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）阳性染色，在50.0％中，孕激素受体（PR）染色阳性。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: BACKGROUND:We examined loss of heterozygosity (LOH) of the P53 gene in bladder cancer, and investigated the role of the P53 gene on malignant progression of papillary tumors. In addition, the clonality of recurrent bladder cancer was examined. METHODS:LOH of the P53 gene was analyzed in 67 bladder cancers from 47 patients. DNA was extracted from formalin-fixed, paraffin-embedded tissues, amplified by the polymerase chain reaction (PCR) at 3 polymorphic loci in the P53 gene, and analyzed with nonradioisotopic single-strand conformation polymorphism (Non-RI SSCP) analysis. RESULTS:Out of 40 informative samples, LOH was detected in 13 samples, containing 4 of 7 in grade 3 (57%), 9 of 23 in grade 2 (39%), and none of 10 in grade 1 (10%). Statistical significance was observed between the LOH in grades 1 and 2, and in grades 1 and 3. An analysis of 5 cases showing malignant progression revealed that 3 (60%) showed an LOH in the primary tumor, and 2 showed LOH in recurrent tumors, in contrast to LOH found in 3 cases of 19 (16%) not showing malignant progression. Four cases with metachronous recurrence exhibited LOH; 2 at recurrent tumors, 1 only at the initial tumor, and 1 at both tumors. CONCLUSIONS:The alterations of the P53 gene were considered to correlate with tumor grade, and contribute to the malignant progression of bladder cancer. LOH in the P53 gene may serve as a clinical indicator for prognosis in superficial bladder cancer.

背景与目标： 背景：我们检查了膀胱癌中P53基因的杂合性（LOH）缺失，并研究了P53基因在乳头状瘤恶性进展中的作用。另外，检查了复发性膀胱癌的克隆性。
方法：分析了47例患者的67例膀胱癌中P53基因的LOH。从福尔马林固定，石蜡包埋的组织中提取DNA，在P53基因的3个多态性位点处通过聚合酶链反应（PCR）进行扩增，并通过非放射性同位素单链构象多态性（Non-RI SSCP）分析。
结果：在40个信息量样本中，在13个样本中检测到LOH，其中3个7级中有4个（57％），2个23级中有9个（39％），1个10级中没有10个（10％）。在1级和2级以及1级和3级的LOH之间观察到统计学意义。对5例恶性进展的分析表明，3例（60％）在原发性肿瘤中显示LOH，2例在复发性肿瘤中显示LOH。 ，与LOH在19例（16％）的3例中未显示出恶性进展的情况相反。 4例异时复发表现为LOH。在复发性肿瘤中2个，仅在初始肿瘤中1个，在两个肿​​瘤中1个。
结论：P53基因的改变被认为与肿瘤的分级有关，并有助于膀胱癌的恶性进展。 P53基因中的LOH可作为浅表性膀胱癌预后的临床指标。

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。增殖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，基因表达的系列分析和微阵列分析，并迅速发现了候选标记尿路上皮癌相关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％，在78中的78）和非常敏感（80.9％，在76中的76），对于浅表G2-G3患者尤其有价值（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。作者特别关注评估与临床反应相关的分子标记，并包括来自其他癌症部位针对EGFR的临床研究的数据，他们预计这将是头颈癌研究和治疗界感兴趣的数据。

BACKGROUND & AIMS: OBJECTIVE:To examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data. METHOD:Poisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150 μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data. RESULTS:Use of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors. CONCLUSION:The cancer rates are higher among the low-dose (<150 μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.

背景与目标： 目的：探讨台湾西南部黑脚病（BFD）流行地区低剂量（井水砷水平<150μg/ L）村庄中砷暴露对癌症死亡率的分析作用数据。
方法：对低剂量（<150μg/ L）村庄的砷暴露量（μg/ kg /天）进行膀胱和肺癌死亡的泊松分析，暴露量由村庄的中位数，平均值或最大值定义或没有区域数据。
结果：使用村庄中井水砷中位数作为暴露指标，通过将水平> 500μg/ L的村庄包括在内，引入了分类错误，但是没有使用村庄平均值或最大值。使用平均砷含量或最大砷含量进行的泊松分析表明，对于膀胱癌以及膀胱癌和肺癌的模型，癌症斜率因子显着为负。当模型包含非砷差异的解释变量时，包含台湾西南地区的数据并没有改变结果。只有将比较人群作为一个单独的数据点，并假设饮用水中砷的暴露量为零，并消除非砷危险因素的变量，才能产生正斜率。
结论：BFD地区低剂量（<150μg/ L）村庄的癌症发生率高于台湾西南地区。但是，在BFD地区的低剂量村庄中，癌症风险提示与井水砷水平呈负相关。与区域数据的正差异似乎归因于非砷生态因素。

BACKGROUND & AIMS: :Epidural blood patch (EBP) is an effective procedure for the treatment of spontaneous intracranial hypotension (SIH). Neurological compromise following EBP, although rare, is recognized as a serious potential complication. We describe a 33-year-old female patient in whom long-term bladder and bowel dysfunction developed following a small volume (10 mL) EBP to treat SIH. We also discuss the possible pathophysiological mechanisms related to this complication in the postprocedure setting.

背景与目标： ：硬膜外补血（EBP）是治疗自发性颅内低血压（SIH）的有效方法。 EBP后的神经功能损害虽然很少见，但被认为是严重的潜在并发症。我们描述了一名33岁的女性患者，在该患者中，小剂量（10 mL）EBP治疗SIH后会出现长期的膀胱和肠功能障碍。我们还将讨论与术后并发症相关的可能的病理生理机制。

BACKGROUND & AIMS: BACKGROUND:The combinations of methotrexate, vinblastine, Adriamycin, cisplatin (Pharmanell, Athens, Greece) (MVAC) or gemcitabine, cisplatin (GC) represent the standard treatment of advanced urothelial cancer (UC). Dose-dense (DD)-MVAC has achieved longer progression-free survival (PFS) than the conventional MVAC. However, the role of GC intensification has not been studied. We conducted a randomized, phase III study comparing a DD-GC regimen with DD-MVAC in advanced UC. PATIENTS AND METHODS:One hundred and thirty patients were randomly assigned between DD-MVAC: 66 (M 30 mg/m(2), V 3 mg/m(2), A 30 mg/m(2), C 70 mg/m(2) q 2 weeks) and DD-GC 64 (G 2500 mg/m(2), C 70 mg/m(2) q 2 weeks). The median follow-up was 52.1 months (89 events). RESULTS:The median overall survival (OS) and PFS were 19 and 8.5 months for DD-MVAC and 18 and 7.8 months for DD-GC (P = 0.98 and 0.36, respectively). Neutropenic infections were less frequent for DD-GC than for DD-MVAC (0% versus 8%). More patients on DD-GC received at least six cycles of treatment (85% versus 63%, P = 0.011) and the discontinuation rate was lower for DD-GC (3% versus 13%). CONCLUSIONS:Although DD-GC was not superior to DD-MVAC, it was better tolerated. DD-GC could be considered as a reasonable therapeutic option for further study in this patient population. Clinical Trial Number ACTRN12610000845033, www.anzctr.org.au.

背景与目标： 背景：甲氨蝶呤，长春碱，阿霉素，顺铂（Pharmanell，雅典，希腊）（MVAC）或吉西他滨，顺铂（GC）的组合代表了晚期尿路上皮癌（UC）的标准治疗方法。与传统的MVAC相比，剂量密集（DD）-MVAC获得了更长的无进展生存期（PFS）。但是，尚未研究GC强化的作用。我们进行了一项随机III期研究，比较了DD-GC方案与DD-MVAC在晚期UC中的比较。
患者与方法：一百三十名患者被随机分配至DD-MVAC：66（M 30 mg / m（2），V 3 mg / m（2），A 30 mg / m（2），C 70 mg / m（2）q 2周）和DD-GC 64（G 2500 mg / m（2），C 70 mg / m（2）q 2周）。中位随访时间为52.1个月（89事件）。
结果：DD-MVAC的中位总体生存期（OS）和PFS为19和8.5个月，DD-GC的中位总体生存期（OS）和PFS为18和7.8个月（分别为P = 0.98和0.36）。与DD-MVAC相比，DD-GC的中性粒细胞减少感染频率较低（0％对8％）。使用DD-GC的患者更多，至少接受了六个周期的治疗（85％对63％，P = 0.011），DD-GC的停药率较低（3％对13％）。
结论：尽管DD-GC并不优于DD-MVAC，但其耐受性更好。 DD-GC被认为是对该患者人群进行进一步研究的合理治疗选择。临床试验编号ACTRN12610000845033，www.anzctr.org.au。

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： 摘要背景：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mRCC患者4,217例，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（≥75 vs. <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：这项真实世界的研究表明，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（CSCs），发现与该细胞相比，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中脂生成基因的主要调控因子SREBP1的异位表达显着增强了干细胞样脂质的生成，并促进了细胞的生长以及乳球的形成。此外，SREBP1表达显着提高了来自MCF10AT的CSC细胞的存活能力，MCF10AT是另一种能够在小鼠和细胞培养物中产生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。我们还表明，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该药物化学预防DCIS的强大理由。