Clinical application of DNA ploidy to cervical cancer screening: A review

Screening for cervical cancer with DNA ploidy assessment by automated quantitative image cytometry has spread throughout China over the past decade and now an estimated 1 million tests per year are done there. Compared to conventional liquid based cytology, DNA ploidy has competitive accuracy with much higher throughput per technician. DNA ploidy has the enormous advantage that it is an objective technology that can be taught in typically 2 or 3 wk, unlike qualitative cytology, and so it can enable screening in places that lack sufficient qualified cytotechnologists and cytopathologists for conventional cytology. Most papers on experience with application of the technology to cervical cancer screening over the past decade were published in the Chinese language. This review aims to provide a consistent framework for analysis of screening data and to summarize some of the work published from 2005 to the end of 2013. Of particular interest are a few studies comparing DNA ploidy with testing for high risk human papilloma virus(hrH PV) which suggest that DNA ploidy is at least equivalent, easier and less expensive than hrH PV testing. There may also be patient management benefits to combining hr HPV testing with DNA ploidy. Some knowledge gaps are identified and some suggestions are made for future research directions.

Evolving treatment landscape for early and advanced pancreatic cancer

Pancreatic ductal adenocarcinoma is an infrequent cancer with a high disease related mortality rate, even in the context of early stage disease. Until recently, the rate of death from pancreatic cancer has remained largely similar whereby gemcitabine monotherapy was the mainstay of systemic treatment for most stages of disease. With the discovery of active multiagent chemotherapy regimens, namely FOLFIRINOX and gemcitabine plus nab-paclitaxel, the treatment landscape of pancreatic cancer is slowly evolving. FOLFIRINOX and gemcitabine plus nab-paclitaxel are now considered standard first line treatment options in metastatic pancreatic cancer. Studies are ongoing to investigate the utility of these same regimens in the adjuvant setting. The potential of these treatments to downstage disease is also being actively examined in the locally advanced context since neoadjuvant approaches may improve resection rates and surgical outcomes. As more emerging data become available, the management of pancreatic cancer is anticipated to change significantly in the coming years.

Heat shock protein 47 promotes tumor survival and therapy resistance by modulating AKT signaling via PHLPP1 in colorectal cancer

Objective:Heat shock protein 47(HSP47)is a collagen-specific molecular chaperone that facilitates collagen maturation.Its role in cancer remains largely unknown.In this study,we investigated the roles o f HSP47 in colorectal cancer(CRC)and therapy resistance.Methods:Expression o f HSP47 in CRC tissues was examined(1)in paired human CRC/adjacent normal tissues,using real time quantitative reverse transcription polymerase chain reaction(qRT-PCR),The Cancer Genome Atlas(TCGA)database,and 22 independent m icroarray databases(curated CRC).In vitro studies on several CRC cell lines(H C T 116,RKO and C C L228)with modulated HSP47 expression were conducted to assess cell viability and apoptosis(TU N EL assay and caspase-3/-7)during exposure to chemotherapy.AKT signaling and co-imm unoprecipitation studies were performed to examine HSP47 and PHLPP1 interaction.In vivo studies using tumor xenografts were conducted to assess the effects of HSP47 modulation on tum or growth and therapy response.Results:HSP47 was upregulated in CRC and was associated with poor prognosis in individuals with CRC.In vitro,HSP47 overexpression supported the survival of CRC cells,whereas its knockdown sensitized cells to 5-fluorouracil(5-FU).HSP47 promoted survival by inhibiting apoptosis,enhancing AKT phosphorylation,and decreasing expression of the AKT-specific phosphatase PHLPP1 when cells were exposed to chemotherapy.These effects were partly results of the interaction between HSP47 and PHLPP1,which decreased PHLPP1 stability and led to more persistent AKT activity.In vivoy HSP47 supported tumor growth despite 5-FU treatment.Conclusions:HSP47 supports the growth of CRC tumors and suppresses the efficacy of chemotherapy via modulation of AKT signaling.

Adaptive response of resistant cancer cells to chemotherapy

Despite advances in cancer therapeutics and the integration of personalized medicine,the development of chemoresistance in many patients remains a significant contributing factor to cancer mortality.Upon treatment with chemotherapeutics,the disruption of homeostasis in cancer cells triggers the adaptive response which has emerged as a key resistance mechanism.In this review,we summarize the mechanistic studies investigating the three major components of the adaptive response,autophagy,endoplasmic reticulum(ER)stress signaling,and senescence,in response to cancer chemotherapy.We will discuss the development of potential cancer therapeutic strategies in the context of these adaptive resistance mechanisms,with the goal of stimulating research that may facilitate the development of effective cancer therapy.

Next generation patient-derived prostate cancer xenograft models

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients＇ tumor tissue into nonobese diabetic/ severe combined immunodeficient （NOD/ SCID） mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer.

Prostate cancer metastasis-driving genes： hurdles and potential approaches in their identification

Metastatic prostate cancer is currently incurable. Metastasis is thoughtto result from changes in the expression of specific metastasis-driving genes in nonmetastatic prostate cancer tissue, leading to a cascade of activated downstream genes that set the metastatic process in motion. Such genes could potentially serve as effective therapeutic targets for improved management of the disease. They could be identified by comparative analysis of gene expression profiles of patient-derived metastatic and nonmetastatic prostate cancer tissues to pinpoint genes showing altered expression,

Leveraging the power of pooled data for cancer outcomes research

Background:Clinical trials continue to be the gold standard for determining the efficacy of novel cancer treatments,but they may also expose participants to the potential risks of unpredictable or severe toxicities.The development of validated tools that better inform patients of the benefits and risks associated with clinical trial participation can facilitate the informed consent process.The design and validation of such instruments are strengthened when we leverage the power of pooled data analysis for cancer outcomes research.Main body:In a recent study published in the Journal of Clinical Oncology entitled "Determinants of early mortality among 37,568 patients with colon cancer who participated in 25 clinical trials from the adjuvant colon cancer endpoints database," using a large pooled analysis of over 30,000 study participants who were enrolled in clinical trials of adjuvant therapy for early-stage colon cancer,we developed and validated a nomogram depicting the predictors of early cancer mortality.This database of pooled individual-level data allowed for a comprehensive analysis of poor prognostic factors associated with early death;furthermore,it enabled the creation of a nomogram that was able to reliably capture and quantify the benefit-to-risk profile for patients who are considering clinical trial participation.This toolcan facilitate treatment decision-making discussions.Conclusion:As China and other Asian countries continue to conduct oncology clinical trials,efforts to collate patient-level information from these studies into a large data repository should be strongly considered since pooled data can increase future capacity for cancer outcomes research,which,in turn,can enhance patient-physician discussions and optimize clinical care.

Colorectal cancer screening: Opportunities to improve uptake, outcomes, and disparities

Colorectal cancer screening has become a standard of care in industrialized nations for those 50 to 75 years of age,along with selected high-risk populations.While colorectal cancer screening has been shown to reduce both the incidence and mortality of colorectal cancer,it is a complex multi-disciplinary process with a number of important steps that require optimization before tangible improvements in outcomes are possible.For both opportunistic and programmatic colorectal cancer screening,poor participant uptake remains an ongoing concern.Furthermore,current screening modalities(such as the guaiac based fecal occult blood test,fecal immunochemical test and colonoscopy) may be used or performed suboptimally,which can lead to missed neoplastic lesions and unnecessary endoscopic evaluations.The latter poses the risk of adverse events,such as perforation and post-polypectomy bleeding,as well as financial impacts to the healthcare system.Moreover,ongoing disparities in colorectal cancer screening persist among marginalized populations,including specific ethnic minorities(African Americans,Hispanics,Asians,Indigenous groups),immigrants,and those who are economically disenfranchised.Given this context,we aimed to review the current literature on these important areas pertaining to colorectal cancer screening,particularly focusing on the guaiac based fecal occult blood test,the fecal immunochemical test and colonoscopy.

Impact of cell death manipulation on the efficacy of photodynamic therapy-generated cancer vaccines

The main task of cancer vaccines is to deliver tumorspecifc antigens to antigen-presenting cells for immune recognition that can lead to potent and durable immune response against treated tumor. Using photodynamic therapy （PDT）-generated vaccines as an example of autologous whole-cell cancer vaccines, the importance is discussed of the expression of death-associated molecules on cancer vaccine cells. This aspect appears critical for the optimal capture of vaccine cells by host’s sentinel phagocytes in order that the tumor antigenic material is processed and presented for immune recognition and elimination of targeted malignancy. It is shown that changing death pattern of vaccine cells by agents modulating apoptosis, autophagy or necrosis can significantly alter the therapeutic impact of PDT-generated vaccines. Improved therapeutic effect was observed with inhibitors of necrosis/necroptosis using IM-54, necrostatin-1 or necrostatin-7, as well as with lethal autophagy inducer STF62247. In contrast, reduced vaccine potency was found in case of treating vaccine cells with apoptosis inhibitors or lethal autophagy inhibitor spautin-1. Therefore, PDT-generated cancer vaccine cells undergoing apoptosis or lethal autophagy are much more likely to produce therapeutic benefit than vaccine cells that are necrotic. These fndings warrant further detailed examination of the strategy using cell death modulating agents for the enhancement of the efficacy of cancer vaccines.

After the Treatment Phase of Colorectal Cancer Care: Survivorship and Follow-Up

The number of long-term colorectal cancer (CRC) survivors has increased substantially over the past three decades due to both ongoing advances in early detection and improvements in cancer therapies. Adult survivors of CRC experience chronic health conditions due to normal issues associated with aging, which is further compounded by the long-term adverse effects of having had cancer and anti-cancer therapies. In addition, they are at a higher risk for CRC recurrences, new primary cancers, and other co-morbidities. This article will provide an overview of the clinical care of adult survivors of CRC. Epidemiologic data will be presented followed by a discussion of the approach to the care of long-term adult survivors of CRC, including surveillance of recurrences and new primary cancers, interventions to manage both physical and psychological consequences of cancer and its treatments, and strategies to address concerns related to unemployment and disability. Finally, we will explore the challenges of healthcare delivery, especially with respect to the coordination of follow-up between cancer specialists and primary care physicians, so as to ensure that all of the survivor’s health needs are met promptly and appropriately.

美国临床肿瘤学会IV期非小细胞肺癌化疗的临床实践指南更新

本文旨在为IV期非小细胞肺癌患者的治疗提供更新版推荐。本文资料检索源自2002年以来公布的相关随机试验文献。此指南范围限于化疗与生物治疗。更新委员会对这些文献进行了总结并提供了推荐更新。162篇文献符合标准被纳入参考。本推荐基于可改善总生存期的治疗方法。仅改善无进展生存期的治疗方法推动了对毒性及生存质量的监测。对于体力状态评分为0分或1分患者的一线治疗,可推荐以铂类为基础的细胞毒性药物的两药联用。对铂类治疗有禁忌的患者,可采用非铂类细胞毒性两药联合。对于体力状态评分为2分的患者,单一细胞毒性药物即可。对于疾病进展或经过4个周期的治疗仍对治疗无反应的患者,应停止一线细胞毒性化疗。即使在6个周期后患者对治疗仍有反应,亦应停止两药细胞毒性化疗。对于伴有明确的表皮生长因子受体(epidermal growth factor receptor,EGFR)突变的患者,可推荐一线采用吉非替尼治疗;对于EGFR突变为阴性或不明确的患者,细胞毒性化疗更佳。除具有特定临床特征的患者外,可推荐贝伐单抗与卡铂-紫杉醇联用。对于通过免疫组化证实EGFR阳性的肿瘤患者,可推荐西妥昔单抗与顺铂-长春瑞滨联用。多西紫杉醇、厄洛替尼、吉非替尼或培美曲塞被推荐作为二线治疗。对于未曾接受过厄洛替尼或吉非替尼治疗的患者,可推荐厄洛替尼作为三线治疗。现有数据不足以推荐常规三线采用细胞毒性药物。已有的证据也不足以推荐常规应用分子标记物选择化疗。

Loss of heterozygosity for loci on chromosome arms 1p and 10q in oligoden-droglial tumors: relationship to outcome and chemosensitivity

Oligodendroglial tumors frequently have deletions ofchromosomal loci on lp and l9q.Loas of heterozygosity(LOH)of chromosome 10 may be a negative prognostic factor.We reviewed 23 patients with oligodendroglial tumors,toevaluate the frequency of lp and 10q LOH and correlate with clinical outcome.Three loci(DlS402,DlSl 172,MCT118)on lp and 2 loci(Dl0S520 and D10S521)on 10q were analyzed for LOH using PCR techniques.

Perceived Barriers to Asthma Therapy in Ethno-Cultural Communities: The Role of Culture, Beliefs and Social Support

Background : Adherence to therapy is integral to successfully managing asthma, which requires comprehension of what, when, and how to use medication and diligence in following management plan. Asthma patients from ethnic minority groups have more morbidity and reported filling their prescriptions less often. Limited information is available in Canadian literature on ethnic differences in their perceptions of asthma management. We aimed to document patient perceived adherence to asthma therapy among targeted ethno-cultural groups. Methods : We evaluated perceived barriers to therapy adherence, including: cultural beliefs and practices, patient/care-provider communication, self-management knowledge, and medication costs. We conducted a cross sectional study and interviewed 85 Chinese or Punjabispeaking adult asthma patients. Results : Lack of sufficient instructions from physicians, language/communication barriers, lack of skills on how to use inhalers, and high medication costs and medication side effects were most reported barriers to proper self-management practices. Most participants lived with others in the same household and reported high social support from home caregivers. The influence of family on self-management practices was obvious. Conclusion: Better understanding of patient needs, provision of culturally and linguistically appropriate education, and inclusion of home caregivers into the management practices are necessary to improve asthma outcomes in Chinese and Punjabi communities.

A Simple Method of Managing the Alveolar Antral Artery during Sinus Lift Surgery

The alveolar antral artery resides lateral to the maxillary sinus and can lead to complications in sinus lift surgery. Traditional approaches that decrease intraoperative bleeding into the surgical field include vessel preservation using multiple bony windows or neutralizing the vessel at the surgical site. Unfortunately, these methods are technique sensitive, time intensive, and may lead to hemosinus and graft loss. The variable distance from the crest of the alveolar ridge and vessel diameter further complicates pre-operative planning. This paper discusses the anatomical features of the alveolar antral artery, techniques for clinical assessment, and current management strategies. We then describe a novel protocol to manage the alveolar antral artery in sinus lift procedures via tamponade of the vessel at a proximal site. This method is faster than those described in the literature, does not require any additional equipment or expertise, and aims to improve long-term graft predictability by decreasing the risk of sinus membrane perforation. The alveolar antral artery is an under-reported source of surgical complications and warrants further research.

浆液性乳头状癌:一种低放射敏感性的子宫内膜癌亚型

Objective. To explore factors that determine the response of endometrial cancer to radiation therapy. Such factors may influence treatment outcome and yield predictive information about individual patients and their tumors. Methods. A retrospective study of the complete pathologic response (pCR) rates in the hysterectomy specimens of patients, who had undergone preoperative radiotherapy for ≥ Stage Ⅱ biopsy-proven endometrial carcinoma, was performed. 62 patient records were reviewed with respect to patient characteristics, tumor stage, histological grade and subtype, radiation technique and dose, and presence or absence of pCR in the post-operative hysterectomy specimen. Results. 24 of 62 specimens exhibited a pCR. The only significant factor with respect to pCR was presence of uterine papillary serous carcinoma (UPSC). None of the seven cases of UPSC displayed a pCR (P = 0.036 Fischer’ s exact test), despite not differing from the non-UPSC cases in any other tumor, treatment, or patient factors. No factors were found that separated non-UPSC cases with a pCR from those without. Conclusions. These data suggest an intrinsic radioresistance within UPSC, which may have implications for future treatment strategies. UPSC has documented genetic aberrations that may account for this, although its true radiosensitivity has yet to be quantitated directly. Future studies should focus on the molecular basis of its response to radiation. The reasons for the heterogeneous response of non-UPSC has yet to be elucidated and should also be investigated.

宫颈癌患者接受包含盆腔及主动脉旁局部野放化疗治疗后并发多发性神经根病2例报道

Background. It is becoming more common to include the paraaortic lymph nodes in the radiation fields of patients treated with concomitant weekly cisplatin for node-positive squamous cell carcinoma of the cervix. Case. We report on two patients who developed unexpected subacute neurological toxicity with lower extremity paresis and paresthesis, beginning 1 and 4 months post-treatment. Conclusion. We believe this to be a rare side effect of chemoradiation. As the dose delivered to the spinal nerve roots was less than 37 Gy in 25 fractions, we believe that the extended fields and concomitant cisplatin had a synergistic effect on the nerves.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely unknown.By integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants.We identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites.Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific.Functional annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency related.Our results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.