Ovarian cancer:a molecularly insidious disease

In this issue of the Chinese Journal of Cancer,European,American,and Chinese experts review the current management and future perspectives of epithelial ovarian cancer(EOC),the leading cause of gynecological cancer deaths.Although major advances have been made in understanding the cellular and molecular biology of this highly heterogeneous malignancy,the survival rate of women with EOC has changed little since the introduction of platinum-based treatment as a front-line therapy.The papers describe the progress in deciphering the molecular complexity of this disease and the newly available molecular-driven therapies,which have been applied by shifting trial designs toward restricting eligibility to specific subgroups of patients rather than testing agents in unselected populations.These new trial designs provide potential opportunities for improved efficacy in targeted populations.Given the molecular complexity of this disease,patient survival may be increased by searching for new molecular prognostic/predictive signatures as well as by translating the recent insight of microRNA involvement in EOC progression into new,targeted therapies.Particular attention has been given to the issue of fertility sparing for women affected by curable diseases.

Role of MGMT as biomarker in colorectal cancer

O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.

Key nodes of a micro RNA network associated with the integrated mesenchymal subtype of high-grade serous ovarian cancer

Metastasis is the main cause of cancer mortality. One of the initiating events of cancer metastasis of epithelial tumors is epithelial-to-mesenchymal transition(EMT), during which cells dedifferentiate from a relatively rigid cell structure/morphology to a flexible and changeable structure/morphology often associated with mesenchymal cells. The presence of EMT in human epithelial tumors is reflected by the increased expression of genes and levels of proteins that are preferentially present in mesenchymal cells. The combined presence of these genes forms the basis of mesenchymal gene signatures, which are the foundation for classifying a mesenchymal subtype of tumors. Indeed, tumor classification schemes that use clustering analysis of large genomic characterizations, like The Cancer Genome Atlas(TCGA), have defined mesenchymal subtype in a number of cancer types, such as high-grade serous ovarian cancer and glioblastoma. However, recent analyses have shown that gene expression-based classifications of mesenchymal subtypes often do not associate with poor survival. This "paradox" can be ameliorated using integrated analysis that combines multiple data types. We recently found that integrating m RNA and micro RNA(mi RNA) data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer. This network consists of 8 major mi RNAs and 214 m RNAs. Among the 8 mi RNAs, 4 are known to be regulators of EMT. This review provides a summary of these 8 mi RNAs, which were associated with the integrated mesenchymal subtype of serous ovarian cancer.

Clear cell adenocarcinoma of the colon is a unique morphological variant of intestinal carcinoma:Case report with molecular analysis

Here we report a new case of clear cell adenocarcinoma (CCA) of the colon in a 54-year-old Caucasian man. Despite of the previous reported cases, the lesion was located in the right colon and was not associated with the conventional adenoma. We performed immunohistochemical and molecular analyses in order to explore whether the CCA had the molecular features generally associated with conventional colorectal carcinoma. The immunohistochemical and molecular analyses showed that the different morphology of CCA does not reflect a distinct biological entity but only an unusual morphological variant of intestinal carcinoma.

Relationships between lymphomas linked to hepatitis C virus infection and their microenvironment

The relationships between lymphomas and their microenvironment appear to follow 3 major patterns:(1)an independent pattern;(2)a dependent pattern on deregulated interactions;and(3)a dependent pattern on regulated coexistence.Typical examples of the third pattern are hepatitis C virus(HCV)-associated marginal zone lymphomas(MZLs)and mucosa-associated lymphoid tissue lymphomas.In these lymphomas,a regulated coexistence of the malignant cells and the microenvironmental factors usually occurs.At least initially,however,tumor development and cell growth largely depend on external signals from the microenvironment,such as viral antigens,cytokines,and cell-cell interactions.The association between HCV infection and B-cell lymphomas is not completely defined,although this association has been demonstrated by epidemiological studies.MZL and diffuse large B-cell lymphoma are the histotypes most frequently associated with HCV infection.Many mechanisms have been proposed for explaining HCV-induced lymphomagenesis;antigenic stimulation by HCV seems to be fundamental in establishing B-cell expansion as observed in mixed cryoglobulinemia and in B-cell lymphomas.Recently,antiviral treatment has been proved to be effective in the treatment of HCV-associated indolent lymphomas.Importantly,clinically responses were linked to the eradication of the HCV-RNA,providing a strong argument in favor of a causative link between HCV and lymphoproliferation.

Occupational exposures and colorectal cancers:A quantitative overview of epidemiological evidence

A traditional belief widespread across the biomedical community was that dietary habits and genetic predisposition were the basic factors causing colorectal cancer.In more recent times,however,a growing evidence has shown that other determinants can be very important in increasing(or reducing) incidence of this malignancy.The hypothesis that environmental and occupational risk factors are associated with colorectal cancer is gaining ground,and high risks of colorectal cancer have been reported among workers in some industrial branches.The aim of this study was to investigate the epidemiologic relationship between colorectal cancer and occupational exposures to several industrial activities,by means of a scientific literature review and meta-analysis.This work pointed out increased risks of colorectal cancer for labourers occupied in industries with a wide use of chemical compounds,such as leather(RR = 1.70,95%CI:1.24-2.34),basic metals(RR = 1.32,95%CI:1.07-1.65),plastic and rubber manufacturing(RR = 1.30,95%CI:0.98-1.71 and RR = 1.27,95%CI:0.92-1.76,respectively),besides workers in the sector of repair and installation of machinery exposed to asbestos(RR = 1.40,95%CI:1.07-1.84).Based on our results,the estimated crude excess risk fraction attributable to occupational exposure ranged from about 11% to about 15%.However,homogeneous pattern of association between colorectal cancer and industrial branches did not emerge from this review.

肺小结节:多层CT在肺癌筛查中容积测量的可重复性

目的评价肺癌筛查研究中使用自动化计算软件对在体肺内小结节容积测量的可重复性。方法本研究经机构伦理委员会批准，并获得所有参与者的书面知情同意书。数据由意大利多中心肺（癌）发现计划收集，此项目为一随机对照肺癌筛查研究。研究分析了在米兰国家肿瘤研究所完成的首批连续1236例的初次CT检查。在登记的全部参与者中．只考虑那些在之后的3个月进行低剂量CT复查并且至少有一个体积超过60mm，（直径≥4．8mm）的不确定结节的病人。

Potential benefit of lymph node dissection during radical nephrectomy for kidney cancer:A review and critical analysis of current literature

Objective:The role of lymph node dissection(LND)is still controversial in patients with renal cell carcinoma undergoing surgery.We aimed to provide a comprehensive review of the literature about the effect of LND on survival,prognosis,surgical outcomes,as well as patient selection and available LND templates.Methods:Recent literature(from January 2011 to December 2021)was assessed through PubMed and MEDLINE databases.A narrative review of most relevant articles was provided.Results:The frequencies in which LNDs are being carried out are decreasing due to an increase in minimally invasive and nephron sparing surgery.Moreover,randomized clinical trials and meta-analyses failed to show any survival advantage of LND versus no LND.However,retrospective studies suggest a survival benefit of LND in high-risk patients(bulky tumors,T3-4 stage,and cN1 patients).Moreover,extended LND might provide important staging information,which could be of interest for adjuvant treatment planning.Conclusion:No level 1 evidence of any survival advantage deriving from LND is currently available in literature.Thus,the role of LND is limited to staging purposes.However,low grade evidence suggests a possible role of LND in high-risk patients.Randomized clinical trials are warranted to corroborate these findings.

Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been described.Case presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.Conclusions: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

Integration of genome scale data for identifying newplayers in colorectal cancer

Colorectal cancers(CRCs) display a wide variety of genomic aberrations that may be either causally linked to their development and progression, or might serve as biomarkers for their presence. Recent advances in rapid high-throughput genetic and genomic analysis have helped to identify a plethora of alterations that can potentially serve as new cancer biomarkers, and thus help to improve CRC diagnosis, prognosis, and treatment. Each distinct data type(copy number variations, gene and micro RNAs expression, Cp G island methylation) provides an investigator with a different, partially independent, and complementary view of the entire genome. However, elucidation of gene function will require more information than can be provided by analyzing a single type of data. The integration of knowledge obtained from different sources is becoming increasingly essential for obtaining an interdisciplinary view of large amounts of information, and also for cross-validating experimental results. The integration of numerous types of genetic and genomic data derived from public sources, and via the use of ad-hoc bioinformatics tools and statistical methods facilitates the discovery and validation of novel, informative biomarkers. This combinatory approach will also enable researchers to more accurately and comprehensively understand the associations between different biologic pathways, mechanisms, and phenomena, and gain new insights into the etiology of CRC.

Nanotherapeutics approaches to improve the efficacy of CAR-T cells in solid tumors

Adoptive cell therapy and Immune Checkpoint Blockade Inhibitors have recently revolutionized the field of oncology.However,these types of immunotherapeutic approaches have limited success in treating solid tumors.In particular,chimeric antigen receptor(CAR)-T cells efficacy is hampered by immunosuppressive signals in the tumor microenvironment(TME)and by a limited infiltration of re-infused T cells to the tumor site.The field of nanobiotechnology applied to oncology is also rapidly expanding.Nanoparticles-based delivery systems can be employed to modulate the activity of immune cells present in the TME enhancing the efficacy of CAR-T cells.Interestingly,nano-backpacks can be attached to CAR-T cells prior to re-infusion to support their homing to the tumor site and to slowly release immunopotentiators directly in the TME.Furthermore,nanovaccines can also be employed to support the in vivo expansion of CAR-T cells with consequent enhancement of their therapeutic potential.In this viewpoint,recent advancement in the field of nanobiotechnology to support CAR-T cell therapy will be discussed.The development of novel therapeutic CAR-T cells protocols together with nanotherapies is warranted in order to take full advantage of the high therapeutic potential of CAR-T cell therapy.

One size does not fit all for pancreatic cancers: A review on rare histologies and therapeutic approaches

Exocrine pancreatic neoplasms represent up to 95%of pancreatic cancers(PCs)and are widely recognized among the most lethal solid cancers,with a very poor 5-year survival rate of 5%-10%.The remaining<5%of PCs are neuroendocrine tumors that are usually characterized by a better prognosis,with a median overall survival of 3.6 years.The most common type of PC is pancreatic ductal adenocarcinoma(PDAC),which accounts for roughly 85%of all exocrine PCs.However up to 10%of exocrine PCs have rare histotypes,which are still poorly understood.These subtypes can be distinguished from PDAC in terms of pathology,imaging,clinical presentation and prognosis.Additionally,due to their rarity,any knowledge regarding these specific histotypes is mostly based on case reports and a small series of retrospective analyses.Therefore,treatment strategies are generally deduced from those used for PDAC,even if these patients are often excluded or not clearly represented in clinical trials for PDAC.For these reasons,it is essential to collect as much information as possible on the management of PC,as assimilating it with PDAC may lead to the potential mistreatment of these patients.Here,we report the most significant literature regarding the epidemiology,typical presentation,possible treatment strategies,and prognosis of the most relevant histotypes among rare PCs.

Pneumothorax Complicating Port-a-Cath and Groshong Catheter Positioning in Children: Our Experience before Routine Ultrasound-Guided Puncture

Objective: To study incidence and management of long term central venous catheter (CVC) placement related pneumothorax (PNX) in children. Aim: To construct a baseline value before the introduction of systematic use of ultrasound guidance, which requires specific training and equipment. Background: Anesthesia Service and Pediatric Oncology of the Italian National Cancer Center;patients were children (age ≤ 18 years) with solid tumors, needing long-term central venous catheters (Groshong or Port-a-Cath). Materials/Methods: Catheter placement was performed, mostly under general anesthesia, utilizing a micropuncture 5-7 Fr needle and fluoroscopy. In the study period ultrasound was used only in case of previously failed attempts. Relevant data were collected retrospectively. Results: From August 2008 to December 2011, 452 catheters were implanted to our patients. The prevalent approach was from subclavian vein (left 85.7%, right 9.7%);in few cases internal jugular vein was chosen (right 2.4%, left 2.2%). Pneumothorax occurred in 14 patients (3.1%;95%CI 1.9-5.1). In 4/14 children the PNX was considered minimal and not treated. In 10 patients the PNX was drained. In 7 cases a traditional, surgical thoracostomy was performed, while in 3 children a 14-Ga polyurethane catheter (Arrow International&#174) was inserted over a wire guide in the pleural space by anaesthetists. Conclusions: In our centre rates of PNX are the same as those described in literature and are expected to lower when ultrasound guidance of the puncture will be routinely applied. Percutaneous drainage of PNX seems as effective as surgically placed thoracostomy catheter, but less invasive.

Update on Therapeutic Strategy in Lung Carcinoids

An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchial tree and into the lungs. Although lung NETs account for less than 1% of all pulmonary malignancies, the incidence of these neoplasms has risen precipitously since the mid 1970s. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Surgery is the treatment of choice for typical and atypical carcinoid lung NETs with loco-regional disease. At diagnosis up to 64% of patients with atypical carcinoid lung NETs present with lymph node metastases, and 5-year survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than 15% of typical carcinoid lung NETs, and 5-year survival exceeds 90%. To date, there is no recognized standard of treatment for advanced carcinoid lung NETs. In recent years only two trials reported intriguing results regarding lung NETs: a phase 2 retrospective study of dacarbazine derivative temozolomide and the phase 3, RADIANT-2 trial in advanced NETs. Successful management requires a multidisciplinary team management. This review is restricted to typical/atypical NETs.

Osteopathia striata with cranial sclerosis, Wilms' tumor and the WTX gene

Osteopathia striata with cranial sclerosis(OSCS, OMIM#300373) is an X-linked dominant sclerosing bone dysplasia that shows a distinct phenotype in females and males. In 2009, Zandra Jenkins et al found that germline mutations in the FAM123 B /WTX /AMER1 gene, mapped to chromosome Xq11.2, cause both the familial and sporadic forms of OSCS. Intriguingly, the WTX gene was already known as a putative tumor suppressor gene, since in 2007 Rivera et al had reported inactivating WTX mutations in Wilms' tumor(WT), the most frequent renal tumor of childhood. Here we review the heterogeneous clinical presentation of OSCS patients and the involvement of WTX anomalies in OSCS and in WT.

The EuroLifeNet Study: How Different Microenvironments Influence Personal Exposure to PM_2.5among High-School Students in Milan

Epidemiological studies show that long-term exposure to PM is associated with an increased risk of cancer. The EuroLifeNet study measured the personal exposure to PM2.5 in 90 pupils attending three schools in Milan, using a portable nephelometer, over a three-week period spanning November and December 2006. Background levels explained 40% of the variability of the exposure. Methods: As a second part of that study we analyzed the role of different microenvironments as determinants of personal exposure to PM2.5. Results: Exposure was influenced by the time of day, zone of the city and different microenvironments. Exposure was higher indoors than out, and indoors it was higher in the kitchen, particularly during cooking. In outdoor environments exposure was higher at bus stops where road traffic was heavy. Conclusions: Even though background concentration can be a good predictor of personal exposure to PM, students’ personal exposure is strongly influenced by different microenvironments and should be considered in population studies. The EuroLifeNet experience gives a contribution to personal exposure measure methodology.

First-line pazopanib in patients with advanced non-clear cell renal carcinoma:An Italian case series

BACKGROUND Non-clear cell(ncc)metastatic renal-cell carcinoma(RCC)has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart.New systemic combination therapies have emerged for metastatic RCC(mRCC),but the pivotal phase III trials excluded patients with nccRCC,which constitute about 30%of metastatic RCC cases.AIM To provide a piece of real-life evidence on the use of pazopanib in this patient subgroup.METHODS The present study is a multicenter retrospective observational analysis aiming to assess the activity,efficacy,and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life setting.RESULTS Overall,48 patients were included.At the median follow-up of 40.6 mo,the objective response rate was 27.1%,the disease control rate was 83.3%,and the median progression-free survival and overall survival were 12.3(95%confidence interval[CI]:3.6-20.9)and 27.7(95%CI:18.2-37.1)mo,respectively.Grade 3 adverse events occurred in 20%of patients,and no grade 4 or 5 toxicities were found.CONCLUSION Pazopanib should be considered as a good first-line option for metastatic RCC with variant histology.

Estimation of the Piecewise Exponential Model by Bayesian P-Splines via Gibbs Sampling: Robustness and Reliability of Posterior Estimates

In the investigation of disease dynamics, the effect of covariates on the hazard function is a major topic. Some recent smoothed estimation methods have been proposed, both frequentist and Bayesian, based on the relationship between penalized splines and mixed models theory. These approaches are also motivated by the possibility of using automatic procedures for determining the optimal amount of smoothing. However, estimation algorithms involve an analytically intractable hazard function, and thus require ad-hoc software routines. We propose a more user-friendly alternative, consisting in regularized estimation of piecewise exponential models by Bayesian P-splines. A further facilitation is that widespread Bayesian software, such as WinBUGS, can be used. The aim is assessing the robustness of this approach with respect to different prior functions and penalties. A large dataset from breast cancer patients, where results from validated clinical studies are available, is used as a benchmark to evaluate the reliability of the estimates. A second dataset from a small case series of sarcoma patients is used for evaluating the performances of the PE model as a tool for exploratory analysis. Concerning breast cancer data, the estimates are robust with respect to priors and penalties, and consistent with clinical knowledge. Concerning soft tissue sarcoma data, the estimates of the hazard function are sensitive with respect to the prior for the smoothing parameter, whereas the estimates of regression coefficients are robust. In conclusion, Gibbs sampling results an efficient computational strategy. The issue of the sensitivity with respect to the priors concerns only the estimates of the hazard function, and seems more likely to occur when non-large case series are investigated, calling for tailored solutions.

Concomitant medications and circulating tumor cells:friends or foes?

The use of concomitant medications by patients with cancer is observed almost globally;however,little attention has been paid to this topic in the medical literature.Most clinical studies do not describe the type and duration of drugs used at the time of inclusion and during treatment or how these drugs may affect the experimental and/or standard therapy.Even less information has been published on the potential interaction between concomitant medications and tumor biomarkers.However,we do know that concomitant drugs can complicate cancer clinical trials and biomarker development,thus contributing to their interaction,leading to side effects,and resulting in suboptimal adherence to anticancer treatment.On the basis of these premises and moving from the study by Jurisova et al.,which reported the effect of commonly used drugs on the prognosis of women with breast cancer and the detection of circulating tumor cells(CTCs),we comment on the role of CTCs as an emerging diagnostic and prognostic tool for breast cancer.We also report the known and hypothesized mechanisms of CTC interplay with other tumor and blood components,possibly modulated by widespread drugs,including over-the-counter compounds,and discuss the possible implications of commonly used concomitant medications on CTC detection and clearance.After considering all these points,it is conceivable that concomitant drugs are not necessarily a problem,but on the contrary,their virtuous mechanisms can be exploited to reduce tumor spread and enhance the effect of anticancer therapies.

CHK2 kinase in the DNA damage response and beyond

serine/threonine kinase CHK2 是 DNA 损坏反应的一个关键部件。在人的房间，跟随 genotoxic 应力， CHK2 被激活并且 phosphorylates >导致适当细胞的反应的 20 蛋白质，它，取决于损坏，房间类型，和另外的因素的程度，能是房间周期检查点激活， apoptosis 或老朽感应， DNA 修理，或损坏的忍耐。最近， CHK2 也被发现了有独立于原子 DNA 损害的存在的细胞的功能。特别地， CHK2 参予涉及 DNA 结构修正和房间周期前进的几个分子的过程。在这评论，我们在不着重的房间响应 DNA 损坏并且在生物功能的维护讨论 CHK2 的活动。这些活动也在 tumorigenesis 在与 CHK2 的一个可能的角色的关系被考虑并且作为后果，作为癌症的一个目标治疗。