Outstanding young Chinese scholars making an impact in the US and China:a joint award program of the US Chinese Anti-Cancer Association and the US National Foundation for Cancer Research

Chinese researchers and physicians are being increasingly recognized for their significant contributions to advancing biomedical research, including cancer research, in China and around the world.To facilitate and strengthen collaboration among cancer researchers and physicians in the United States and China, the US Chinese Anti-Cancer Association (USCACA) and the US National Foundation for Cancer Research (NFCR) have established the USCACA-NFCR Scholar Exchange and Fellowship Program in basic, translational, and clinical studies.The goal of this joint scholar program is to recognize and reward research excellence by Chinese cancer researchers.Recipients are honored with the USCACA-NFCR Scholar Excellence Award for their achievements in cancer research performed while they were in the United States, as well as contributions to eradicating human cancers after their return to China.

Molecular epidemiology of DNA repair gene polymorphisms and head and neck cancer

Although tobacco and alcohol consumption are two common risk factors of head and neck cancer （HNC）, other specific etiologic causes, such as viral infection and genetic susceptibility factors, remain to be understood. Hu- man DNA is often damaged by numerous endogenous and exogenous mutagens or carcinogens, and genetic vari- ants in interaction with environmental exposure to these agents may explain interindividual differences in HNC risk. Single nucleotide polymorphisms （SNPs） in genes involved in the DNA damage-repair response are reported to be risk factors for various cancer types, including HNC. Here, we reviewed epidemiological studies that have assessed the associations between HNC risk and SNPs in DNA repair genes involved in base-excision repair, nucleotide-excision repair, mismatch repair, double-strand break repair and direct reversion repair pathways. We found, however, that only a few SNPs in DNA repair genes were found to be associated with significantly in- creased or decreased risk of HNC, and, in most cases, the effects were moderate, depending upon locus-locus in- teractions among the risk SNPs in the pathways. We believe that, in the presence of exposure, additional pathway- based analyses of DNA repair genes derived from genome-wide association studies （GWASs） in HNC are needed.

Evaluation of conventional radiotherapy vs. conformal radiotherapy in the treatment of non-small-cell lung cancer after surgical resection

Objective： To compare the survival fractions and radiation-induced complications of conventional radiotherapy （CV） vs. conformal radiotherapy （CF） for non-small-cell lung cancer （NSCLC） after surgical resection. Methods： Between 1990 and 2002, 167 patients underwent post-radiotherapy either CV （n = 90） or CF （n = 77） for pathological IliA NSCLC at the University of Texas M.D. Anderson Cancer Center. Patients and tumor charactedstics were balanced in the two treatment groups. Surgical resection mainly consisted of Iobectomy and mediastinal lymph node dissection. In the CV group, postoperative radiotherapy was delivered to 54.3 Gy （range 22-69.6 Gy） in 27 fractions （range 11-58 f） for 5-6 weeks, while the CF group with RT to 53.9 Gy （range 50-63 Gy） in 26 fractions （range 25-33 f） for 5-6 weeks. Overall survival, disease-free survival, local control and distant metastasis-free survival were calculated using the Kaplan-Meier method. The complications of radiotherapy were also compared between the two groups. The median follow-up duration was 36 months in the CV group while 24 months in the CF group. Results： No statistically significant differences were found in terms of disease-free survival, local-regional control and distant metastasis-free survival in the two treatment groups. However, the overall survival was found statistically significant different in the two groups （P = 0.014）. Postoperative radiotherapy complications such as weight loss, skin reaction, dysphagia, and cardiac related complication were similar in the two groups although the lung fibrosis, cardiac complications and hematologic complications were significantly different, and 8 cases of death in the CV group associated with cardiac complications while none was observed in the CF group. Conclusion： The treatment of stage IliA NSCLC using either CV or CF postoperative radiotherapy resulted in similar outcomes in terms of local control, disease-free survival and most of complications. However, CF could achieve better overall survival and less complications such as lung fibrosis, cardiac complications and hematologic complications. The advantage is worth further observation.

Granisetron Transdermal Patch for Treatment of Nausea in Patients Undergoing Cisplatin Based Chemotherapy for Cervical Cancer

Objective: The purpose of this study was to define the incidence of chemotherapy-induced nausea and vomiting (CINV) in newly diagnosed cervical cancer patients receiving cisplatin and radiation treatment;and to determine if the granisetron transdermal patch (Sancuso?) would be appropriate to recommend as part of standard antiemetic regimen for the cisplatin radiation chemotherapy order set. Methods: This is a retrospective case-controlled study of cervical cancer patients receiving cisplatin chemotherapy with radiation (cisXRT);comparing patients receiving the granisetron transdermal patch to matched patients receiving oral 5HT3 blockers. All patients prescribed cisXRT between September 15th 2008 and November 30, 2011 were identified using pharmacy dispensing records. Patients were included if they received at least a partial dose of cisXRT and Sancuso? patch as standard antiemetic prophylaxis prior to cisXRT for cervical cancer treatment. Exclusion criteria included concomitant investigational agents, biotherapy and/or chemotherapy agents;prior chemotherapy;or incomplete or restricted medical records. Patients will be matched based on age. Patients were matched 3:1 (oral:patch). A total of 404 patients that received and completed cisXRT were identified utilizing an existing de-identified database from previous study were reviewed to evaluate parameters of interest. Results: A total of 285 patients’ medication records were reviewed for Sancuso? use, and 47 were identified. Of these 47 charts only five patient cases met eligibility criteria to be included in the study. All five patients that received the granisetron patch had at least three known risk factors for nausea. The nausea/vomiting in these patients did not worsen after receiving the Sancuso? patch, and four out of five had subjective improvement. CINV was unrelated to changes in laboratory values or incidence of other toxicity and was not dose-related. Conclusions: While no definitive conclusions could be drawn from this retrospective analysis, the limited data suggests that patients’ nausea and vomiting did not worsen after receiving the Sancuso? patch, and four out of five patients had subjective improvement. The challenges met and limitations identified justify the need for a prospective study that is now underway to control other contributing variables and evaluate overall efficacy of the granisetron patch for controlling CINV in patients receiving cisplatin plus radiation.

Comparative study of breast cancer in Mexican and Mexican-American women

Breast cancer is the number one cause of can- cer deaths among Hispanic women in the United States, and in Mexico, it recently became the primary cause of cancer deaths. This malign- nancy represents a poorly understood and un- derstudied disease in Hispanic women. The ELLA Binational Breast Cancer Study was es- tablished in 2006 as a multi-center study to as- sess patterns of breast tumor markers, clinical characteristics, and their risk factors in women of Mexican descent. We describe the design and implementation of the ELLA Study and provide a risk factor comparison between women in the U.S. and those in Mexico based on a sample of 765 patients (364 in the U.S. and 401 in Mexico). Compared to women in Mexico, U.S. women had significantly (p < 0.05) lower parity (3.2 vs. 3.9 mean live births) and breastfeeding rates (57.5% vs. 80.5%), higher use of oral contraceptives (60.7% vs. 50.1%) and hormone replacement therapy (23.3% vs. 7.6%), and higher family history of breast cancer (15.7% vs. 9.0%). Re- sults show that differences in breast cancer risk factor patterns exist between Mexico and U.S. women. We provide lessons learned from the conduct of our study. Binational studies are an important step in understanding disease pat- terns and etiology for women in both countries.

Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients

AIM：To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal adenocarcinoma. METHODS：Methylation-specific polymerase chain reaction （MSPCR） was used to examine the promoter methylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal disease （30 with benign gastric disease and 30 with benign colorectal disease）, and 30 healthy donor controls. Apaired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postopertive serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent surgical therapy. RESULTS：The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric （34.0%） and colorectal （28.9%） adenocarcinoma patients were significantly higher than those in patients with benign gastric （3.3%） or colorectal （6.7%） disease or in healthy donors （0%） （P 〈 0.01）. The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis. CONCLUSION：Aberrant CpG island methylation within the promoter region of RASSF1A is a promising biomarker for gastric and colorectal cancer.

Esophageal cancer:diagnosis and management

Esophageal cancer is the 7th leading cause of cancer deaths worldwide.While squamous cell carcinoma is the most prevalent histology internationally,adenocarcinoma of the distal esophagus accounts for nearly 50% of cases in developed countries due to the differences in the etiologic factors such as gastroesophageal reflux disease(GERD) and obesity that predominate.While surgery is the mainstay of treatment of this disease,the utilization of chemoradiation,eitherused postoperatively or neoadjuvantly,has become a standard practice in the United States.What is the optimal management approach is still an area of contention,however,and may be different in different regions around the world.This article reviews some of these controversies,including the role for surgery in patients treated with definitive chemoradiation.At the end,we will also outline recommendations regarding radiotherapy procedures and techniques.

Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma

Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.

Magnetic resonance imaging:Review of imaging techniques and overview of liver imaging

Magnetic resonance imaging(MRI) of the liver is slowly transitioning from a problem solving imaging modality to a first line imaging modality for many diseases of the liver.The well established advantages of MRI over other cross sectional imaging modalities may be the basis for this transition.Technological advancements in MRI that focus on producing high quality images and fast imaging,increasing diagnostic accuracy and developing newer function-specific contrast agents are essential in ensuring that MRI succeeds as a first line imaging modality.Newer imaging techniques,such as parallel imaging,are widely utilized to shorten scanning time.Diffusion weighted echo planar imaging,an adaptation from neuroimaging,is fast becoming a routine part of the MRI liver protocol to improve lesion detection and characterization of focal liver lesions.Contrast enhanced dynamic T1 weighted imaging is crucial in complete evaluation of diseases and the merit of this dynamic imaging relies heavily on the appropriate timing of the contrast injection.Newer techniques that include fluorotriggered contrast enhanced MRI,an adaptation from 3D MRA imaging,are utilized to achieve good bolus timing that will allow for optimum scanning.For accurate interpretation of liver diseases,good understanding of the newer imaging techniques and familiarity with typical imaging features of liver diseases are essential.In this review,MR sequences for a time efficient liver MRI protocol utilizing newer imaging techniques are discussed and an overview of imaging features of selected common focal and diffuse liver diseases are presented.

Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

Acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow （BM） niche is critical to the maintenance and retention of hematopoietic stem cells （HSC）, including leukemia stem cells （LSC）, and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy- induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDFI/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.

Mouse models of Mdm2 and Mdm4 and their clinical implications

Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 induces p53-dependent apoptosis,whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest.Compared to Mdm4 deletion,Mdm2 deletion causes more severe phenotypic defects.Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53,suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis.Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis,which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes.Studies from these mouse models strongly suggest that blocking Mdm2and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.

Mouse models for cancer research

Mouse models of cancer enable researchers to learn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Journal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue.

Challenge of hepatitis C in Egypt and hepatitis B in Mauritania

Egypt has one of the highest prevalence rates of hepatitis C virus(HCV) in the world,mostly with genotype 4 that is highly associated with severe fibrosis. As a consequence,hepatocellular carcinoma has become the leading cause of cancer in this country. Mauritania is a highly endemic area for hepatitis B virus(HBV). HBV and HCV could both be iatrogenically transmitted through infected blood products,infected needles,and medical equipment improperly sterilized. Adequate and efficient healthcare and public health measures with good surveillance programs,access for screening,prevention strategies,and successful treatment are needed to halt the spread of these diseases. Herein,we have reviewed the epidemiology,modes of transmission,predisposing factors,and novel treatment modalities of these viruses. We have proposed practices and interventions to decrease the risk of transmission of HCV and HBV in the affected countries,including strict adherence to standard precautions in the healthcare setting,rigorous education and training of patients and healthcare providers,universal screening of blood donors,use of safetyengineered devices,proper sterilization of medical equipment,hepatitis B vaccination,as well as effective direct-acting antiviral agents for the treatment of HCV.

Imaging of benign and malignant cystic pancreatic lesions and a strategy for follow up

Cystic lesions in a variety of organs are being increasingly recognized as an incidental finding on cross-sectional imaging.These lesions can be benign,premalignant or malignant.When these cystic lesions are small it can be difficult to characterize them radiologically.However,with appropriate clinical history and knowledge of typical imaging features of cystic pancreatic lesions this can enable accurate diagnosis and thus guide appropriate treatment.In this review,we provide an overview of the most common types of cystic lesions and their appearance on computer tomography,magnetic resonance imaging and ultrasound.We will also discuss the follow up and management strategies of these cystic lesions.

The Role of Everolimus in the Treatment of Breast Cancer

The development of resistance to chemotherapy, endocrine therapy and anti HER2 agents in breast cancer is an important and common problem that impacts in the management of patients, particularly in the metastatic setting. This resistance has been explained in part by the activation of signal transduction pathways, including the PI3K/AKT/mTOR. The blockade with mTOR inhibitors such as everolimus is a new target agent for therapy that attempts to enhance treatment efficacy and restore tumor sensitivity. In this review article, we present the data about the use of everolimus for the treatment of breast cancer in all tumor phenotypes. Future studies that evaluate biomarkers for treatment response are needed to identify the specific populations that have the highest benefit of this new targeted therapy.

Sapacitabine,the prodrug of CNDAC,is a nucleoside analog with a unique action mechanism of inducing DNA strand breaks

Sapacitabine is an orally bioavailable prodrug of the nucleoside analog 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine(CNDAC).Both the prodrug and active metabolite are in clinical trials for hematologic malignancies and/or solid tumors.CNDAC has a unique mechanism of action:after incorporation into DNA,it induces single-strand breaks(SSBs) that are converted into double-strand breaks(DSBs) when cells go through a second S phase.In our previous studies,we demonstrated that CNDAC-induced SSBs can be repaired by the transcription-coupled nucleotide excision repair pathway,whereas lethal DSBs are mainly repaired through homologous recombination.In the current work,we used clonogenic assays to compare the DNA damage repair mechanism of CNDAC with two other deoxycytidine analogs:cytarabine,which is used in hematologic malignacies,and gemcitabine,which shows activity in solid tumors.Deficiency in two Rad51 paralogs,Rad51D and XRCC3,greatly sensitized cells to CNDAC,but not to cytarabine or gemcitabine,indicating that homologous recombination is not a major mechanism for repairing damage caused by the latter two analogs.This study further suggests clinical activity and application of sapacitabine that is distinct from that of cytarabine or gemcitabine.

Morphological and molecular basis of ovarian serous carcinoma

Serous carcinoma is the most common type of epithelial ovarian cancer. In this review, we provide a com- prehensive picture of ovarian serous cancers from multiple aspects： the first part of this review summarizes the morphological, histological, and immunological signatures of ovarian serous carcinoma; subsequently, we review the history of the evolvement of different grading systems used in ovarian serous cancer; in the end, we focus on characterizing the genetics that underlie the 2-tiered pathways through which ovarian serous cancers are believed to arise： the low-grade and the high-grade pathways.