictive power of DILI. Based on the important mechanisms of DILI, this review introduces the endpoints that can be used for in vitro evaluation of DILI,such as hepatotoxicity,mitochondrial toxicity,cholestatic,liver injury caused by active metabolites,and immune-based liver injury.The application of these endpoints in DILI detection systems and the challenges in the application process are summarized so as to provide refer?ence for in vitro evaluation of hepatotoxicity in the early stage of new drug development.

Nutrition Therapy in Crohn’s Disease / 胃肠病学

Nutrition therapy is an important part of the treatment of Crohn’s disease(CD),which plays an important role in correcting malnutrition,inducing disease remission,and for the perioperative management. Nutrition therapy, especially enteral nutrition(EN),has been studied for its effect on CD. We have long been focusing on the use of nutrition therapy in the treatment of CD,especially the use of EN in the perioperative management of CD. Here,we reviewed the indications,effects,endpoints and the underlying mechanisms of preoperative nutrition therapy,through which we hope can shed light on improving the optimization of preoperative management as well as the standardization of preoperative nutrition therapy in CD.

Desenlaces clínicos en hematoncología: diez años de investigaciones en Pubmed / Clinical outcomes in Hemato-Oncology: Ten year Pubmed literature review

Objetivo: Determinar cuáles son los desenlaces clínicos empleados en los estudios fase III de tratamiento de neoplasias hematoncológicas y qué proporción de ellos emplean supervivencia global como desenlace primario. Método: Mediante una búsqueda en Pubmed, analizar todos los experimentos clínicos aleatorios publicados en los últimos 10 años, de tratamientos de novo, en población adulta. Resultados: La búsqueda inicial arrojó 310 referencias, entre las que se seleccionaron 90 estudios clínicos. La enfermedad más estudiada fue mieloma múltiple, con 29 estudios, seguida de linfoma no Hodgkin, con 26. Las otras fueron: leucemia mieloide aguda (12), leucemia linfocítica crónica (10), leucemia mieloide crónica (8), síndromes mielodisplásicos (3) y linfoma de Hodgkin (2). En 20 estudios (22%) se empleó la supervivencia global como desenlace primario (en solo 3 de ellos alcanzó significación estadística), en 37 más (41%) se agrupó con otros desenlaces para conformar un desenlace compuesto. En 55 estudios (61%) la supervivencia global fue un desenlace secundario. Conclusiones: Aunque la supervivencia global es el estándar de oro en terapia oncológica, los desenlaces agrupados u otros, como tiempo libre de enfermedad o indicadores paraclínicos de actividad de la enfermedad, son más empleados, quizá por ser buenos predictores y requerir muestras y seguimientos menores. Su capacidad para predecir supervivencia global (en algunos casos calidad de vida) debe ser validada. Solo en las formas más agresivas de cáncer se justifica usar de rutina la supervivencia global como el desenlace primario.

Objective: To describe the clinical outcomes used in phase III studies in Hematology-Oncology malignancies, and to determine what proportion use overall survival as the primary outcome. Methods: Using a systematic literature search in PubMed, an analysis was made of phaseIII randomized clinical trials with de novo treatments of hematology-oncological neoplasias in adult populations published in the last 10 years. Results: The initial search yielded 310 references, 90 of which were finally selected. The overall survival rate was used in 20 studies (22%) as the primary outcome (in 3 of them it reached statistical significance). Grouped intermediate outcomes were used in 37 others (41%). As a secondary outcome the overall survival rate was used in 55 studies (61%). Among the intermediate outcomes used were, response rates, disease-free or relapse-free survival rates, and progression-free survival rate. Multiple myeloma was the most studied disease, with 29 studies (32%), followed by non-Hodgkin lymphoma (28%). Conclusions: Although overall survival rate is the gold standard in cancer therapy, it is not the most often used outcome. Intermediate outcomes, such as disease-free survival or biomarkers are often good predictors, and require smaller samples and less follow-up time. Nevertheless, their predictive capacity for overall survival rate (or, in some cases, quality of life) should also be assessed. The use of the overall survival rate as the routine primary outcome is only justified in the most aggressive forms of cancer.

Developmental and neurobehavioural toxicity study of arsenic on rats following gestational exposure.

To characterize developmental and behavioral alterations induced by arsenic exposure, Albino rats were exposed to arsenic (0, 1.5, 3.0 and 4.5 mg/kg/day/po) from gestation day 8 to till parturition and the offspring were observed over the first 3 postnatal weeks, until they were weaned on post-natal day (PND) 21. Once the pups were delivered (PND0), the treatment was discontinued. All pups were assessed for physical development, reflex development, strength and motor coordination from standard neurobehavioural developmental test batteries beginning on PND1. Gestational administration of arsenic at tested dose levels, showed no significant changes in the day of appearance of eye opening, startle reflex, negative geotaxis and spontaneous alteration performance in comparison to the control group. The number of live fetuses, mean fetal body weight and percentages of resorptions or malformations per litter were not affected by arsenic exposure. No treatment-related malformations or developmental variations were noted at any exposure level, suggesting that arsenic exposure at this dose level did not adversely affect behavioural endpoints of developmental toxicity.

Beware – statistics may deceive you.

Statistics is a tool by which a researcher analyzes the data in his research. Sometimes statistics tend to be manipulated to get desired results. This article explains some methods researchers use to get results they desire, why these methods are incorrect and how they can be taken care of. Readers should be aware of these tricks and watch out for such instances of manipulation when analyzing a research paper.

Refining Animal Models to Enhance Animal Welfare / 中国比较医学杂志

The use of animals in research will be necessary for scientific advances in the basic and biomedical sciences for the foreseeable future.As we learn more about the ability of animals to experience pain,suffering,and distress,and particularly for mammals,it becomes the responsibility of scientists,institutions,animal caregivers,and veterinarians to seek ways to improve the lives of research animals and refine their care and use.Refinement is one of the three R's emphasized by Russell and Burch,and refers to modification of procedures to minimise the potential for pain,suffering and distress. It may also refer to procedures used to enhance animal comfort. This paper summarizes considerations for refinements in research animal.

GraPT: Genomic InteRpreter about Predictive Toxicology

Toxicogenomics has recently emerged in the field of toxicology and the DNA microarray technique has become common strategy for predictive toxicology which studies molecular mechanism caused by exposure of chemical or environmental stress. Although microarray experiment offers extensive genomic information to the researchers, yet high dimensional characteristic of the data often makes it hard to extract meaningful result. Therefore we developed toxicant enrichment analysis similar to the common enrichment approach. We also developed web-based system graPT to enable considerable prediction of toxic endpoints of experimental chemical.