The genetics and biology of KRAS in lung cancer

Mutational activation of KRAS is a common oncogenic event in lung cancer and other epithelial cancer types.Efforts to develop therapies that counteract the oncogenic effects of mutant KRAS have been largely unsuccessful,and cancers driven by mutant KRAS remain among the most refractory to available treatments.Studies undertaken over the past decades have produced a wealth of information regarding the clinical relevance of KRAS mutations in lung cancer.Mutant Kras-driven mouse models of cancer,together with cellular and molecular studies,have provided a deeper appreciation for the complex functions of KRAS in tumorigenesis.However,a much more thorough understanding of these complexities is needed before clinically effective therapies targeting mutant KRAS-driven cancers can be achieved.     

Targeting inflammation in pancreatic cancer: Clinical translation

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma.     

Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations

PURPOSE： Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities.     

Cancer stem cell hypothesis and gastric carcinogenesis: Experimental evidence and unsolved questions

Traditionally, the clonal evolution model has been used to explain gastric cancer (GC) growth dynamics. According to this model, GC cells result from multiple mutations over time resulting in a population of continually diversifying cells. This heterogeneity enables the survival of different clones under particular conditions allowing growth at metastatic locations or resistance to chemotherapeutics. Cancer stem cell (CSC) theory completely overturns this traditional understanding of cancer suggesting that only CSCs can self-renew and promote tumor growth. CSCs are relatively refractory to conventional therapies, thus explaining why anti-cancer therapies are far from curative and why relapses of cancer are frequent. The identification of the CSC component of a tumor might, thus, open new therapeutic perspective based on the selective targeting of this small population of cells. In this review we examine the current scientific evidence supporting the existence of CSC in gastric tumors and analyze the main unsolved questions of this difficult field of cancer research.     

Application of next-generation sequencing in clinical oncology to advance personalized treatment of cancer

With the development and improvement of new sequencing technology,next-generation sequencing(NGS) has been applied increasingly in cancer genomics research over the past decade.More recently,NGS has been adopted in clinical oncology to advance personalized treatment of cancer.NGS is used to identify novel and rare cancer mutations,detect familial cancer mutation carriers,and provide molecular rationale for appropriate targeted therapy.Compared to traditional sequencing,NGS holds many advantages,such as the ability to fully sequence all types of mutations for a large number of genes(hundreds to thousands) in a single test at a relatively low cost.However,significant challenges,particularly with respect to the requirement for simpler assays,more flexible throughput,shorter turnaround time,and most importantly,easier data analysis and interpretation,will have to be overcome to translate NGS to the bedside of cancer patients.Overall,continuous dedication to apply NGS in clinical oncology practice will enable us to be one step closer to personalized medicine.     

Function of PCA3 in prostate tissue and clinical research progress on developing a PCA3 score

Prostate cancer gene 3 （PCA3, also known as DD3） is a new biomarker that could improve the accuracy of prostate cancer diagnosis. It is a great biomarker with fairly high specificity and sensitivity. The incidence of prostate cancer is rising steadily in most countries. The commonly used prostate-specific antigen （PSA） test once gave people hope for early diagnosis of prostate cancer. However, the low specificity of the PSA test has resulted in a large number of unnecessary biopsies and overtreatment. During the past decade, many new prostate cancer biomarkers have been found. Among these, PCA3 is the most promising. Due to its great performance in distinguishing prostate cancer from other prostate conditions, PCA3 could likely be applied for early diagnosis of prostate cancer, patient follow-up, prognosis prediction, and targeted therapy. After years of research, we have obtained some knowledge about the sequence of PCA3 gene. We have also determined the relationship between PCA3 and the proliferation of prostate cancer cells and learned some information about how PCA3 affects tumor-related genes and proteins. A PCA3 score has been created, and it has been used in a variety of studies. Some researchers have even applied PCA3 to targeted therapy and obtained a good effect in vitro. This review describes the current state of research, and explores the future prospects for PCA3.     

The Current Adjuvant Therapies for the Glioblastoma multiforme: Chemotherapy, Targeted Molecular Therapy and Immunogene Therapy

Glioblastoma multiforme （GBM） is by far the most common type of primary brain tumors and regarded as grade IV tumors by WHO classification. Although the treatment strategies including maximal surgical resection, concurrent radiation and chemotherapy with temozolomide are current recommendations to patients with GBM, the prognosis is still poor and the median survival is less than 2 yem~. Major challenge for the successful treatment of GBM is the diversity of cell types and mutations in the tumor. These tumors are composed of highly heterogeneous cell populations that are often characterized by high chemo-resistance. Furthermore, because a variety of genes may be mutated or overexpressed in different areas of the tumors, no one treatment is likely to destroy the tumor, With advance in the molecular biology in the field of oncology, new critical signaling pathway involved in development and progression of GBM have been discovered, which leads to emergency of new treatment strategies to target these signaling pathways with the goal to increase specific efficacy. These targeted therapies hold the promise of providing new, more effective treatment options with minimal toxicity. In this review, we described current chemotherapeutic modalities for GBM and introduce the new targeted therapies in the context of current treatment options for patients with GBM. In addition, it is also addressed the issue of drug delivery as a factor limiting the efficacy＇ of systemic administration of therapeutics and attempt to overcome this barrier. To improve outcomes of treatment for GBM, futtn-e investigation will focus on elucidating the novel molecular signaling pathways and oncogenic mechanisms underlying tumor resistance to treatment and tumor recurrence.     

The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer

The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.     

Therapeutic resistance in cancer： microRNA regulation of EGFR signaling networks

Receptor tyrosine kinases （RTKs） such as the epidermal growth factor receptor （EGFR） regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies. A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs （miRs） as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.     

编者按:胰腺癌的临床与基础研究

With its incidence （10-11 per 100, 000 people） almost equaling its prevalence, pancreatic cancer is one of the most aggressive human tumors. Understanding the exceptionally aggressive behavior has been the objective of clinical and basic research elucidating in detail the molecular changes that lead to the development and the progression of this disease. The molecular alterations observed range from gross chromosomal abnormalities to gene mutations and epigenetic changes, which contribute together to the aggressive growth of pancreatic cancer with retroperitoneal and perineural infiltration, angioinvasion, and early metastases. Clinically, pancreatic cancer is characterized by high rates of local relapse after resection,     

胰腺癌:靶向治疗的前景

Pancreatic cancer is a devastating disease characterized by almost identical incidence and mortality rates. Since this tumour is mostly diagnosed in an advanced stage there is usually no option for a curative surgical resection. In addition, pancreatic cancers known to be resistant to conventional treatment modalities such as chemotherapy and radiotherapy. Therefore, novel strategies for targeting these tumors are urgently needed. The increasing knowledge on the underlying pathogenetic mechanisms has led to the identification of surface receptor molecules that initiate intracellular signalling cascades upon ligand binding, thus leading to tumor progression. Targeting these receptors or their secreted ligands is therefore an attractive new approach for cancer therapy. The epidermal growth factor receptor （EGFR） and the vascular endothelial growth factor receptor （VEGFR） are transmembrane tyrosine kinase receptors which can be targeted by various compounds such as antibodies or small molecule inhibitors. In addition, various molecules targeting proteins secreted by pancreatic cancers such as matrix metalloproteinases （MMP＇s） or intracellular oncogenic signalling components such as the farnesyltransferase have been proposed as potential new approaches for targeted cancer therapy. The use of these agents alone or in combination with conventional therapeutic regimens is currently being evaluated and shows first promising results for pancreatic cancer therapy.     

Asian trends in primary androgen depletion therapy on prostate cancer

There are notable differences in the incidence and mortality rates for prostate cancer between Asia and Western countries. It is also recognized that there are differences in thinking with regard to treatment options. Recently it is also the case that opinions have been reported concerning the differences between Asian and Western patients with regard to their reaction to androgen depletion therapy （ADT）. Given that ADT is a method of treatment that focuses on the elimination of testosterone, an inevitable symptom of its administration is testosterone losing syndrome. It is for this reason that in Western countries ADT has only been recommended in cases of advanced or metastatic cancer. On the other hand, in Asia, ADT is used in relatively many cases, including non-metastatic localized cancer and invasive localized cancer. To date, however, there has been little substantive discussion concerning this difference in utilization ofADT. ADT-related drugs for prostate cancer and the development of new drugs for castration resistant prostate cancer （CRPC） have been actively tested in recent years. It could be the case that analyzing the differences in concepts about ADT between Asia and the West could contribute to the effective use of ADT-related drugs and also help to build new treatment strategies for prostate cancer.     

胰腺癌:姑息性化学治疗

Single-agent Gemcitabine has been the standard treatment for advanced pancreatic adenocarcinoma in the past years. Due to the aggressive and often chemotherapy-refractory character of this malignancy, systemic treatment options still remain limited. Many combination therapies have been evaluated in clinical trials to improve survival over Gemcitabine alone, until recently without satisfying results. Based on the positive results of a recent randomized trial, the combination of Gemcitabine and Capecitabine might become a new standard as first-line treatment for advanced pancreatic cancer. The clinical advantage of Erlotinib as a novel targeted agent in combination with Gemcitabine seems to be only marginal. Due to the small number of studies, there is still no standard of care in second-line therapy, but Oxaliplatin seems to be an active treatment option in Gemcitabine refractory disease. This article will review the development of cytotoxic antitumoral treatment for advanced pancreatic adenocarcinoma （locally advanced, irresectable and/or metastatic disease） including monotherapies and newer approaches with combination therapies.     

Radiotherapy for Carcinoma of the Esophagus： Progress of Treatment and Research in China

ABSTRACT Carcinoma of the esophagus is a common malignancy in China. Radiotherapy is one of the most important modalities of treatment. This article provides a review of the natural history of this disease, the results of radiotherapy for esophageal cancer and the recent advances in radiation techniques in China. Significant progress has been made in this area of research and treatment. Combined treatment modalities and new therapies are being evaluated and may be expected to contribute to improved patient outcomes and better palliation of symptoms in the future.     

Inhibition of human esophageal squamous cell carcinomas by targeted silencing of tumor enhancer genes： an overview

Esophageal cancer has been reported as the ninth most common malignancy and ranks as the sixth most frequent cause of death worldwide. Esophageal cancer treatment involves surgery, chemotherapy, radiation therapy, or combination therapy. Novel strategies are needed to boost the oncologic outcome. Recent advances in the molecular biology of esophageal cancer have documented the role of genetic alterations in tumorigenesis. Oncogenes serve a pivotal function in tumorigenesis. Targeted therapies are directed at the unique molecular signature of cancer cells for enhanced efficacy with low toxicity. RNA interference（RNAi） technology is a powerful tool for silencing endogenous or exogenous genes in mammalian cells. Related results have shown that targeting oncogenes with siRNAs, specifically the mRNA, effectively reduces tumor cell proliferation and induces apoptotic cell death. This article will briefly review studies on silencing tumor enhancer genes related to the induction of esophageal cancer.     

Inducing immunogenic cell death in immuno-oncological therapies

Immunotherapy has revolutionized cancer treatment and substantially improved patient outcomes with respect to multiple types of tumors. However, most patients cannot benefit from such therapies, mainly due to the intrinsic low immunogenicity of cancer cells(CCs) that allows them to escape recognition by immune cells of the body.Immunogenic cell death(ICD), which is a form of regulated cell death, engages in a complex dialogue between dying CCs and immune cells in the tumor microenvironment(TME),...     

Circulating tumor cells (CTCs) in breast cancer: a diagnostic tool for prognosis and molecular analysis

Metastatic breast cancer(MBC)is characterized by a combination of tumor growth,proliferation and metastatic progression and is typically managed with palliative intent.The benefit of standard systemic therapies is relatively limited and the disease is considered incurable suggesting the need to investigate the biological drivers of the various phases of the metastatic process in order to improve the selection of molecularly driven therapies.The detection,enumeration and molecular analysis of circulating tumor cells(CTCs)provide an intriguing opportunity to advance this knowledge.CTCs enumerated by the Food and Drugs Administration-cleared CellSearch TM system are an independent prognostic factor of progressionfree survival(PFS)and overall survival(OS)in MBC patients.Several published papers demonstrated the poor prognosis for MBC patients that presented basal CTC count ≥5 in 7.5mL of blood.Therefore,the enumeration of CTCs during treatment for MBC provides a tool with the ability to predict progression of disease earlier than standard timing of anatomical assessment using conventional radiological tests.During the metastatic process cancer cells exhibit morphological and phenotypic plasticity undergoing epithelialmesenchymal transition(EMT).This important phenomenon is associated with down regulation of epithelial marker(e.g.,EpCAM)with potential limitations in the applicability of current CTCs enrichment methods.Such observations translated in a number of investigations aimed at improving our capabilities to enumerate and perform molecular characterization of CTCs.Theoretically,the phenotypic analysis of CTCs can represent a "liquid" biopsy of breast tumor that is able to identify a new potential target against the metastatic disease and advance the development and monitoring of personalized therapies.     

D2 lymphadenectomy in gastric cancer surgery

Gastric cancer is one of the most common causes of cancer death worldwide. Surgery is the most widely utilized treatment for resectable gastric cancer. Evidence indicates that lymph node involvement and depth of invasion of the primary tumor are the most important prognostic factors for gastric cancer patients. Therefore, lymph node clearance is deemed a key procedure in gastric cancer surgery for the prognostic value to patients. Although the appropriate lymphadenectomy during gastrectomy for cancer still remains controversial, extended lymph node dissection （D2 lymphadenectomy） should be recommended in high volume hospitals.     

Analysis of Clinicopathologic Features of Esophageal Carcinoma Patients Undergoing Surgery--a Report of 4,329 Cases

OBJECTIVE To investigate the clinicopathological features of esophageal carcinoma （EC） patients, and to analyze epidemiologic characteristics and the current situation of esophageal cancioma in the southern area of Hebei Province.
METHODS A total of 4329 patients with esophageal cancinoma, undergoing surgery in the Fourth Hospital of Hebei Medical University during a period from January 1996 to December 2005, were selected. Collection and statistical analysis of the pathologic data were performed using a SAS 6.0 software package.
RESULTS Over the past ten years, there has been a tendency for an increase in the mean age of EC onset （P 〈 0.05）, a downtrend in the percentage of squamous cancer （SqCa） （P 〈 0.05） and an uptrend in the frequency of small cell carcinoma （P 〈 0.05）. In clinical stages, there was a drop in the percentage of Stage-Ⅱ squamous EC patients （P 〈 0.05）, and an increase in that of Stage-Ⅳ patients （P 〈 0.05）. There were statistical differences in sex, age, pathologic types, depth of infiltration, ratio of stages and lymph node metastasis, etc. among the superior, middle and inferior segments of the EC diseased region （P 〈 0.05）.
CONCLUSION It was relatively late for the EC patients from this area to see a doctor, resulting in a drop in the ratio of SqCa and an ascensus in that of small cell cancer. However, due to a low incidence of adenocarcinoma, no obvious ascending tendency was found in the frequency of this carcinoma over the past ten years.