The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing

Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer ＇omics＇, including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.

The role of mRNA splicing in prostate cancer

Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.

Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?

Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.

Breast Cancer Therapies Present and Future

Significant advances in breast cancer treatment have been made where it is now possible to treat localized disease to a curable state. However, for approximately 30% of women with primary disease, metastatic breast cancer (MBC) or recurrent disease, treatment has remained challenging. Major obstacles in the effective treatment of breast cancer in these populations include: 1) the molecular heterogeneity of the disease;2) treatment of MBC and more specifically brain metastasis;and 3) defining combination therapies that address the evolution of resistance with disease relapse. The acknowledgement of these difficulties has led to an effort to further understand the roadblocks to therapy with the anticipation that more appropriate treatments will result. Here we describe the current state of breast cancer treatment, and the potential for improved therapy.

Gastroesophageal cancer and retroperitoneal fibrosis: Two case reports and review of the literature

Retroperitoneal fibrosis secondary to malignant disease is a rare condition associated with a dismal prognosis. We herein present the first ever reported case of ret-roperitoneal fibrosis related to esophageal adenocarcinoma in a 63-year-old patient who developed bilateral ureteral obstruction due to extensive retroperitoneal fibrosis 18 mo after having completed neoadjuvant chemoradation followed by surgery for a pT3N0 ad-enocarcinoma of the distal esophagus. We also report the case of a previously healthy woman who presented with bilateral ureteral obstruction and diffuse narrowing of the common biliary duct and was found to have extensive retroperitoneal fibrosis as a consequence of metastatic gastric adenocarcinoma. Both patients had poor performance status and were unsuitable for pallia-tive chemotherapy. This paper shows that urinary and biliary obstructive symptoms might represent retroperi-toneal fibrosis as a consequence of gastroesophageal malignancy.

Competing risks of death in younger and older postmenopausal breast cancer patients

AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival(P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival(P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific(Br Ca) and other cause(OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1(IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-OH vitamin D were associated with(1) all cause mortality, and if so; and(2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447(82%) < 70 years and 120(18%) ≥ 70 years. There were 170 deaths: 106(62.3%) BrC a; 55(32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9(5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrC a and OC deaths were not significantly different by treatment arm(P = 0.40): tamoxifen patients experienced 50 BrC a and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 Br Ca and 23 OC deaths. Proportionately more deaths(P = 0.004) were from BrC a for patients< 70 years, where 70% of deaths were due to Br Ca, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index(BMI)(P = 0.02). Higher pathologic T and N were associated with more BrC a deaths(P < 0.0001 and 0.002, respectively). The cumulative hazard plot for Br Ca and OC mortality indicated the concurrent accrual of both types of death throughout followup, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality(P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC(P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrC a mortality(respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrC a mortality(P = 0.002); there was weak evidence that, lower C-peptide(P = 0.08) was associated with less BrC a mortality, while higher BMI(P = 0.01) was associated with worse OC mortality.CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

鼻咽癌离体组织拉曼光谱的测量

拉曼光谱分析技术在探测与组织病理学相关的分子变化方面具有特别的潜力和优势,并且使无损、实时、快速的光学诊断成为可能。采用785nm半导体激光器,透射式的全息光栅,背向感光、深度耗尽的CCD探测器及特殊设计的光纤拉曼探头构建了一台快速拉曼光谱测试装置。所设计的光纤拉曼探头可在减少荧光信号和瑞利散射影响的同时,最大限度地收集生物组织的拉曼信号,同时解决了平面光栅衍射光束的谱线弯曲问题,提高了仪器的信噪比,使装置具有较高的灵敏度并可快速测量获得人体组织的近红外拉曼信号。通过新鲜猪肉的脂肪和肌肉组织的拉曼光谱信号的检测,验证了测试装置的良好性能;在此基础上,研究了鼻咽癌组织样品存放时间对拉曼光谱的影响,并在1～5s时间内快速测量获得了人离体鼻咽癌组织的近红外拉曼光谱。

Neuroendocrine tumor metastatic to the orbit treated with radiotherapy

Neuroendocrine tumors are rare neoplasms that infrequently metastasize to the orbit.Given that patients with these tumors may have prolonged survival despite dissemination,maintaining quality of life by providing early diagnosis and effective treatment to preserve vision and comfort is a fundamental issue.We report the case of a79-year old woman who presented with well-differentiated metastatic neuroendocrine tumor to the liver with no carcinoid syndrome and was started on intramuscular long-acting octreotide with disease stabilization.Two years later she developed right-sided diplopia associated with mild eye discomfort,proptosis and reddening.An magnetic resonance imaging showed a 2.1 cm mass in the right orbit and further biopsy confirmed a neuroendocrine tumor metastasis.The patient was treated with a four-week course of stereotactic radiotherapy to the right orbital metastasis(4000 cGy in 20 fractions)with minor conjunctivitis as the only side effect.Eighteen months later,she remains well with no visual loss.

Chromoplexy： a new paradigm in genome remodeling and evolution

Early massively-parallel sequencing stu-dies have revealed the mutational land-scape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of geno- mic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abun-dance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed ＇chromoplexy＇, which may drive can-cer evolution through the phenomena of punctuated equilibrium by concurrently dys-regulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defin-ing discovery undoubtedly offers an impor- tant glimpse into the evolutionary process of prostate cancer.

Gamma-Index Passing Rates in Baseline Plans Measured with a Detector Array

Purpose: This study provides a simple protocol for validation of the gamma passing rates and to identify the optimum values of % dose and mm criteria for dose distributions measured with a detector array. Methods: We chose ArcCHECK detector array to illustrate the concepts. We used plans with uniform or quasi-uniform dose distributions along the detector array for testing in the presence of dose errors. For testing sensitivity to spatial shift we employed a plan with approximately constant dose gradient along the axis of the instrument. Results: We identified a representative set of parameters which describe performance of a detector array. We determined the minimum gamma-index acceptance criteria allowing the passing rates to reach 100% in the absence of errors, and identified the minimum fully detectable errors for such criteria. For our baseline plans delivered to ArcCHECK, 100% passing rates were obtained for 1.5% dose criterion together with ±3% minimum error detectable at 100% rate, and for 1.5 mm criterion together with the minimum fully detectable error of ±3 mm. We inspected the impact of selected program options on the passing rates. Conclusions: The protocol we developed provides a simple method of commissioning-style analysis of a detector array without a need for analysis of a large number of clinical plans.

Evaluation of New Commercially Available Metal Artifact Reduction (MAR) Algorithm on Both Image Quality and Relative Dosimetry for Patients with Hip Prosthesis or Dental Fillings

Streaking artifacts on computed tomography (CT) images are caused by high density materials such as hip prosthesis, surgical clips and dental fillings. The artifacts can lead to compromised clinical outcome due to the inability to differentiate tumor volume and the uncertainties in dose calculation. The goals of our study are to evaluate how GE’s smart metal artifact reduction (MAR) algorithm impacts image quality on phantoms and dosimetry on head and neck patients with dental fillings and pelvic patients with hip prosthesis. Treatment plans calculated on the MAR and non-MAR datasets with the same beam arrangements and fluence are compared. Dose differences between the MAR and non-MAR datasets are not significant. However, substantial reductions of metal artifacts are observed when MAR algorithm is applied. Planning on the MAR dataset is recommended since it improves image quality and CT number accuracy. It also negates the need to contour the artifacts and override the density which can be time consuming.

An exciting time to launch the World Journal of Hematology

This first issue of the World Journal of Hematology(WJH) marks the birth of a new member of the World Series Journal family and comes at one of the most exciting times in stem cell biology and translational medicine. The pace of discovery in the field of hematology has accelerated signeificantly in recent years, due to important scientific discoveries and new technologies for purification of hematopoietic stem cells and identification of specific stem cell biomarkers; whole genome sequencing using next-generation sequencing technology; and development of molecularly-targeted therapies, leading to the translation of highly promising science into advanced diagnosis and proven targeted therapies for hematopoietic disorders. The WJH is an open-access, peer-reviewed journal, which is officially published on June 6, 2012. The WJH Editorial Board consists of 102 experts in hematology from 26 countries. There is clearly a niche for this new journal, which provides access to all articles without boundaries to all internet users throughout the world. The WJH aims to provide rapid access to high impact publications in fundamental and clinical hematology, with multidisciplinary coverage, through an established system that is targeted at dissemination to the scientific community via online openaccess.

Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia

Background and Aims:The aim was to determine if liver biochemistry indices can be used as biomarkers to help differentiate patients with neonatal Dubin–Johnson syndrome(nDJS)from those with biliary atresia(BA).Methods:Patients with genetically-confirmed nDJS or cholangiographically confirmed BA were retrospectively enrolled and randomly assigned to discovery or verification cohorts.Their liver chemistries,measured during the neonatal period,were compared.Predictive values were calculated by receiver operating characteristic curve analysis.Results:A cohort of 53 nDJS patients was recruited,of whom 13 presented with acholic stools,and 14 underwent diagnostic cholangiography or needle liver biopsy to differentiate from BA.Thirty-five patients in the cohort,with complete biochemical information measured during the neonatal period,were compared with 133 infants with cholangiographically confirmed BA.Total and direct bilirubin,alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bile acids,alkaline phosphatase,and gamma-glutamyl transferase were significantly lower in nDJS than in BA.In the discovery cohort,the areas under the curve for ALT and AST were 0.908 and 0.943,respectively.In the validation cohort,13/15 patients in the nDJS group were classified as nDJS,and 10/53 in the BA control group were positive(p<0.00001)with an ALT biomarker cutoff value of 75 IU/L.Thirteen of 15 patients were classified as nDJS and none were classified positive in the BA group(13/15 vs.0/53,p<0.00001)with an AST cutoff of 87 IU/L.Conclusions:Having assembled and investigated the largest cohort of nDJS patients reported to date,we found that nDJS patients could be distinguished from BA patients using the serum AST level as a biomarker.The finding may be clinically useful to spare cholestatic nDJS patients unnecessary invasive procedures.

实时拉曼光谱分析技术及其在临床早期癌症检测中的应用

拉曼光谱分析技术可以在分子水平上研究物质分子结构和生化组成信息,具有快速、准确、无创(或低创)等优点,已成为临床早期癌症检测和组织病理生理分析的重要工具。近年来,激光技术、光纤探测器件和光电检测技术的发展,不仅极大促进了新型拉曼光谱分析仪器与技术的研发,更进一步扩展了其临床应用的广度和深度,彰显出其独特的科学内涵与应用价值。对临床拉曼光谱分析技术的理论基础进行了阐述,归纳总结了临床快速拉曼光谱分析集成系统设计思路。在此基础上,以作者相关研究工作为例,探讨了拉曼光谱分析技术在临床癌症早期检测与病理分析中的应用特点,为推动相关基础研究及技术创新提供有益参考。

Raman spectroscopy of Chinese human skin in vivo

A novel and compact near-infrared （NIR） Raman system is developed using 785-nm diode laser, volumephase technology （VPT） holographic system, and NIR intensified charge-coupled device （CCD）. Signal-tonoise ratio （SNR） and resolution are improved compared with ordinary acquisition method by a specially designed optical fiber detector and the spectrograph image aberration correction with a parabolic-line fiber array. In 1-5 s, Raman spectra of different parts of Chinese human skin are acquired. Autofluorescence is subtracted from the raw spectrum by polynomial fitting and skin Raman spectrum is then smoothed for further analysis.