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Tumor‐agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor‐agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability‐high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor‐agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody‐drug conjugate (Her2‐positive–immunohistochemistry 3+ expression) with pan‐cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue‐agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options. [ABSTRACT FROM AUTHOR]

The last decade has seen rapid progress in the use of genomic tests, including gene panels, whole‐exome sequencing, and whole‐genome sequencing, in research and clinical cancer care. These advances have created expansive opportunities to characterize the molecular attributes of cancer, revealing a subset of cancer‐associated aberrations called driver mutations. The identification of these driver mutations can unearth vulnerabilities of cancer cells to targeted therapeutics, which has led to the development and approval of novel diagnostics and personalized interventions in various malignancies. The applications of this modern approach, often referred to as precision oncology or precision cancer medicine, are already becoming a staple in cancer care and will expand exponentially over the coming years. Although genomic tests can lead to better outcomes by informing cancer risk, prognosis, and therapeutic selection, they remain underutilized in routine cancer care. A contributing factor is a lack of understanding of their clinical utility and the difficulty of results interpretation by the broad oncology community. Practical guidelines on how to interpret and integrate genomic information in the clinical setting, addressed to clinicians without expertise in cancer genomics, are currently limited. Building upon the genomic foundations of cancer and the concept of precision oncology, the authors have developed practical guidance to aid the interpretation of genomic test results that help inform clinical decision making for patients with cancer. They also discuss the challenges that prevent the wider implementation of precision oncology. [ABSTRACT FROM AUTHOR]

Key Points: Head and neck mucosal melanomas have a diverse mutational landscape with low mutational burden.A molecular subset (∼13%) has ROS1 mutations, which is an actionable driver mutation.ROS1‐mutated patients have improved overall survival likely due to high mutational burden. [ABSTRACT FROM AUTHOR]

Introduction: The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable histology Wilms tumor (FHWT) enrolled on AREN0532 or AREN03B2 alone. Patients and Methods: A total of 635 stage III FHWT vincristine/dactinomycin/doxorubicin (DD4A)–treated patients met inclusion criteria. Event‐free survival (EFS) and overall survival are reported overall and by LN sampling, LN status, LOH 1p, LOH 16q, and a combination of LN status and singular LOH. Patients with unknown or positive combined LOH of 1p and 16q status and AREN03B2‐only patients with unknown outcomes or treatment other than DD4A were excluded. Results: EFS did not differ by study, supporting pooling. Lack of LN sampling (hazard ratio [HR], 2.12; p =.0037), LN positivity (HR, 2.78; p =.0002), LOH 1p (HR, 2.18; p =.0067), and LOH 16q (HR, 1.72; p =.042) were associated with worse EFS. Compared with patients with both LN– and LOH–, those with negative nodes but positive LOH 1p or 16q and those with LN+ but LOH– for 1p or 16q had significantly worse EFS (HR, 3.05 and 3.57, respectively). Patients positive for both LN and LOH had the worst EFS (HR, 6.33; overall group factor, p <.0001). Conclusion: Findings confirm LN+ status as an adverse prognostic factor amplified by presence of singular LOH 1p or 16q, supporting study of intensified therapy for patients with LN+ in combination with singular LOH in a prospective clinical trial. Stage III patients with favorable histology Wilms tumor and a combination of loss of heterozygosity of 1p or 16q and lymph node involvement were examined in an expanded Children's Oncology Group cohort. The combination of loss of heterozygosity status with lymph node status correlated with inferior outcome. [ABSTRACT FROM AUTHOR]

Objective: To examine if idiopathic inflammatory myopathies (IIMs) share familial susceptibility with cancer, we estimated the familial co‐aggregation of these diseases. Methods: This Swedish population‐based family study with data from national registers included 8,460 first‐degree relatives of patients with IIM and 41,127 relatives of matched individuals without IIM. We modeled the adjusted odds ratios (ORs) of familial co‐aggregation of IIM and cancer using conditional logistic regressions and adjusted for sex and birth year of index individuals and their first‐degree relatives. We examined the associations for cancer overall and stratified by several factors of interest. We also performed exploratory analyses for specific cancer types. Results: We observed no statistically significant familial associations between IIM and cancer overall. However, there was a familial association in male relative pairs of patients with dermatomyositis (adjusted OR for familial association 1.39 [95% confidence interval (95% CI) 1.15–1.68]). The association remained statistically significant after controlling for multiple testing. Moreover, this finding was consistent between kinships. Familial co‐aggregation of IIM and cancer diagnosed before 50 years of age was only observed in offspring. In exploratory analyses, only the familial associations for myeloid malignancies (adjusted OR 2.27 [95% CI 1.43–3.60]) and liver cancer (adjusted OR 2.01 [95% CI 1.21–3.33]) in male relative pairs remained significant after controlling for multiple testing. Conclusion: We found little evidence of shared familial susceptibility as a major pathologic mechanism contributing to the co‐occurrence of IIM and cancer overall. There could be subsets of patients and cancer types for which familial factors including genetics and shared environments are of more importance, but these findings need replication. [ABSTRACT FROM AUTHOR]

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan‐cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second‐generation drugs designed to overcome first‐generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription‐polymerase chain reaction, and (DNA and/or RNA‐based) next‐generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first‐ and second‐generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors. [ABSTRACT FROM AUTHOR]

Cell-free (cf)DNA captures tumor genetics and can be used to assess disease kinetics and minimal residual disease (MRD). B Introduction: b The European MCL Network trial TRIANGLE (NCT02858258) evaluated the addition of ibrutinib to standard treatment with autologous stem cell transplantation (ASCT) (arm A+I) in comparison to ASCT alone (arm A) and ibrutinib plus chemoimmunotherapy without ASCT (arm I) demonstrating significant and clinically relevant superiority of additional ibrutinib on outcome. CELL-FREE DNA KINETICS DECIPHER POTENTIAL MECHANISMS OF ACTION OF IBRUTINIB COMBINATION THERAPY IN MANTLE CELL LYMPHOMA (MCL). [Extracted from the article]

A study published in CA: A Cancer Journal for Clinicians found that most patients with cancer do not undergo germline genetic testing to determine if their cancer may be associated with an inherited gene mutation. The study analyzed data from patients in California and Georgia and found that non-Hispanic White patients with male breast cancer, female breast cancer, or ovarian cancer were the most likely to undergo testing, while Black/African American patients were the least likely. The study also revealed an increase in testing over time, with pancreatic cancer patients showing the greatest increase. The authors emphasized the importance of clinicians identifying and testing patients at risk for genetic alterations that increase cancer risk. [Extracted from the article]

Urological cancers are common malignancies worldwide. Several conventional models, for example, two‐dimensional cell culture and animal models have been used for decades to study tumor genetics. Nonetheless, these methods have limitations in reflecting the real tumor microenvironment in vivo, thereby hindering the development of anti‐cancer therapeutic agents. Recently, three‐dimensional culture models have gained attention because they can overcome the drawbacks of traditional methods. Above all, three‐dimensional organoid models are able to mimic the tumor microenvironment in human bodies more closely as they are able to demonstrate the interactions between cells and extracellular matrix. This type of model has therefore extended our understanding of urological cancers. Tumor cells in organoid models can also be co‐cultured with other cellular components, such as peripheral blood lymphocytes, and allow further understanding of the effect of tumor microenvironments on tumor growth. Furthermore, organoid models allow a prolonged culturing period, therefore, tumor evolution, progression and maintenance can also be assessed. Organoid models can be derived from each specific patient, and this facilitates investigation of individual cancer‐specific mutations and their subtypes. As a result, the development of personalized medication targeting the signaling pathways or biomolecules of interest will be possible. In the present review, we summarize the development and applications of three‐dimensional organoid cultures in urological cancers, mainly focusing on prostate, urinary bladder and kidney cancers, and assess the future prospects of this model. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Glioblastomas (GBMs) that involve the subventricular zone (SVZ) have a poor prognosis, possibly due to recruitment of neural stem cells. The purpose of this study was to evaluate whether SVZ involvement by lower grade gliomas (LGG), WHO grade II and III, similarly predicts poorer outcomes. We further assessed whether tumor genetics and cellularity are associated with SVZ involvement and outcomes. METHODS: Forty‐five consecutive LGG patients with preoperative imaging and next generation sequencing were included in this study. Regional SVZ involvement and whole tumor apparent diffusion coefficient (ADC) values, as a measure of cellularity, were assessed on magnetic resonance imaging. Progression was determined by RANO criteria. Kaplan‐Meier curves and Cox regression analyses were used to determine the hazard ratios (HR) for progression and survival. RESULTS: Frontal, parietal, temporal, and overall SVZ involvement and ADC values were not associated with progression or survival (P ≥.05). However, occipital SVZ involvement, seen in two patients, was associated with a higher risk of tumor progression (HR = 6.6, P =.016) and death (HR = 31.5, P =.015), CDKN2A/B mutations (P =.03), and lower ADC histogram values at the 5th (P =.026) and 10th percentiles (P =.046). Isocitrate dehydrogenase, phosphatase and tensin homolog, epidermal growth factor receptor, and cyclin‐dependent kinase 4 mutations were also prognostic (P ≤.05). CONCLUSIONS: Unlike in GBM, overall SVZ involvement was not found to strongly predict poor prognosis in LGGs. However, occipital SVZ involvement, though uncommon, was prognostic and found to be associated with CDKN2A/B mutations and tumor hypercellularity. Further investigation into these molecular mechanisms underlying occipital SVZ involvement in larger cohorts is warranted. [ABSTRACT FROM AUTHOR]

Reports on pediatric low‐grade diffuse glioma WHO‐grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2‐entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub‐entities proved unfavorable for survival. Within the prospectively registered, population‐based German/Swiss SIOP‐LGG 2004 cohort 100 patients (age 0.8‐17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event‐free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3‐K27M‐mutation in 4, IDH1‐mutation in 11, BRAF‐V600‐mutation in 12, KIAA1549‐BRAF‐fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549‐BRAF‐fusions. Histone3‐K27M‐mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2‐entities, with the exemption of Histone3‐K27M‐mutant tumors that require a HGG‐related treatment strategy. Our data confirm the importance to genetically define pediatric low‐grade diffuse gliomas for proper treatment decisions and risk assessment. What's new? Pediatric low‐grade diffuse gliomas histologically resemble their adult counterparts, but they differ greatly in terms of genetics, clinical behavior, and prognosis. Here, the authors investigated genetic mutations in 65 pediatric grade 2 diffuse gliomas (DG2), looking for a correlation with long‐term outcome. All 4 tumors carrying the K27M mutation in the Histone3 gene were fatal. Conversely, none of the 6 tumors carrying a particular duplication of the BRAF gene, called the KIAA1549‐BRAF fusion, progressed to malignant glioma. The authors characterized the tumor genetics with respect to prognosis, age at onset, and response to treatment. [ABSTRACT FROM AUTHOR]

The article focuses on tools to dissect the cancer genome. Topics include the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG) being an international collaborative project to which investigators have contributed, the genome sequencing data and RNA sequencing data from donors, and the PCAWG landing page being a good starting point from which to access these resources.

Thousands of candidate cancer biomarkers have been proposed, but so far, few are used in cancer screening. Failure to implement these biomarkers is attributed to technical and design flaws in the discovery and validation phases, but a major obstacle stems from cancer biology itself. Oncogenomics has revealed broad genetic heterogeneity among tumors of the same histology and same tissue (or organ) from different patients, while tumors of different tissue origins also share common genetic mutations. Moreover, there is wide intratumor genetic heterogeneity among cells within any single neoplasm. These findings seriously limit the prospects of finding a single biomarker with high specificity for early cancer detection. Current research focuses on developing biomarker panels, with data assessment by machine‐learning algorithms. Whether such approaches will overcome the inherent limitations posed by tumor biology and lead to tests with true clinical value remains to be seen. [ABSTRACT FROM AUTHOR]

The recent development of cancer precision medicine is associated with the emergence of 'molecular tumour boards' (MTBs). Attended by a heterogenous set of practitioners, MTBs link genomic platforms to clinical practices by establishing 'actionable' connections between drugs and molecular alterations. Their activities rely on a number of evidential resources – for example databases, clinical trial results, basic knowledge about mutations and pathways – that need to be associated with the clinical trajectory of individual patients. Experts from various domains are required to master and align diverse kinds of information. However, rather than examining MTBs as an institution interfacing different kinds of expertise embedded in individual experts, we argue that expertise is the emergent outcome of MTBs, which can be conceptualised as networks or 'agencements' of humans and devices. Based on the ethnographic analysis of the activities of four clinical trial MTBs (three in France and an international one) and of two French routine‐care MTBs, the paper analyses how MTBs produce therapeutic decisions, centring on the new kind of expertise they engender. The development and activities of MTBs signal a profound transformation of the evidentiary basis and processes upon which biomedical expertise and decision‐making in oncology are predicated and, in particular, the emergence of a clinic of variants. [ABSTRACT FROM AUTHOR]

Glioma is the most common malignant primary brain tumors with poor prognosis. Genome wide association studies (GWAS) of glioma in populations with Western European ancestry were completed in the US and UK. However, our previous results strongly suggest the genetic heterogeneity could be important in glioma risk. To systematically investigate glioma risk–associated variants in Chinese population, we performed a multistage GWAS of glioma in the Han Chinese population, with a total of 3,097 glioma cases and 4,362 controls. In addition to confirming two associations reported in other ancestry groups, this study identified one new risk‐associated locus for glioma on chromosome 12p11.23 (rs10842893, pmeta = 2.33x10‐12, STK38L) as well as a promising association at 15q15‐21.1 (rs4774756, pmeta = 6.12x10‐8, RAB27A) in 3,097 glioma cases and 4,362 controls. Our findings demonstrate two novel association between the glioma risk region marked by variant rs10842893 and rs4774756) and glioma risk. These findings may advance the understanding of genetic susceptibility to glioma. What's new? While very few brain tumors are attributed to familial risk factors, the previous identification of inherited genetic variants linked to glioma has raised new questions about the impact of genetics on brain tumor risk. In this genome‐wide association study in a Han Chinese population, two independent genetic variants, one on chromosome 12p11.23 and the second on 15q15‐21.1, were found to be significantly associated with glioma risk. In addition, two risk‐associated variants previously reported in other ancestry groups were also associated with glioma risk in Han Chinese patients. The findings may help advance understanding of genetic susceptibility to glioma. [ABSTRACT FROM AUTHOR]

Tumour genetics is currently turning into a massive clinical approach. This paper is an enquiry into its practices as they expand beyond expert and experimental contexts and become routinised in clinical hospital settings. Studying a French university hospital, we unpack the content and everyday organization of diagnostic labour in this context. Exploring the sociotechnical frictions that arise in the process, we describe the ways in which they are collectively controlled, and stabilized through organizational fictions, that are instrumental in making tumour genetics doable in the hospital, at a large scale. We further show that the new role of external regulations in the production of clinical values for mutations has a strong impact on diagnostic work, making it possible to be performed locally without resorting to expert bioclinical collectives, and outside the professional jurisdiction of clinical geneticists. This division of labour appears as a necessary condition for the rise in clinical productivity required by a new function assigned to genetics: to guide the prescription of drugs for common diseases. This turn in the way genetics is embedded in the clinic calls for a thorough reassessment of its impacts on clinical discourses, practices and decisions. [ABSTRACT FROM AUTHOR]

In recent years, with both the development of next‐generation sequencing approaches and the Supreme Court decision invalidating gene patents, declining costs have contributed to the emergence of a new model of hereditary cancer genetic testing. Multigene panel testing (or multiplex testing) involves using next‐generation sequencing technology to determine the sequence of multiple cancer‐susceptibility genes. In addition to high‐penetrance cancer‐susceptibility genes, multigene panels frequently include genes that are less robustly associated with cancer predisposition. Scientific understanding about associations between many specific moderate‐penetrance gene variants and cancer risks is incomplete. The emergence of multigene panel tests has created unique challenges that may have meaningful psychosocial implications. Contrasted with the serial testing process, wherein patients consider the personal and clinical implications of each evaluated gene, with multigene panel testing, patients provide broad consent to whichever genes are included in a particular panel and then, after the test, receive in‐depth genetic counseling to clarify the distinct implications of their specific results. Consequently, patients undergoing multigene panel testing may have a less nuanced understanding of the test and its implications, and they may have fewer opportunities to self‐select against the receipt of particular types of genetic‐risk information. Evidence is conflicting regarding the emotional effects of this testing. [ABSTRACT FROM AUTHOR]

Optimistic predictions that genetic and genomic testing will provide health benefits have been tempered by the concern that individuals who receive their results may experience negative psychosocial outcomes. This potential ethical and clinical concern has prompted extensive conversations between policy‐makers, health researchers, ethicists, and the general public. Fortunately, the psychosocial consequences of such testing are subject to empirical investigation, and over the past quarter century, research that clarifies some of the types, likelihood, and severity of potential harms from learning the results of the testing has accumulated. I aim to provide an overview of the findings of this research by looking at selected systematic reviews. This will convey the gist of the literature's quality and coverage, reveal gaps in existing knowledge, and highlight promising areas for future scholarship. [ABSTRACT FROM AUTHOR]

The recently updated World Health Organization (WHO) Classification of myeloid neoplasms and leukemia reflects the fact that research in the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Gene mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk‐stratification schemes and have been proven to be clinically relevant, targetable lesions. We here discuss the utility of molecular markers in AML in prognostication and treatment decision making, specifically highlighting the aberrations included in the current WHO classification. [ABSTRACT FROM AUTHOR]

The tumour susceptibility gene 101 (TSG101) is reported to play important roles in the development and progression of several human cancers. However, its potential roles and underlined mechanisms in human hepatocellular carcinoma (HCC) are still needed to be further clarified. In the present study, we reported that knock down of TSG101 suppressed the proliferation, migration and invasion of HCC cells, while overexpression of TSG101 facilitated them. Molecularly, the results revealed that knock down of TSG101 significantly decreased the cell cycle related regulatory factor p53 and p21. In another point, knock down of TSG101 also obviously decreased the level of metallopeptidase inhibitor TIMP1 (Tissue inhibitors of metalloproteinases 1), which results in inhibition of MMP2, MMP7 and MMP9. In contrast, overexpression of TSG101 had opposite effects. The iTRAQ proteomics analysis identified that oncogenic protein PEG10 (Paternally expressed gene 10) might be a potential downstream target of TSG101. Further investigation showed that TSG101 interacted with PEG10 and protected it from proteasomal degradation thereby regulating the expression of p53, p21 and MMPs. Finally, we found that both TSG101 and PEG10 proteins are up‐regulated and presented a direct correlation in HCC patients. In conclusion, these results suggest that TSG101 is up‐regulated in human HCC patients, which may accelerate the proliferation, migration and invasion of HCC cells through regulating PEG10. [ABSTRACT FROM AUTHOR]

The management of advanced prostate cancer today follows a multidisciplinary approach and involves multi‐target treatments. The paradigm has shifted from traditional hormonal therapy, surgery and radiation, to the use of chemotherapy, and until recently the development of various immunotherapies and radiopharmaceuticals. Recent advances turn to molecular medicine combining the expertise of molecular pathology and genetics. In this review, germline genetics, advances in castrate‐sensitive metastatic disease, androgen receptor alterations, potential new targeted therapy and novel radiopharmaceuticals will be discussed as the newest perspectives for treating prostate cancer. With better staging and new imaging techniques, patients who could be cured by localized treatments and who could benefit from more intensive regimens can be identified. In future, careful patient selection and novel combinations are likely to be required in the management of prostate cancer. [ABSTRACT FROM AUTHOR]

Rectal cancer is a heterogeneous disease, presenting with distinct biological behaviors and treatment responses which suggest the complexity and diversity of its genetic and molecular characteristics. A deep learning model based on MRI and clinical factors facilitates noninvasive prediction of KRAS mutation in rectal cancer. [Extracted from the article]

Key Clinical Message: Few studies reported patients who harbored three kinds of primary tumors simultaneously. Here, we present a 9‐year‐old boy with colon carcinoma, brain medulloblastoma, and lymphoma. Genetic mutation detection was explored with next‐generation sequencing, and compound heterozygous mutations in gene MSH6 c.3103C>T p.Arg1035Ter and c.3261dupC p.Phe1088LeufsTer were discovered. [ABSTRACT FROM AUTHOR]

Abstract: Serum alpha‐fetoprotein (AFP) is the most commonly used tumor biomarker for screening and diagnosis of primary hepatocellular carcinoma (HCC). However, the predictive effect for HCC risk is still unsatisfactory. The aim of this prospective study was to estimate whether the individual genetic correction could improve the prediction efficiency of AFP for HCC risk. A prospective analysis with 9819 baseline HCC‐free individuals based on a large population‐based Chinese cohort study was performed. Two single‐nucleotide polymorphisms (SNPs) associated with serum AFP level were used to calculate the genetic corrected AFP level (rs12506899 and rs2251844). Statistical analysis including logistic regression analysis and the area under the receiver operating characteristic (ROC) curve were used to assess the discriminative ability of the original and genetic corrected AFP level for HCC risk. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were presented. Fifty‐seven participants were diagnosed with HCC for the first time. After adjusting AFP level with genetic effects, the participants for HCC risk increased compared to those with AFP level alone (OR = 5.34, 95% CI = 2.57–11.13; P < 0.001 vs. OR = 5.04, 95% CI = 2.46–10.30; P < 0.001). In addition, the area under the curve (AUC) for the discrimination of HCC elevated from 0.611 to 0.726. The efficiency in HCC prediction using serum AFP level can be improved by adjusting AFP level based on genetic effects. The genetic correction effect on serum AFP should be considered in the clinic application of such tumor biomarkers. [ABSTRACT FROM AUTHOR]

Angiogenesis is known as one of the hallmarks in cancer which could play a key role in providing oxygen and nutrients for tumor cells. It has been shown that tumor cannot grow without sufficient development of new blood vessels. Accordingly, targeting angiogenesis, especially endothelial cells, could be considered as a common therapeutic target in tumors and more investigation on already existing biomarkers and potentially new biomarkers of endothelial cells seems to be necessary in cancer therapy. Moreover, the use of effective targeting approaches such as proteins and peptides, aptamers, and small molecules is an important step for targeting biomarkers associated with endothelial cells and angiogenesis in cancer therapy. These agents are FDA approved, or are currently under investigation in pre-clinical and clinical studies. Among various biomarkers for angiogenesis microRNAs are suitable candidates for target therapy. These molecules play key roles in tumor angiogenesis which exert their effect via targeting a variety of cellular and molecular pathways involved in tumor angiogenesis. Here, we summarize a variety of biomarkers which their expressions or their functions could change the function of endothelial cells in tumor microenvironments. Moreover, we highlighted various therapeutic agents which could target these biomarkers. [ABSTRACT FROM AUTHOR]

Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis‐specific protein Y‐encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation, and also harbours the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a non‐invasive neoplasm that is the precursor of germinoma and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical gonadoblastoma and contains germ cells with delayed maturation that express octamer‐binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non‐neoplastic condition that should be distinguished clearly from ‘dissecting gonadoblastoma’, a neoplasm derived from classical gonadoblastoma that is the precursor of some germinomas. ‘Dissecting gonadoblastoma’ is a variant of classical gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of ‘dissecting gonadoblastoma’. [ABSTRACT FROM AUTHOR]

We designed a multimeric nuclease‐resistant 63‐bp trimeric small‐interfering RNA (tsiRNA) comprising in one duplex the sequence of siRNAs targeting mRNAs of MDR1, LMP2, and LMP7 genes. We show that such tsiRNA is able to suppress the expression of all the target genes independently and with high efficiency, acting via a Dicer‐dependent mechanism. tsiRNA is diced into 42‐ and 21‐bp duplexes inside the cell. tsiRNA‐induced gene silencing is characterized by kinetics similar to that of canonical siRNA, while the silencing efficiency is significantly higher than that of canonical siRNA with the same sequence. [ABSTRACT FROM AUTHOR]

Objective Thymic neuroendocrine tumour ( TH- NET) accounts for almost 20% of multiple endocrine neoplasia type 1 ( MEN1)-associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice. Design and Patients We performed a retrospective analysis of patients treated for TH- NET associated with MEN1 in a single institution and meta-analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis. Results TH- NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH- NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0-72.0 years). Forty-three patients died with a median survival time of 8.4 years. Older age at diagnosis ( HR = 1.4, 95% CI = 1.0-1.8, P = .03), maximum tumour diameter ( HR = 1.5, 95% CI = 1.0-2.3, P = .04) and presence of metastasis ( HR = 1.6, 95% CI = 1.0-2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports. Conclusion TH- NET is a rare but fatal component of MEN1. Earlier detection of TH- NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference. [ABSTRACT FROM AUTHOR]

Retinoblastoma, an intraocular pediatric cancer, develops in the embryonic retina following biallelic loss of RB1. However, there is a wide range of genetic and epigenetic changes that can affect RB1 resulting in different clinical outcomes. In addition, other transformations, such as MYCN amplification, generate particularly aggressive tumors, which may or may not be RB1 independent. Recognizing the cellular characteristics required for tumor development, by identifying the elusive cell-of-origin for retinoblastoma, would help us understand the development of these tumors. In this review we summarize the heterogeneity reported in retinoblastoma on a molecular, cellular and tissue level. We also discuss the challenging heterogeneity in current retinoblastoma models and suggest future platforms that could contribute to improved understanding of tumor initiation, progression and metastasis in retinoblastoma, which may ultimately lead to more patient-specific treatments. [ABSTRACT FROM AUTHOR]

Aims To compare the oncogenic mutation status among mucinous cystic neoplasms (MCNs) of different histological grades and between liver and pancreatic MCNs. Methods and results KRAS, GNAS, RNF43 and PIK3CA were sequenced in 25 surgical cases of hepatopancreatic MCN. Molecular features were correlated with clinicopathological and immunohistochemical findings. KRAS mutations were identified in five cases (20%), whereas GNAS, RNF43 and PIK3CA were wild-type in all cases. KRAS mutations were uncommon in cases of low-grade dysplasia (1/20, 5%), whereas KRAS was mutated in all cases of higher grades, except for one liver MCN with intermediate-grade dysplasia (4/5, 80%; P = 0.002). This genetic alteration was slightly more frequent in the pancreas than in the liver [4/17 (24%) versus 1/8 (13%), P = not significant]. KRAS-mutated MCNs more commonly had a multilocular cystic appearance ( P = 0.040) and expression of mucin (MUC) 1 ( P = 0.040), MUC2 ( P = 0.016) and MUC5AC ( P = 0.015) than KRAS-wild-type tumours. In cases of KRAS-mutated MCNs with intermediate-grade or high-grade dysplasia, identical mutations were also detected in areas of adjacent low-grade dysplasia. Conclusions KRAS mutations appear to be major driver genetic alterations in both liver and pancreatic MCNs. As identical KRAS mutations were present in low-grade and higher-grade areas in individual cases, KRAS mutations occurring in low-grade MCNs may lead to tumour progression. Thus, preoperative KRAS testing may contribute to estimations of malignant potential. The lower incidence of KRAS mutations in liver MCNs may also explain why the risk of malignant transformation in liver MCNs is lower than that in pancreatic MCNs. [ABSTRACT FROM AUTHOR]

Cutaneous syncytial myoepithelioma is a recently described rare tumor of the dermis. It is derived and composed purely of myoepithelial cells and shows a characteristic syncytial growth pattern of neoplastic cells with little intervening stroma and no recognizable ductal structures. It represents a diagnostic challenge to dermatopathologists given its rarity and unusual immunophenotype. Molecular testing for rearrangement of the EWSR1 gene plays a significant role in confirming the diagnosis in most cases. Herein, we present 2 cases with mundane clinical presentations and challenging histopathological findings. In both cases, the lesion was composed of relatively well-circumscribed proliferation of epithelioid and spindle cells in the superficial dermis growing in a syncytial fashion and showing focal adipocytic metaplasia. The 2 cases had slightly different immunohistochemical profiles, but shared focal positivity for S100, EMA and pan-keratin or p63. Break-apart FISH demonstrated the presence of an EWSR1 gene rearrangement confirming the diagnosis in both cases. We discuss the most important differential diagnoses, particularly melanocytic lesions and epithelioid sarcoma and the original diagnostic considerations that the cases were referred to us with. We also review the molecular features and spectrum of immunohistochemical findings in these lesions and their role in excluding entities in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Conventional chondrosarcoma is the most common primary bone tumor in adults. Prognosis corresponds with tumor grade but remains variable, especially for individuals with grade (G) II disease. There are currently no biomarkers available for monitoring or prognostication of chondrosarcoma. Circulating tumor DNA (ct DNA) has recently emerged as a promising biomarker for a broad range of tumor types. To date, little has been done to study the presence of ct DNA and its potential utility in the management of sarcomas, including chondrosarcoma. In this study, we have assessed ctDNA levels in a cohort of 71 patients, 32 with sarcoma, including 29 individuals with central chondrosarcoma (CS) and 39 with locally aggressive and benign bone and soft tissue tumors, using digital PCR. In patients with CS, ctDNA was detected in pretreatment samples in 14/29 patients, which showed clear correlation with tumor grade as demonstrated by the detection of ctDNA in all patients with GIII and dedifferentiated disease ( n = 6) and in 8/17 patients with GII disease, but never associated with GI CS. Notably detection of ctDNA preoperatively in GII disease was associated with a poor outcome. A total of 14 patients with CS had ctDNA levels assessed at multiple time points and in most patients there was a clear reduction following surgical removal. This research lays the foundation for larger studies to assess the utility of ctDNA for chondrosarcoma diagnosis, prognostication, early detection of residual disease and monitoring disease progression. [ABSTRACT FROM AUTHOR]

Background: CD68 and lysozyme expression in cannibalistic tumor cells of oral squamous cell carcinoma (OSCC) is well established. Transformation of cancer cells into cannibalistic cells is a process involving sequential events. Initial event could be genetic expression of proteins that is required for execution of cannibalism. Hence, it is quite possible that some non-cannibalistic tumor cells can also show expression of cannibalistic markers (CD68 and lysozyme).Methodology: Formalin-fixed tissues of 30 OSCC cases with cellular cannibalism (CC) (positive control), 30 OSCC cases without CC, and 17 normal oral epithelium specimens (negative control) were subjected to immunohistochemical analysis for CD68 and lysozyme expression.Results: OSCC with CC showed CD68 and lysozyme expression in 30 (100%) cases each {CD68: [weak: 21 (70%), strong: 9 (30%)]; lysozyme: [weak: 24 (80%), strong: 6 (20%)]}. In OSCCs without CC, CD68-positive tumor cells were present in 13 (43.33%) cases [weak: 10 (33.33%); strong: 3 (10%)] and lysozyme expression was present in 13 (43.33%) cases [weak: 12 (40%); strong: 1 (3.33%)]. Control group showed negative expression for CD68 and lysozyme in the oral epithelium. The CD68 and lysozyme expression in OSCCs without CC, OSCCs with CC, and control group showed statistically significant differences (P < 0.001). Significant correlation was also observed between CD68 and lysozyme expression and different grades of OSCC.Conclusion: CD68 and lysozyme expression in non-cannibalistic tumor cells of OSCC can be related to CC. [ABSTRACT FROM AUTHOR]

Background: The role of BRAF mutations in cancerogenesis has been demonstrated in several solid tumor types. However, in salivary gland tumors, this genetic alteration is very uncommon, and its role still remains unclear. Thus, the aim of this study was to analyze BRAF V600E (VE1) protein expression with BRAF mutation status in codon 600, in malignant and benign salivary gland tumors.Methods: Studies were performed on archived formalin-fixed paraffin-embedded tissue sections derived from 95 patients who underwent surgery for tumors of the salivary gland. Immunohistochemical staining (IHC) on tissue microarray slides was performed for evaluation of BRAF V600E (VE1) protein expression, and the automatic molecular diagnostics platform was used for the evaluation of mutations in codon 600 of BRAF gene.Results: IHC cytoplasmic expression of BRAF V600E (VE1) protein was found in two of 95 cases: one case of adenocarcinoma NOS (one of three; 33%) and one case of carcinoma ex pleomorphic adenoma (one of five; 20%). Although, in IHC studies, nuclear BRAF V600E (VE1) protein expression was found in 14 (15%) of the analyzed cases: nine of 28 (32%) cases of pleomorphic adenoma, three of five (60%) cases of ductal carcinoma, one of nine (11%) case of mucoepidermoid carcinoma, and in one of five (20%) case of carcinoma ex pleomorphic adenoma. All cases were negative for polymerase chain reaction PCR-based analyses of BRAF mutations in codon 600.Conclusions: In studied salivary gland cancers, no PCR-based prove mutations of BRAF V600 were detected. Further molecular analyses are necessary to rapid molecular arrays for the identification of specific mutations, optimal for individualized targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Ameloblastoma (unicystic, UA, or multicystic, MA) is a rare tumor associated with bone destruction and facial deformity. Its malignant counterpart is the ameloblastic carcinoma (AC). The BRAFV600E mutation is highly prevalent in all these tumors subtypes and cannot account for their different clinical behaviors.Methods: We assessed copy number alterations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) in UA (n = 2), MA (n = 3), and AC (n = 1) using the CytoScan HD Array (Affymetrix) and the BRAFV600E status. RT-qPCR was applied in four selected genes (B4GALT1, BAG1, PKD1L2, and PPP2R5A) covered by rare alterations, also including three MA and four normal oral tissues.Results: Fifty-seven CNAs and cnLOH were observed in the ameloblastomas and six CNAs in the AC. Seven of the CNAs were rare (six in UA and one in MA), four of them encompassing genes (gains of 7q11.21, 1q32.3, and 9p21.1 and loss of 16q23.2). We found positive correlation between rare CNA gene dosage and the expression of B4GALT1, BAG1, PKD1L2, and PPP2R5A. The AC and 1 UA were BRAF wild-type; however, this UA showed rare genomic alterations encompassing genes associated with RAF/MAPK activation.Conclusion: Ameloblastomas show rare CNAs and cnLOH, presenting a specific genomic profile with no overlapping of the rare alterations among UA, MA, and AC. These genomic changes might play a role in tumor evolution and in BRAFV600E-negative tumors. [ABSTRACT FROM AUTHOR]

The authors review and discuss the implications of genomic analyses documenting the diversity of tumors, both among patients and within individual tumors. Genetic diversity among solid tumors limits targeted therapies, because few mutations that drive tumors are both targetable and at high prevalence. Many more driver mutations and how they affect cellular signaling pathways must be identified if targeted therapy is to become widely useful. Genetic diversity within a tumor-intratumor genetic heterogeneity-makes the tumor a collection of subclones: related yet distinct cancers. Selection for pre-existing, resistant subclones by conventional or targeted therapies may explain many treatment failures. Immune therapy faces the same fundamental challenges. Nevertheless, the processes that generate and maintain heterogeneity might provide novel therapeutic targets. Addressing both types of diversity requires genomic tumor analyses linked to detailed clinical data. The trend toward sequencing restricted cancer gene panels, however, limits the ability to discover new driver mutations and assess intratumor heterogeneity. Clinical data currently collected with genomic analyses often lack critical information, substantially limiting their use in understanding tumor diversity. Now that diversity among and within tumors can no longer be ignored, research and clinical practice must adapt to take diversity into account. Cancer 2017;123:917-27. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

The recently available genomic sequencing techniques have led to breakthroughs in understanding of the underlying genetic mechanisms in adrenocortical tumours. Disease-causing mutations have been described for aldosterone-producing adenomas, cortisol-producing adenomas and adrenocortical carcinomas. Further, knowledge gained from transcriptome analyses and methylation arrays has provided new insights into the development of these tumours. Elucidation of the genomic landscape of adrenocortical tumours and improved techniques may in the future be useful for early diagnosis through the detection of mutated DNA in the circulation. Moreover, compounds that bind specifically to altered proteins may be used as screening targets or therapeutic agents. Regulation of cortisol release by interaction with an altered subunit in adenylate cyclase may be more complex, but may provide a new option for regulating steroid release. Information about derangements in adrenocortical carcinoma is already helpful for determining patient prognosis. With further knowledge, we may be able to identify novel biomarkers that effectively and noninvasively help in differentiating between benign and malignant disease. It is clear that the next few years will provide much novel information that hopefully will aid in the treatment of patients with adrenocortical tumours. [ABSTRACT FROM AUTHOR]

Next-generation sequencing ( NGS)-based circulating tumour DNA (ct DNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ct DNA was associated with outcome after allogeneic haematopoietic stem cell transplantation ( HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced-intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre-specified time points before and after HSCT and were assayed for ct DNA by sequencing of the immunoglobulin or T-cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ct DNA prior to progression at a median of 3·7 months prior to relapse/progression. Patients with detectable ct DNA 3 months after HSCT had inferior progression-free survival ( PFS) (2-year PFS 58% vs. 84% in ct DNA-negative patients, P = 0·033). In multivariate models, detectable ct DNA was associated with increased risk of progression/death (Hazard ratio 3·9, P = 0·003) and increased risk of relapse/progression (Hazard ratio 10·8, P = 0·0006). Detectable ct DNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS-based minimal residual disease monitoring in lymphoma patients after HSCT. [ABSTRACT FROM AUTHOR]

Identifying genetic alterations in tumors is critical for molecular targeting of therapy. In the clinical setting, formalin-fixed paraffin-embedded ( FFPE) tissue is usually employed for genetic analysis. However, DNA extracted from FFPE tissue is often not suitable for analysis because of its low levels and poor quality. Additionally, FFPE sample preparation is time-consuming. To provide early treatment for cancer patients, a more rapid and robust method is required for precision medicine. We present a simple method for genetic analysis, called touch imprint cytology combined with massively paralleled sequencing (touch imprint cytology [ TIC]-seq), to detect somatic mutations in tumors. We prepared FFPE tissues and TIC specimens from tumors in nine lung cancer patients and one patient with breast cancer. We found that the quality and quantity of TIC DNA was higher than that of FFPE DNA, which requires microdissection to enrich DNA from target tissues. Targeted sequencing using a next-generation sequencer obtained sufficient sequence data using TIC DNA. Most (92%) somatic mutations in lung primary tumors were found to be consistent between TIC and FFPE DNA. We also applied TIC DNA to primary and metastatic tumor tissues to analyze tumor heterogeneity in a breast cancer patient, and showed that common and distinct mutations among primary and metastatic sites could be classified into two distinct histological subtypes. TIC-seq is an alternative and feasible method to analyze genomic alterations in tumors by simply touching the cut surface of specimens to slides. [ABSTRACT FROM AUTHOR]

Molecular routine diagnostics for BCR- ABL1-negative myeloproliferative neoplasms ( MPN) currently focusses on mutations in JAK2, CALR and MPL. In recent years, recurrent mutations in MPNs have been identified in several other genes. We here present the validation of a next generation sequencing ( NGS)-based 28-gene panel and its use in MPN. We analysed the mutation status of 28 genes in 100 MPN patients [40 essential thrombocythaemia ( ET), 30 primary myelofibrosis ( PMF), 30 polycythaemia vera ( PV)] and found two or more mutated genes in 53 patients. Moreover, significantly more mutated splicing genes ( SF3B1, SRSF2 and U2 AF1) were present in PMF (0·60 mutated genes/patient) compared to ET (0·15) while no mutations in splicing genes were found in PV. Additionally, chromatin modification genes ( ASXL1 and EZH2) were frequently mutated in PMF patients (0·50) and, to a significantly lesser extent, in ET (0·13) and PV (0·07). Contrarily, DNA methylation genes ( DNMT3A, IDH1, IDH2 and TET2) were mutated most often in PV (0·5) and less frequently in ET (0·23) and PMF (0·20), but without reaching statistical significance. Our results demonstrate the feasibility and utility of NGS-based panel diagnostics for MPN. With 53% of the patients bearing two or more mutated genes, their prognostic relevance needs further studies. [ABSTRACT FROM AUTHOR]

Recently, an increasing number of TFE3 rearrangement-associated tumours have been reported, such as TFE3 rearrangement-associated perivascular epithelioid cell tumours ( PEComas), melanotic Xp11 translocation renal cancers and melanotic Xp11 neoplasms. We have suggested that these tumours belong to a single clinicopathological spectrum. 'Xp11 neoplasm with melanocytic differentiation' or 'melanotic Xp11 neoplasm' have been proposed to designate this unique neoplasm. Herein, we describe the first case of an Xp11 neoplasm with melanocytic differentiation to be described in the prostate, bearing the novel NONO- TFE3 gene fusion. This study both adds to the spectrum regarding melanotic Xp11 neoplasms and expands its gene fusion spectrum. Moreover, we discuss the relationship of these rare tumours to neoplasms such as conventional PEComas, alveolar soft part sarcomas, malignant melanomas, clear cell sarcomas and Xp11 translocation renal cancers. [ABSTRACT FROM AUTHOR]

Background: During the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling.Methods: A 45-item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor.Results: The possibility of discovering non-cancer-related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information.Conclusions: Patients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588-97. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Aims The role of tumour metabolic and proliferative indices in predicting non-small-cell lung cancer ( NSCLC) patients' prognosis is unclear. We correlated fluorine 18 (18F)-fluorodeoxyglucose ( FDG)-positron emission tomography ( PET) value and Ki67 index to patients' survival, taking into account tumour heterogeneity, disease characteristics and genetic aberrations. Methods and results A series of 383 NSCLCs was arranged into tissue microarrays and Ki67 staining was analysed by immunohistochemistry. The maximum standardized uptake ( SUVMAX) value detected by 18F- FDG- PET analysis was calculated over a region of interest. Large-cell and squamous cell carcinomas had higher proliferative and metabolic activities than adenocarcinomas, and the two measures were correlated significantly. The hot-spot Ki67 value was correlated with patients' survival and the cut-off to discriminate patients in the survival risk groups was 20%. Ki67 hot-spot values were greater in anaplastic lymphoma kinase ( ALK) rearranged tumours. Adenocarcinomas showed the highest intratumour heterogeneity in proliferative activity and the hot-spot Ki67 value predicted only the prognosis of patients in this group. Although tumour metabolic activity was not associated with patients' prognosis, a SUVMAX > 2 was related to nodal metastases, tumour size and grade. Conclusions Our results highlight how tumour heterogeneity influences evaluation of prognostic biomarkers. Our data support Ki67 evaluation to estimate NSCLC patients' prognosis, particularly for adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background Podoplanin (PDPN) is a prognostic factor for head and neck squamous cell carcinoma (HNSCC). However, PDPN expression in circulating tumor cells (CTCs) and its prognostic value are not clear. Methods The PowerMag system was used to enumerate CTCs from 53 patients with HNSCC prechemotherapy and 61 healthy donors. PDPN expression was determined by immunofluorescence staining. Results were correlated with clinicopathological parameters and clinical outcome, such as patient survival by receiver operating characteristic (ROC) and univariate and multivariate analyses. Results PDPN was expressed in a subset of CTCs. Both EpCAM-positive CTC and PDPN-positive CTC counts were statistically different between the disease and nondisease groups ( p < .0001) with no prognostic value. After a median follow-up of 10.5 months (range, 6.6-18.5 months), the PDPN-positive/EpCAM-positive CTC ratio >20% was a significant prognostic factor for death within 6 months ( p = .011) and was correlated with poor progression-free survival ( p = .016) and overall survival ( p = .015). Conclusion PDPN-positive/EpCAM-positive CTC ratio is a prognostic factor and defining the ratio in patients with HNSCC might be valuable to clinical management. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1448-1455, 2015 [ABSTRACT FROM AUTHOR]

Background Metastatic pheochromocytomas ( PCs) and paragangliomas ( PGLs) are rare neuroendocrine tumours with a strong genetic background. Design We searched the PubMed database through February 2015 to identify studies characterizing metastatic PCs/ PGLs as well as currently established and evolving therapies. Results Large size tumours (> 5 cm), PASS score > 6 and Ki-67 labelling index > 3% are the most robust indices of metastatic PCs/ PGLs albeit with great variability. Germline succinate dehydrogenase complex, subunit B ( SDHB) mutation constitutes the main reliable molecular predictor of malignancy. Plasma and urinary methoxytyramine are the biochemical markers characterizing metastatic PCs/ PGLs along with evolving molecular markers such as mi RNAs and SNAIL. Conventional imaging is used for tumour localization, whereas 18F- FDG- PET for staging of metastatic PCs/ PGLs especially those related to SDHB gene mutations. In addition, 68 Ga- DOTATATE PET/ CT is emerging as a highly sensitive alternative. Surgery remains the gold standard treatment in reducing tumour bulk and/or controlling the clinical syndrome. Treatment with 131I- MIBG or radiolabelled somatostatin analogues is considered for unresectable disease. Conventional chemotherapy is reserved for more advanced and refractory to other therapies disease although new schemes are currently evolving. Recent genetic studies have highlighted a number of pathways involved in PCs/ PGLs pathogenesis directing towards the use of targeted therapies which have still to be validated in clinical practice. Conclusions Metastatic PCs/ PGLs remain an orphan disease that is only curable by surgery. However, advances in genomic analyses have improved the pathogenesis of these tumours and may lead to effective and more personalized treatments in the near future. [ABSTRACT FROM AUTHOR]

Similar to phosphorylation, transient conjugation of ubiquitin to target proteins (ubiquitination) mediated by the concerted action of ubiquitin ligases and de-ubiquitinating enzymes (DUBs) can affect substrate function. As obligate intracellular parasites, viruses rely on different cellular pathways for their own replication and the well conserved ubiquitin conjugating/de-conjugating system is not an exception. Viruses not only usurp the host proteins involved in the ubiquitination/de-ubiquitination process, but they also encode their own ubiquitin ligases and DUBs. Here we report that an N-terminal variant of the herpes simplex virus (HSV) type-1 large tegument protein VP1/2 (VP1/21-767), encompassing an active DUB domain (herpesvirus tegument ubiquitin specific protease, htUSP), and TSG101, a component of the endosomal sorting complex required for transport (ESCRT)-I, functionally interact. In particular, VP1/21-767 modulates TSG101 ubiquitination and influences its intracellular distribution. Given the role played by the ESCRT machinery in crucial steps of both cellular pathways and viral life cycle, the identification of TSG101 as a cellular target for the HSV-1 specific de-ubiquitinating enzyme contributes to the clarification of the still under debate function of viral encoded DUBs highly conserved throughout the Herpesviridae family. J. Cell. Physiol. 230: 1794-1806, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

It is well known that there is a significant racial divide in breast cancer incidence and mortality rates. African American women are less likely to be diagnosed with breast cancer than white women but are more likely to die from it. This review explores the factors that may contribute to the racial survival disparity. Consideration is paid to what is known about the role of differences in tumor biology, genomics, cancer screening, and quality of cancer care. It is argued that it is the collision of 2 forces, tumor biology and genomics, with patterns of care that leads to the breast cancer mortality gap. The delays, misuse, and underuse of treatment for African American patients are of increased significance when these patients are presenting with more aggressive forms of breast cancer. In the current climate of health care reform ushered in by the Affordable Care Act, this article also evaluates interventions to close the disparity gap. Prior interventions have been too narrowly focused on the patient rather than addressing the system and improving care across the continuum of breast cancer evaluation and treatment. Lastly, areas of future investigation and policy initiatives aimed at reducing the racial survival disparity in breast cancer are discussed. CA Cancer J Clin 2015;65: 221-238. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia ( CLL) remains at the forefront of the genetic analysis of human tumours, principally due its prevalence, protracted natural history and accessibility to suitable material for analysis. With the application of high-throughput genetic technologies, we have an unbridled view of the architecture of the CLL genome, including a comprehensive description of the copy number and mutational landscape of the disease, a detailed picture of clonal evolution during pathogenesis, and the molecular mechanisms that drive genomic instability and therapeutic resistance. This work has nuanced the prognostic importance of established copy number alterations, and identified novel prognostically relevant gene mutations that function within biological pathways that are attractive treatment targets. Herein, an overview of recent genomic discoveries will be reviewed, with associated biological and clinical implications, and a view into how clinical implementation may be facilitated. [ABSTRACT FROM AUTHOR]

In order to increase the cytotoxic activity of a S almonella strain carrying a salicylate-inducible expression system that controls cytosine deaminase production, we have modified both, the vector and the producer bacterium. First, the translation rates of the expression module containing the E scherichia coli codA gene cloned under the control of the Pm promoter have been improved by using the T7 phage gene 10 ribosome binding site sequence and replacing the original GUG start codon by AUG. Second, to increase the time span in which cytosine deaminase may be produced by the bacteria in the presence of 5-fluorocytosine, a 5-fluorouracyl resistant S almonella strain has been constructed by deleting its upp gene sequence. This new S almonella strain shows increased cytosine deaminase activity and, after infecting tumour cell cultures, increased cytotoxic and bystander effects under standard induction conditions. In addition, we have generated a purD mutation in the producer strain to control its intracellular proliferation by the presence of adenine and avoid the intrinsic S almonella cell death induction. This strategy allows the analysis and comparison of the cytotoxic effects of cytosine deaminase produced by different S almonella strains in tumour cell cultures. [ABSTRACT FROM AUTHOR]