Application of patient-derived tumor models in anticancer drug development and individualized medicine

Malignant tumor is the second leading cause of death due to its high incidence, lack of effective treatment and poor prognosis. The evaluation of anticancer drugs used to based on NCI-60 cell line models, but the limited heterogeneity and the divorce from clinical practice of models lead to extremely low success rate of novel anticancer drugs during clinical trials (less than 10%). In recent years, because of the high heterogeneity and human derived tumor matrix, patient-derived tumor models have been gradually applied to the preclinical evaluation of various antitumor drugs, which shows certain advantages in predicting the clinical efficacy of antitumor drugs. Optimize the drug combination through patient-derived tumor models to achieve individualized medicine has gradually become an indispensable strategy in clinical cancer therapy. The current review summarized the development of patient-derived tumor models, characterized the application, advantages and challenges of them in preclinical antitumor drug evaluation and clinical precise medicine, which will provide a scientific basis and novel insights for further basic research, drug development and clinical application.

Pathological images for personal medicine in Hepatocellular carcinoma:Cross-talk of gene sequencing and pathological images

Background:Considering the great heterogeneity of Hepatocellular carcinoma(HCC),more accurate prognostic models are urgently needed.This paper combined the advantages of genomics and pathomics to construct a prognostic model.Methods:First,we collected data from hepatocellular carcinoma patients with complete mRNA expression profiles and clinical annotations from the TCGA database.Then,based on immune-related genes,we used random forest plots to screen prognosis-related genes and build prognostic models.Bioinformatics was used to identify biological pathways,evaluate the tumor microenvironment,and perform drug susceptibility testing.Finally,we divided the patients into different subgroups according to the gene model algorithm.Pathological models were constructed by obtaining HE-stained sections from TCGA in corresponding subgroups of patients.Results:In this study,we constructed a stable prognostic model that could predict overall survival in HCC patients.The signature consisted of six immune-related genes(BX537318.1,TMEM147,CSPG4P12,AC015908.3,CEBPZOS,and SRD5A3).We found increased levels of infiltration of immune cells in the tumor microenvironment in patients with low risk scores,indicating significant antitumor immunity and corresponding to better clinical outcomes.We then screened nine drugs that were more sensitive in the low-risk group than in the high-risk group.Finally,we addressed the complex cellular changes and phenotypic heterogeneity in the HCC microenvironment by combining genomics and pathomics analysis methods.Conclusion:Our study showed that the prognostic evaluation model of HCC based on the immune signaling pathway is feasible and provided a reference value for potential immunotherapy for HCC.

Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.

Enlightenment about using TCM constitutions for individualized medicine and construction of Chinese-style precision medicine:research progress with TCM constitutions

TCM constitution is a new branch of TCM.It provides enlightenment on individualized medicine,including the development of new models of individualized research based on nine constitutions,the acquisition of comprehensive health information for individuals,and establishment of a consistent individualized diagnosis and treatment system.Further,we propose a Chinesestyle“precision medicine”based on individualization using the TCM constitutions.

Individualized medicine,health medicine,and constitutional theory in Chinese medicine

The patterns of modern science and changes in the medical model can result in the transformation of the current state of individualized and health medicines into being the primary trend in medical development.Chinese and Western medical systems are dissimilar in terms of value orientations,thinking style,and research directions because of their different historical and cultural backgrounds.Individualized treatment in modern medicine is mainly established based on individual genome information and the differences in mononucleotide polymorphisms.However,such treatment method is expensive,creates an uncertain genetic marker,and leads to different result interpretations,among other problems.The Chinese constitutional theory developed in the 1970s expresses the principle behind Chinese health medicine and individual treatment and provides the corresponding methods.The Chinese constitutional theory divides the constitution of the Chinese population into nine categories based on established classification criteria.It promotes the study of the relationship of each constitution to diseases and Chinese medicine preparation toward adjusting the constitution and preventing diseases.The theory also provides methods and tools for individualized treatment.Constitution identification shows the direction and provides the core technology for the evaluation of the health status.By combining the developments in modern biotechnology,new diagnostic techniques and treatment models of constitution-differentiation,disease-differentiation,and syndrome-differentiation can be established for the development of individualized Chinese medicine treatment and health medicine for the international medical community.

Incorporating Pattern Identification of Chinese Medicine into Precision Medicine:An Integrative Model for Individualized Medicine

On 20 January, 2015, U.S. President Obama announced an ambitious plan called ＂Precision Medicine （PM） Initiative＂, aiming to deliver genetics- based medical treatments. PM has shown a promising prospect by tailoring disease treatments and preventions to individuals. However, a predominantly genetics-based method restricts its benefit and applicability in most chronic and complex diseases. Pattern identification （PI） is one of the representative characteristics of Chinese medicine implying the concept of holism and individualized treatment. It is another classification method taking environmental, psychosocial and other individual factors into account. Integrating PI with disease diagnosis of Western medicine will provide a strong complement to genetics-based PM, thus establish an integrative model for individualized medicine. PI provides new perspectives for PM, not only in clinical practice, but also in new drug development and clinical trial design. It is for sure that the integrative approach will ultimately lead to a safer, more convenient and effective patient-centered healthcare and most patients will benefit in the era of PM.

New WHO-reference limits--revolution or storm n a teapot？

Since release of the latest WHO manual with the new lower reference values of semen parameters, a lot of discussion has been raised about their usefulness and appropriateness for assessment of male fertility. As with the previous reference values the new limits do neither allow an andrological diagnosis based on nosological criteria nor clear-cut differentiation between fertility and sub-/infertility. Therefore, considering the fact that fertility is a continuum, the new lower reference limits should not be overestimated. Most probably, more sperm function tests, such as determination of DNA integrity, and--in the future--assessment of biomarkers, such as sperm proteomics will be included into andrological work-up, thus resulting in a more personalized approach of infertility management. On the other hand, the detailed instructions for standard and advanced semen analysis provided in the new manual are very much appreciated and should be adopted by each seriously workin~ laboratory.

Definition and application of precision medicine

In 2011, four major research institutes in America--Academy of Science, National Academy of Engineering, National Institutes of Health and National Science Foundation, released a joint research plan on precision medicine. In January 2015, President Obama announced a propose on research of precision medicine in State of the Union Address, aiming to cure and close to cure cancer, diabetes and other diseases, and obtain the medical records of individuals and families that they may need.

Individual Patient Data Meta-Analysis Is Needed in Chinese Medical Research

Publication biases and collection limitations are the main disadvantages of a traditional meta-analysis based on aggregate patient data（APD）from published articles.Individual patient data（IPD）meta-analysis,as the gold standard of systematic review,is a possible alternative in this context.However,the publications relative to IPD meta-analyses are still rare compared with the traditional ones,especially in the research oriented to Chinese medicine（CM）.In this article,the strengths and detailed functioning of IPD meta-analysis are described.Furthermore,the need for IPD meta-analysis to assess the treatments based on CM was also discussed.Compared with the traditional APD meta-analysis,the IPD meta-analysis might give a more accurate and unbiased assessment and is worth to be recommended to CM researchers.

Surgical strategies for petroclival meningioma in 57 patients

Background Resection of petroclival meningioma （PCM） is difficult for neurosurgeons and usually brings poor performance status. In this study, we evaluated the possible risk factors for unfavorable clinical outcomes of surgical treatment of PCM, and tried to explore the optimal surgical strategies for better postoperative quality of life.Methods We recruited 57 patients （14 male, 43 female, mean age, 50.5 years） who underwent surgical resection of PCM in Huashan Hospital during 2002-2006. The primary outcomes including postoperative neurological deficits,modified Rankin scale （mRS） score and recurrence rate were evaluated, and all potential risk factors were assessed by the X2 test. Odds ratio and 95% confidence interval were calculated by univariate Logistic regression. The mean follow-up time was 34 months.Results Gross total resection was achieved in 58% of patients. One patient died during the perioperative period because of intracranial hemorrhage. Sixty-seven percent of patients experienced new postoperative neurological deficits and 26% had a higher mRS score at follow-up assessment. Postoperative complications were observed in 24 patients.Within the follow-up period, radiographic recurrence occurred in 12.3% of patients at a mean follow-up of 42 months.Postoperative radiosurgery was administered to 19 patients who had residual tumors or recurrence and no furtherprogression was found. Tumor adhesion, hypervascularity and engulfment of neurovascular structures were three risk factors for increased mRS score （P=0.0002; P=0.0051; P=0.0009）. Tumor adherence to adjacent structures clearly affected the extent of resection （P=0.0029）. The risk of postoperative cranial nerve deficits increased with tumor engulfment of neurovascular structures （P=0.0004）.Conclusions Intraoperatively defined tumor characteristics played a critical role in identifying postoperative functional status. An individual treatment strategy after careful preoperative evaluation could help improve quality of life.

Intensified Antiplatelet Treatment Reduces Major Cardiac Events in Patients with Clopidogrel Low Response： A Meta-analysis of Randomized Controlled Trials

Background：Clopidogrel low response （CLR） is an independent risk factor of adverse outcomes in patients undergoing percutaneous coronary intervention （PCI）,and intensified antiplatelet treatments （IAT） guided by platelet function assays might overcome laboratory CLR.However,whether IAT improves clinical outcomes is controversial.Methods：Relevant trials were identified in PubMed,the Cochrane Library,and the Chinese Medical Journal Network databases from their establishment to September 9,2014.Trials were screened using predefined inclusion criteria.Conventional meta-analysis and cumulative meta-analysis were performed using the Review Manager 5.0 and STATA 12.0 software programs.Results：Thirteen randomized controlled trials involving 5111 patients with CLR were recruited.During a follow-up period of 1-12 months,the incidences of cardiovascular （CV） death,nonfatal myocardial infarction （MI）,and stent thrombosis were significantly lower in the IAT arm than in the conventional antiplatelet treatment arm （relative risk [RR] =0.45,95% confidence interval [CI]：0.36-0.57,P 〈 0.000,01）,whereas bleeding was similar between the two arms （RR =1.05,95% CI：0.86-1.27,P =0.65）.Conclusions：IAT guided by platelet function assays reduces the risk of CV death,nonfatal MI,and stent thrombosis （ST） without an increased risk of bleeding in patients undergoing PCI and with CLR.

Metabolic syndrome and androgen deprivation therapy in metabolic complications of prostate cancer patients

Background Incidence of prostate cancer in Chinese males grows significantly in the past decades. Androgen deprivation therapy has been generally employed in the treatment of locally advanced and metastatic prostate cancer for many years, yet only little data was known about the metabolic syndrome in patients receiving hormonal therapy. This study described the prevalence and the changing trends of hormone-related metabolic complications, and analyzed their correlation with different therapies. Methods In 125 patients treated with castration or maximal androgen blockage for at least 12 months, metabolic indicators were analyzed. Results Totally, 13.5% patients in castration group and 30.1% patients in maximal androgen blockage group were diagnosed metabolic syndrome 12 months after the beginning of treatments （X2=4.739, P=0.029）. In castration group, increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 12, increased fasting plasma glucose and blood pressure were significant at the month 4. In maximal androgen blockage group, increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 4, increased fasting plasma glucose and blood pressure were significant at the month 8. Total testosterone and free testosterone in maximal androgen blockage group were significantly lower than castration group at all visits, which were proved to show positive or negative correlations with metabolic indications. Severity of metabolic complications in maximal androgen blockage group was generally more serious than people received castration, with significantly statistical difference or not. Trends of high-density lipoprotein-cholesterol and fasting plasma glucose were significant different between two kinds of therapy （P=0.005, P=-0.019, respectively）.

Progress of radiation oncology： known and unknown

Objective To elaborate known and unknown aspects of radiation oncology.Data sources Data cited in this review were obtained mainly from PubMed and Medline in English from 1999 to 2013,with keywords ＂individualized medicine＂,＂personalized medicine＂,＂radiation dose＂,＂radiation target＂,＂molecular targeted therapy＂,＂molecular imaging＂ and ＂functional imaging＂.Study selection Articles regarding radiation target delineation,radiation doses,new technology and equipment,combination of radiotherapy and molecular targeted therapy as well as other aspects were identified,retrieved and reviewed.Results A larger radiation field and a higher radiation dose are not always better.New equipment and technology are also not always better than conventional equipment and technologies.Effectiveness of radiotherapy combined with molecular targeted therapy needs more data to verify.Conclusion Personalized radiotherapy is the direction for the future.

Practice guidance documents for the diagnosis and management of non-alcoholic fatty liver disease-recent updates and open questions

Primarily driven by an increasingly sedentary lifestyle and hypercaloric nutritionally imbalanced diets,non-alcoholic fatty liver disease(NAFLD)has emerged as the most prevalent liver disease in the US and Europe.NAFLD constitutes an umbrella term that includes a spectrum of disease from non-alcoholic fatty liver(NAFL)to non-alcoholic steatohepatitis(NASH),NASH fibrosis and NASH cirrhosis that are all characterized by≥5%of all hepatocytes being steatotic in patients with little alcohol intake and no apparent alternative causes.