BACKGROUND & AIMS: :Outside the nasopharynx, undifferentiated carcinomas occur only rarely at other head and neck locations. Although the association between undifferentiated nasopharyngeal carcinoma and Epstein-Barr virus (EBV) is consistent, there is conflicting evidence as to the association of EBV with undifferentiated carcinomas outside the nasopharynx. Here, we report on a case of undifferentiated carcinoma of the tongue base. A 71-year-old male, who had been treated with irradiation for primary unknown right neck metastatic EBV-positive undifferentiated carcinoma 9 years previously, was referred to our clinic with masses at the tongue base and right neck. The lesion at the tongue base was revealed to be an EBV-positive undifferentiated carcinoma. He was treated with resection of tongue base tumor and bilateral-neck dissection, and the defect at the tongue base was reconstructed with a free rectus abdominis myocutaneous flap. Re-irradiation was added post-operatively because of a positive surgical margin at the tongue base. The patient is presently alive without recurrence or distant metastasis 20 months after treatment. Although it is unclear whether our case is recurrent or newly developed EBV-latently infected undifferentiated carcinoma, we propose that EBV-associated tumors should be carefully observed after treatment at least for more than 10 years.

背景与目标： ：在鼻咽以外，未分化癌仅在其他头颈部位置很少发生。尽管未分化的鼻咽癌和爱泼斯坦-巴尔病毒（EBV）之间的关联是一致的，但关于EBV与鼻咽外未分化癌的关联有相互矛盾的证据。在这里，我们报道一例未分化舌基癌。一位71岁的男性在9年前接受过放射治疗，原发性右颈部转移性EBV阳性原发性未分化癌已经接受了放射治疗，现被转诊至我们的诊所，舌头和右颈部有肿块。舌根处的病变显示为EBV阳性未分化癌。对他进行了舌根肿瘤切除术和双侧颈淋巴结清扫术，并用游离的腹直肌肌皮瓣修复了舌根缺损。由于舌根的手术切缘阳性，因此在术后增加了再次照射。治疗后20个月，该患者目前尚无复发或远处转移。尽管尚不清楚我们的病例是复发的还是新发的EBV潜伏感染的未分化癌，但我们建议治疗至少10年后应仔细观察与EBV相关的肿瘤。

BACKGROUND & AIMS: :Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.0-mm diameter needles, we constructed TMAs from specimens obtained from 32 women with breast cancer containing the following targets: (1) 28 terminal duct lobular units (TDLUs); (2) 28 ductal carcinomas in situ, and (3) 23 invasive carcinomas. Using careful target selection, we achieved representation of approximately 80% of noninvasive targets with sustained preservation through section 30 of the TMAs. Immunohistochemical staining of TDLU targets demonstrated positive staining for estrogen receptor (ER) in 30.8% of tubules and for progesterone receptor (PR) in 50.0%. To establish an efficient method to evaluate staining results in TDLUs, we created a categorical scoring system to approximate the percentage of tubules containing positive stained cells (<10%, 10% to 50%, >or=50%), and compared the results with those obtained by tubule counting. Comparison between the two methods demonstrated exact agreement for 70.8% of ER and 79.2% of PR stains without two-category discrepancies. ER/PR expression levels in multiple (up to 4) noninvasive targets of the same tissue type (TDLU or DCIS) from a single block showed good correlation. These data suggest that it is feasible to produce TMAs of noninvasive breast structures, albeit with careful selection of targets, and that immunostains of such cores may permit efficient immunohistochemical characterization of peritumoral tissues. Additional exploration of this approach is needed.

背景与目标： ：通过免疫组织化学法构建组织微阵列（TMA）以有效表征乳腺中大量非侵袭性上皮病变的方法是一种有吸引力的研究方法，但也带来了技术挑战。我们报告进行的方法学研究，以优化从大型乳腺癌病例对照研究中收集的无创乳腺组织中构建TMA的方法。我们使用直径为2.0毫米针头的手动排列技术，从32位乳腺癌女性的标本中构建了TMA，这些标本包括以下目标：（1）28个末梢小叶单位（TDLU）； （2）28例原位导管癌，（3）23例浸润性癌。通过精心选择目标，我们通过TMA第30节实现了约80％的非侵入性目标的代表，并得到了持续的保护。 TDLU靶标的免疫组织化学染色显示，在30.8％的肾小管中，雌激素受体（ER）和50.0％的孕酮受体（PR）都呈阳性染色。为了建立一种有效的方法来评估TDLU中的染色结果，我们创建了一个分类评分系统，以估计含有阳性染色细胞的小管的百分比（<10％，10％至5​​0％，>或= 50％），并比较结果与那些通过肾小管计数获得的。两种方法之间的比较表明，ER染色的70.8％和PR染色的79.2％完全吻合，没有两类差异。单个区域中相同组织类型（TDLU或DCIS）的多个（多达4个）非侵入性靶标中的ER / PR表达水平显示出良好的相关性。这些数据表明，尽管精心选择了靶标，但生产无创性乳房结构的TMA是可行的，并且此类核心的免疫染色可允许对肿瘤周围组织进行有效的免疫组织化学表征。需要对该方法进行其他探索。

BACKGROUND & AIMS: :Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.

背景与目标： ：野生型（WT）序列p53肽是广泛应用的癌症疫苗的诱人候选物。这项研究的目的是评估肝细胞癌（HCC）患者基于WT p53的免疫治疗方法的潜力。通过在24 HCC中使用肽/HLA-A2.1四聚体直接在外周血中鉴定出对WT p53（149-157）和WT p53（264-272）HLA-A * 0201限制性表位具有特异性的循环CD8 T细胞耐心。 WT p53肽特异性刺激后的细胞毒性T淋巴细胞（CTL）活性通过使用实时定量聚合酶链反应测定的颗粒酶B和干扰素-γmRNA转录分析来评估。进行肿瘤免疫表型分析以评估新鲜分离的肿瘤细胞中p53的状态，主要组织相容性复合体（MHC）的表达和共刺激分子。与健康对照相比，HCC患者表现出明显更高的WT p53特异性记忆CD8 T细胞频率和更强的WT p53特异性CTL活性。 p53特异性CD8 T细胞的频率增加及其活性与选择性HLA-A2等位基因缺失和肿瘤细胞共刺激分子表达降低有关。此外，p53特异性T细胞数量的增加与肿瘤细胞中II类MHC的高表达相吻合，但与肿瘤淋巴结转移分期系统的T状态呈负相关。我们的结果表明，在肝癌患者中存在自然免疫监视和肿瘤免疫逃避，涉及针对WT p53肿瘤抗原的T细胞应答。这些发现可能对癌症疫苗的未来发展具有重要意义。

BACKGROUND & AIMS: :Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemotherapy and chemoradiotherapy are new alternatives for locally advanced disease, particularly induction chemotherapy for patients with unresectable tumors. In recurrent/metastatic disease and after progression to platin-based regimens, no treatments other than best supportive care are currently available. Most SCCHN tumors overexpress the epidermal growth factor receptor (EGFR). This is a tyrosine kinase membrane receptor and has a clear implication in angiogenesis, tumor progression and resistance to different cancer treatments. Cetuximab is a monoclonal antibody that binds to EGFR and alters the tyrosine kinase-mediated signal transduction pathway. The drug is active in colon cancer and is currently being tested in SCCHN patients. For locally advanced disease, cetuximab/radiotherapy combination has demonstrated a benefit in survival when compared with radiotherapy alone as radical treatment. Cetuximab is an active treatment in platin-refractory patients with recurrent/metastatic disease.

背景与目标： ：外科手术和放射疗法是头颈部鳞状细胞癌（SCCHN）患者的标准治疗选择。化学疗法和放化疗是局部晚期疾病的新选择，特别是对于无法切除的肿瘤患者的诱导化疗。在复发/转移性疾病中，以及发展为以铂为基础的治疗方案之后，除最佳支持治疗外，目前尚无其他治疗方法。大多数SCCHN肿瘤过表达表皮生长因子受体（EGFR）。这是酪氨酸激酶膜受体，在血管生成，肿瘤进展和对不同癌症治疗的抗性中具有明显的含义。西妥昔单抗是与EGFR结合并改变酪氨酸激酶介导的信号转导途径的单克隆抗体。该药物在结肠癌中有活性，目前正在SCCHN患者中进行测试。对于局部晚期疾病，西妥昔单抗/放疗联合治疗与单纯放疗作为根治性治疗相比，已显示出生存获益。西妥昔单抗是铂类难治性复发/转移性疾病患者的积极治疗方法。

BACKGROUND & AIMS: :Oral cancer is a neoplasm with some known causes. Proliferation genes are significant among its few pathogenetic and prognostic factors. Calcyclin is a cell-cycle-related gene, the function of which is still unclear. Its expression and that of Haras and histone-H3 have been investigated in an assessment of their pathogenetic role in squamous cell carcinoma. RNA extracted from the pathological and normal mucosa of patients with squamous cell carcinoma (SCC) and benign lesions was reverse transcribed and amplified by the polymerase chain reaction (PCR). The expression of all three genes in the pathological mucosa was enhanced in SCC only. This suggests that they may be involved in its pathogenesis and provides another parameter for the differentiation of malignant and benign lesions.

背景与目标： ：口腔癌是一种具有某些已知原因的肿瘤。增生基因在其少数致病和预后因素中很重要。钙环蛋白是与细胞周期相关的基因，其功能尚不清楚。为了评估它们在鳞状细胞癌中的致病作用，已经研究了它的表达以及Haras和组蛋白H3的表达。从鳞状细胞癌（SCC）和良性病变的病理和正常粘膜中提取的RNA通过聚合酶链反应（PCR）进行逆转录和扩增。仅在SCC中，病理黏膜中所有三个基因的表达均得到增强。这表明它们可能参与其发病机理，并为区分恶性和良性病变提供了另一个参数。

BACKGROUND & AIMS: :Immune therapy have shown new and exciting perspectives for cancer treatment. Aim of our study was to evaluate toxicity and possible adverse effects from vaccination of patients with advanced colorectal cancer with autologous dendritic cells (DC) pulsed with lysate from a newly developed melanoma cell line, DDM-1.13. Six patients were enrolled in the phase I trial. Autologous DCs were generated in vitro from peripheral blood monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). DCs were pulsed with melanoma cell lysate from a cloned and selected melanoma cell line enriched in expression of MAGE-A antigens and deficient in expression of melanoma differentiation antigens: tyrosinase, MART-1 and gp100. Vaccinations were administered intradermally on the proximal thigh with a total of five given vaccines at 2 weeks intervals. Each vaccine contained 3-5 x 10(6) DCs. Five of the six patients received all five vaccines. The treatment was well tolerated in all patients without any observed vaccine-correlated adverse effects. Treatment with this DC-based cancer vaccine proved safe and non-toxic.

背景与目标： ：免疫疗法已显示出令人兴奋的癌症治疗新观点。我们研究的目的是评估用来自新开发的黑素瘤细胞系DDM-1.13的裂解物脉冲的自体树突状细胞（DC）对晚期结直肠癌患者进行疫苗接种的毒性和可能的​​不良反应。一期试验招募了六名患者。在粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白介素-4（IL-4）的存在下，由外周血单核细胞体外产生自体DC。用来自克隆和选择的黑色素瘤细胞系的黑色素瘤细胞裂解液对DC进行脉冲处理，该黑色素瘤细胞系富含MAGE-A抗原的表达，而黑色素瘤分化抗原（酪氨酸酶，MART-1和gp100）的表达不足。在大腿近端皮内注射疫苗，每两周间隔注射五种给定的疫苗。每种疫苗均包含3-5 x 10（6）个DC。六名患者中有五名接受了全部五种疫苗的治疗。所有患者对治疗的耐受性良好，没有观察到疫苗相关的不良反应。事实证明，使用这种基于DC的癌症疫苗进行治疗是安全且无毒的。

BACKGROUND & AIMS: PURPOSE:The most common genitourinary malignancy in China is bladder transitional cell carcinoma (TCC). Early diagnosis of new and recurrent bladder cancers, followed by timely treatment, will help decrease mortality. There are currently no satisfactory markers for bladder cancer available in clinics. Better diagnostic methods are highly demanded. EXPERIMENTAL DESIGN:In this research, we have used comprehensive expressed sequence tag analysis, serial analysis of gene expression, and microarray analysis and quickly discovered a candidate marker, urothelial carcinoma associated 1 (UCA1). The UCA1 gene was characterized and its performance as a urine marker was analyzed by reverse transcription-PCR with urine sediments. A total of 212 individuals were included in this study, 94 having bladder cancers, 33 ureter/pelvic cancers, and 85 normal and other urinary tract disease controls. RESULTS:UCA1 was identified as a novel noncoding RNA gene dramatically up-regulated in TCC and it is the most TCC-specific gene yet identified. The full-length cDNA was 1,439 bp, and sequence analysis showed that it belonged to the human endogenous retrovirus H family. Clinical tests showed that UCA1 assay was highly specific (91.8%, 78 of 85) and very sensitive (80.9%, 76 of 94) in the diagnosis of bladder cancer and was especially valuable for superficial G2-G3 patients (sensitivity 91.1%, 41 of 45). It showed excellent differential diagnostic performance in various urinary tract diseases without TCC. CONCLUSIONS:UCA1 is a very sensitive and specific unique marker for bladder cancer. It could have important implications in postoperative noninvasive follow-up. This research also highlights a shortcut to new cancer diagnostic assays through integration of in silico isolation methods with translational clinical tests based on RNA detection protocols.

背景与目标： 目的：在中国最常见的泌尿生殖系统恶性肿瘤是膀胱移行细胞癌（TCC）。尽早诊断出新发和复发性膀胱癌，然后及时进行治疗，将有助于降低死亡率。目前，临床上尚无令人满意的膀胱癌标记物。迫切需要更好的诊断方法。
实验设计：在这项研究中，我们使用了全面的表达序列标签分析，基因表达的序列分析和微阵列分析，并迅速发现了候选标记物，尿路上皮癌相关1（UCA1）。对UCA1基因进行了表征，并通过逆转录PCR与尿沉渣一起分析了其作为尿液标记物的性能。这项研究总共包括212位个体，其中94位患有膀胱癌，33位输尿管/盆腔癌以及85位正常和其他泌尿系统疾病对照。
结果：UCA1被鉴定为TCC中上调的新型非编码RNA基因，是迄今鉴定到的最具TCC特异性的基因。全长cDNA为1439 bp，序列分析表明它属于人内源性逆转录病毒H家族。临床测试表明，UCA1检测对膀胱癌的诊断具有高度特异性（91.8％，78 of 85）和非常敏感（80.9％，76 of 94），对于浅表G2-G3患者特别有价值（敏感性91.1％，41） 45）。在没有TCC的各种泌尿系统疾病中，它表现出出色的鉴别诊断性能。
结论：UCA1是膀胱癌非常敏感和特异的独特标志物。它可能对术后无创性随访产生重要影响。这项研究还突出了通过将计算机隔离方法与基于RNA检测方案的转化临床测试相集成的新癌症诊断测定方法的捷径。

BACKGROUND & AIMS: :Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.

背景与目标： ：几种针对分子的疗法已在临床试验中用于治疗头颈部鳞状细胞癌（HNSCC）。其中，针对表皮生长因子受体（EGFR）的疗法已得到最广泛的研究，某些药物已证明可测量的临床有效性。然而，旨在定义可能对EGFR靶向治疗有反应的HNSCC患者亚组的分子研究尚未发现与临床反应相关的分子标志。在这里，作者总结了相关的临床发现，并着重报道了针对HNSCC的EGFR靶向治疗药物的分子相关研究。作者尤其关注评估与临床反应相关的分子标志物，并包括来自其他癌症部位针对EGFR的临床研究的数据，他们预期这将是头颈癌研究和治疗界感兴趣的数据。

BACKGROUND & AIMS: OBJECTIVES:We evaluated the functional and oncological outcomes of transoral laser microsurgery (TLM) in patients with previously untreated supraglottic carcinoma compared with the outcomes in salvage cases after radiation-based treatment. METHODS:We conducted a retrospective case-control study at a single academic tertiary care institution. The functional outcomes were stratified by prior irradiation and were assessed at baseline, less than 1 week after operation, and at last follow-up. RESULTS:Five patients underwent TLM for previously untreated disease, and 5 previously irradiated patients underwent salvage TLM for local failure. No patient required tracheostomy. There was no local recurrence after TLM as primary therapy, and none of those patients required radiotherapy. One salvage patient developed local recurrence. The duration of feeding tube dependence (p = 0.049) and the rates of chronic aspiration (more than 1 month after operation; p = 0.048) were significantly higher in the salvage TLM cases than in the previously untreated cases. The median scores on the PSS-HN Understandability of Speech were 75 ("usually understandable") in the salvage group and 100 ("always understandable") in the previously untreated group. CONCLUSIONS:Both local control and function were better in the previously untreated patients than in the salvage patients. Our findings provide support for the use of TLM as a primary treatment modality for selected supraglottic carcinomas, but also suggest a potential for functional recovery in both previously untreated and salvage cases.

背景与目标： 目的：我们评估了先前未经治疗的声门上癌患者经口激光显微外科手术（TLM）的功能和肿瘤学结果，与基于放射治疗的抢救病例的结果相比。
方法：我们在一家单一的三级学术机构中进行了一项回顾性病例对照研究。功能结局通过事先照射进行分层，并在基线，手术后不到1周和最后一次随访时进行评估。
结果：5例接受过TLM的患者先前未接受过治疗，而5例接受过放射线的患者则接受了TLM进行局部衰竭治疗。没有患者需要气管切开术。 TLM作为主要疗法后没有局部复发，而且这些患者均不需要放疗。一名抢救患者出现局部复发。抢救性TLM病例的进食管依赖性持续时间（p = 0.049）和慢性误吸率（术后1个月以上； p = 0.048）显着高于先前未治疗的病例。挽救组的PSS-HN语音可理解性中位数为75（“通常可理解”），以前未治疗的组为100（“始终可理解”）。
结论：先前未治疗的患者的局部控制和功能均优于抢救患者。我们的发现为TLM作为选定的声门上癌的主要治疗手段提供了支持，但也暗示了先前未治疗和挽救病例的功能恢复潜力。

BACKGROUND & AIMS: BACKGROUND:This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era. METHODS:Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (M1) and the elderly (aged≥75y). RESULTS:A total of 4,217 patients with mRCC were identified, including 1,533 patients with M1 and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (≥75 vs.<75y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, M1, and elderly populations. CONCLUSION:This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in M1 and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age.

背景与目标： 背景：这项回顾性研究调查了瑞典转移性肾细胞癌（mRCC）患者在治疗前（2002-2005），早期（2006-2008）和晚期（2009-2012）的总生存（OS）和影响OS的因素。靶向治疗（TT）时代。
方法：瑞典的三个国家登记册确定了mRCC患者。中位数操作系统是使用Kaplan-Meier方法估算的。使用Cox比例风险回归进行多变量分析。对同步转移患者（M1）和老年人（年龄≥75岁）进行亚组分析。
结果：共鉴定出4,217例mRCC患者，其中1,533例M1患者和1,275例老年患者。对于2002年至2005年，2006年至2008年以及2009年至2012年诊断为mRCC的患者，中位OS​​为10.0、13.0和18.0个月。同样，M1和老年人口的OS中位数有所改善。老年患者接受TT的可能性较小（≥75vs. <75y）：18.3 vs. 63.5％（在2006-2008年）和28.6％vs. 55.9％（在2009-2012年）。 2009年至2012年，对mRCC的诊断，肾切除术和TT处方与总mRCC，M1和老年人口的OS改善相关。
结论：这项现实世界的研究表明，在TT时代后期，包括M1和老年人群，mRCC OS持续显着改善。对于所有mRCC患者，无论年龄大小，均应考虑TT。

BACKGROUND & AIMS: :Nuclear protein in testis (NUT)-midline carcinoma (NMC) is a rare, aggressive disease typically presenting with a single t(15;19) translocation that results in the generation of a bromodomain-containing protein 4 (BRD4)-NUT fusion. PER-624 is a cell line generated from an NMC patient with an unusually complex karyotype that gave no initial indication of the involvement of the NUT locus. Analysis of PER-624 next-generation transcriptome sequencing (RNA-Seq) using the algorithm FusionFinder identified a novel transcript in which Exon 15 of BRD4 was fused to Exon 2 of NUT, therefore differing from all published NMC fusion transcripts. The three additional exons contained in the PER-624 fusion encode a series of polyproline repeats, with one predicted to form a helix. In the NMC cell line PER-403, we identified the 'standard' NMC fusion and two novel isoforms. Knockdown by small interfering RNA in either cell line resulted in decreased proliferation, increased cell size and expression of cytokeratins consistent with epithelial differentiation. These data demonstrate that the novel BRD4-NUT fusion in PER-624 encodes a functional protein that is central to the oncogenic mechanism in these cells. Genomic PCR indicated that in both PER-624 and PER-403, the translocation fuses an intron of BRD4 to a region upstream of the NUT coding sequence. Thus, the generation of BRD4-NUT fusion transcripts through post-translocation RNA-splicing appears to be a common feature of these carcinomas that has not previously been appreciated, with the mechanism facilitating the expression of alternative isoforms of the fusion. Finally, ectopic expression of wild-type NUT, a protein normally restricted to the testis, could be demonstrated in PER-403, indicating additional pathways for aberrant cell signaling in NMC. This study contributes to our understanding of the genetic diversity of NMC, an important step towards finding therapeutic targets for a disease that is refractory to current treatments.

背景与目标： ：睾丸（NUT）-中线癌（NMC）中的核蛋白是一种罕见的侵袭性疾病，通常表现为单个t（15; 19）易位，导致含溴结构域的蛋白4（BRD4）-NUT融合的产生。 PER-624是由具有异常复杂核型的NMC患者产生的细胞系，未初步显示NUT基因座的参与。使用FusionFinder算法对PER-624下一代转录组测序（RNA-Seq）进行分析，发现了一种新颖的转录本，其中BRD4的第15外显子与NUT的第2外显子融合，因此不同于所有已发表的NMC融合转录本。 PER-624融合物中包含的三个附加外显子编码一系列聚脯氨酸重复序列，其中一个被预测会形成螺旋。在NMC细胞系PER-403中，我们确定了“标准” NMC融合蛋白和两种新型同工型。在任一细胞系中通过小分子干扰RNA敲低导致增殖减少，细胞大小增加和与上皮分化一致的细胞角蛋白表达。这些数据表明，PER-624中的新型BRD4-NUT融合蛋白编码的功能蛋白是这些细胞中致癌机制的核心。基因组PCR表明，在PER-624和PER-403中，易位将BRD4的内含子融合到NUT编码序列上游的区域。因此，通过易位后RNA剪接产生BRD4-NUT融合转录本似乎是这些癌的一个共同特征，以前尚未被人们认识到，其机制促进了融合的其他亚型的表达。最后，可以在PER-403中证实野生型NUT（通常限于睾丸的蛋白质）的异位表达，这表明NMC中异常细胞信号传导的其他途径。这项研究有助于我们了解NMC的遗传多样性，这是为目前治疗难以治疗的疾病寻找治疗靶标的重要一步。

BACKGROUND & AIMS: :Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.

背景与目标： ：脂肪生成的上调是癌症的标志，已知阻断脂肪生成途径会通过凋亡导致肿瘤细胞死亡。然而，尚不清楚脂肪生成在肿瘤起始中的确切作用。我们检查了乳腺导管原位癌（DCIS）临床样品中关键脂肪形成基因的表达谱，发现这些基因在DCIS中显着上调。我们还使用细胞表面标记（CS24（-）CD44（）ESA（））从DCIS.com细胞系中分离了癌干样细胞（CSC），发现与该细胞群相比，该细胞群具有更高的产生DCIS的肿瘤启动能力与非茎状种群。此外，CSCs显示所有脂肪形成基因的表达水平均高于非致瘤性乳腺癌细胞系MCF10A的对应群体。重要的是，MCF10A中异源表达的主调节因子SREBP1在MCF10A中的异位表达显着增强了干样细胞的脂肪生成，并促进了细胞生长以及乳球形成。此外，SREBP1表达显着提高了来自MCF10AT的CSC在小鼠和细胞培养物中的细胞存活能力，MCF10AT是另一种能够产生DCIS的细胞系。这些结果表明，通过赋予细胞存活能力，脂肪生成的上调是DCIS形成的先决条件。我们还显示白藜芦醇能够阻断CSC中脂肪基因的表达，并显着抑制其在动物体内生成DCIS的能力，这为我们提供了使用这种药物化学预防DCIS的强大理由。

BACKGROUND & AIMS: :Esophageal squamous cell carcinoma is the sixth most common cancer in the developing world. The aggressive nature of esophageal squamous cell carcinoma, its tendency for relapse, and the poor survival prospects of patients diagnosed at advanced stages, represent a pressing need for the development of new therapies for this disease. Chronic inflammation is known to have a causal link to cancer pre-disposition. Nuclear factor kappa B and signal transducer and activator of transcription 3 are transcription factors which regulate immunity and inflammation and are emerging as key regulators of tumor initiation, progression, and metastasis. Although these pro-inflammatory factors in esophageal squamous cell carcinoma have been well-characterized with reference to protein-coding targets, their functional interactions with non-coding RNAs have only recently been gaining attention. Non-coding RNAs, especially microRNAs and long non-coding RNAs demonstrate potential as biomarkers and alternative therapeutic targets. In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. We also discuss how these recent discoveries can pave way for future therapeutic options to treat esophageal squamous cell carcinoma.

背景与目标： ：食管鳞状细胞癌是发展中国家第六大最常见的癌症。食管鳞状细胞癌的侵略性，其复发趋势以及晚期诊断出的患者生存前景差，迫切需要开发针对该疾病的新疗法。已知慢性炎症与癌症易感性有因果关系。核因子κB和信号转导子及转录激活子3是调节免疫力和炎症的转录因子，并逐渐成为肿瘤起始，进展和转移的关键调节剂。尽管这些食管鳞状细胞癌中的促炎因子已针对蛋白质编码靶标进行了很好的表征，但它们与非编码RNA的功能相互作用只是最近才受到关注。非编码RNA，尤其是microRNA和长的非编码RNA，具有作为生物标志物和替代治疗靶标的潜力。在这篇综述中，我们总结了关于非编码RNA的最新文献和概念，这些非编码RNA在食管癌进展中受核因子κB和信号转导子及转录激活子3的调控。我们还讨论了这些最新发现如何为将来治疗食管鳞状细胞癌的治疗选择铺平道路。

BACKGROUND & AIMS: PURPOSE:To investigate the epidemiology and clinicopathological management for ocular sebaceous carcinoma (OSC) in the UK. METHODS:Observational prospective cohort study of patients with newly-diagnosed OSC. The British Ophthalmological Surveillance Unit captured incident cases of OSC between 2008 and 2010. Incident and 6-month follow-up questionnaires from reporting ophthalmologists captured OSC demographic and clinical data. RESULTS:Data were available on 51 patients with unilateral OSC (response rate 85%). The UK estimated annual incidence was 0.41 cases per million population (95% CI 0.31 to 0.54). Median age was 70 years (SD 14, range 28-98) with 57% women. OSC location was upper lid (54%), lower lid (20%), multicentric (14%) and caruncle (12%). Most common misdiagnoses included chalazion (42%), basal cell carcinoma (30%) and blepharoconjunctivitis (16%), with median delay in diagnosis of 10 months (SD 9, range 0.5-36). Specialist ophthalmic pathologists performed diagnostics in 62%, with pagetoid/intraepithelial spread present in 39%. Misdiagnosis of chalazion (p=0.019) and pagetoid tumour spread (p=0.016) was associated with a significant diagnostic delay (one-way ANOVA/R(2)). Primary surgical management involved excision with reconstruction (49%), primary exenteration (10%) and Mohs surgery (8%). There were three deaths (out of 51) during the study period; one patient died of OSC-related disease and the other two due to other causes. CONCLUSIONS:This population-based prospective study confirms OSC as a rare cancer in the UK. Masquerade syndromes result in significant diagnostic delays and increase the risk of pagetoid tumour spread. There is considerable UK variation in pathological and surgical management, and ocular reconstruction and radical surgery is often required for OSC due to delayed presentation.

背景与目标： 目的：探讨英国眼皮脂腺癌（OSC）的流行病学和临床病理管理。
方法：对新诊断为OSC的患者进行观察性前瞻性队列研究。英国眼科监视部门捕获了2008年至2010年之间发生OSC的事件。来自报告眼科医师的事件和6个月的后续调查表捕获了OSC的人口统计和临床数据。
结果：有51例单侧OSC患者的数据（有效率85％）。英国估计的年发病率为每百万人口0.41例（95％CI为0.31至0.54）。中位年龄为70岁（SD 14，范围28-98），其中女性占57％。 OSC位置是上盖（54％），下盖（20％），多中心（14％）和and形（12％）。最常见的误诊包括睑板裂（42％），基底细胞癌（30％）和睑结膜炎（16％），中位诊断时间延迟10个月（SD 9，范围0.5-36）。专门的眼科病理学家对62％的患者进行了诊断，其中39％的患者出现了页面状/上皮内扩散。查拉净的错误诊断（p = 0.019）和页面状肿瘤扩散（p = 0.016）与显着的诊断延迟（单向ANOVA / R（2））相关。主要的外科手术管理包括切除术，重建术（49％），初次切除术（10％）和莫氏手术（8％）。在研究期间，有3例死亡（共51例）。一名患者死于OSC相关疾病，另一例死于其他原因。
结论：这项基于人群的前瞻性研究证实了OSC在英国是一种罕见的癌症。假面舞会综合症会导致严重的诊断延迟，并增加页面状肿瘤扩散的风险。英国在病理和手术管理上存在很大差异，由于延迟出现，OSC经常需要眼球重建和根治性手术。

BACKGROUND & AIMS: :Serous carcinomas most commonly arise within the uterine corpus or ovary/fallopian tube, but there are 2 prior case reports of primary vaginal serous carcinoma. We report 2 examples of high-grade serous carcinoma arising within the urethra or a urethral diverticulum (1 case each). Both neoplasms exhibited the classic morphologic features of high-grade serous carcinoma, and a combination of clinical, radiologic, and pathologic examination excluded other possible sites of primary neoplasm.

背景与目标： ：浆液性腺癌最常见于子宫体或卵巢/输卵管，但已有2例先前的原发性阴道浆液性癌病例报告。我们报告2例发生在尿道或尿道憩室内的高度浆液性癌的例子（每例1例）。两种肿瘤均表现出高级别浆液性癌的经典形态学特征，临床，影像学和病理学检查的结合排除了其他可能的原发性肿瘤部位。