分化型甲状腺癌碘拮抗相关基因研究进展

甲状腺癌是最常见的内分泌系统恶性肿瘤,其中分化型甲状腺癌占多数,后者的主要治疗手段有手术治疗、术后碘放射性同位素(131I)治疗和促甲状腺激素抑制治疗等.131I在分化型甲状腺癌的诊断与治疗中有较为广泛的应用,然而,一部分分化型甲状腺癌患者因钠-碘转运体基因、BRAF基因、双链复合蛋白8、微小RNA、细胞角蛋白19等基因的改变而降低或丧失对131I的摄取能力.这些基因在分化型甲状腺癌的治疗中尤为重要,可作为肿瘤治疗疗效评估的重要指标.     

分化型甲状腺癌相关基因的研究进展

目的:总结近年来国内外分化型甲状腺癌(DTC)相关基因的研究进展。方法:应用PubMed、Elsevier Sciencedirect、CNKI及万方期刊全文数据库检索系统,以"分化型甲状腺癌、RET、Ras、BRAF"等为关键词,检索是2005-2010年发表的相关文献,共检索到文献252条。纳入标准:1)相关基因与分化型甲状腺癌发生、发展。2)相关基因与分化型甲状腺癌诊断、治疗及预后。根据纳入标准,纳入分析文献36篇。结果:甲状腺癌是最常见的内分泌肿瘤,近年来其发病率逐年增高,研究显示甲状腺癌的发生、发展是在不同的时间和空间上以多个原癌基因激活和(或)抑癌基因的失活为基础的多步骤过程。不同的病理类型有其相对特异性的基因改变:RET/PTC重排、BRAF突变多见于乳头状腺癌(papillary thyroid cancer,PTC),而Ras基因突变、PAX8-PPARG融合基因主要见于滤泡状腺癌(follicular thyroid cancer,FTC)。此外抑癌基因p53突变在甲状腺癌进展中起重要作用,PTEN则通过使PI3K/Akt的信号转导通路的持续激活促进了甲状腺癌的发生发展。相关的信号转导通路也参与其中。将有关基因用于分化型甲状腺癌的诊断、治疗、疗效预测及预后分析有着广阔的前景。结论:分化型甲状腺癌是个多因素多基因的疾病,其发生发展与基因的改变密切相关。     

基因表达谱芯片筛选甲状腺癌失分化相关基因的初步研究

目的应用基因芯片技术筛查甲状腺癌失分化相关基因,为进一步研究其发病机制提供新的思路和线索。方法分别用Cy5和Cy3两种不同的荧光染料通过逆转录反应将失分化甲状腺癌组和对照组分化型甲状腺癌组织的mRNA分别标记成探针,并与载有一组靶基因的基因表达谱芯片进行杂交。通过扫描荧光强度,计算机软件分析,寻找两组差异表达基因。结果分化型甲状腺癌与失分化甲状腺癌组织之间存在一系列差异表达基因,共有373条差异表达基因,其中表达增加的有209条(2.0倍以上),表达降低的有164条(0.5倍以下)。结论基因芯片为筛选甲状腺癌失分化相关基因提供了有效的方法。     

分化性甲状腺癌组织中p53基因蛋白表达及临床意义

目的探讨ｐ５３基因蛋白与分化性甲状腺癌的关系。方法采用免疫组织化学法检测６６例分化性甲状腺癌组织和３７例良性甲状腺病变组织中ｐ５３基因蛋白。结果分化性甲状腺癌组织中ｐ５３基因蛋白阳性表达率为５７５％，良性甲状腺病变组织中阳性表达率为２７％，两者差异有显著意义（Ｐ＜００１）。结论ｐ５３基因蛋白阳性表达与分化性甲状腺癌的发生及淋巴结转移有密切关系。     

精确放疗治疗甲状腺癌的研究进展

甲状腺癌是最常见的内分泌系统恶性肿瘤,按组织病理类型可以分为乳头状甲状腺癌、滤泡状甲状腺癌、髓样甲状腺癌和未分化型甲状腺癌。前两者因分化水平较高统称为分化型甲状腺癌。分化型甲状腺癌首选手术治疗,其次针对术中未能切除的残余病灶进行放射碘治疗。外照射放疗在分化型甲状腺癌及甲状腺髓样癌中的作用仅局限于手术治疗失败、肿瘤不能切除或者有肉眼可见远处转移灶残留的患者。精确放疗可增加肿瘤的局部控制率,减少正常组织的放射损伤。而甲状腺未分化癌大多数不能完全手术切除,外照射放疗联合化疗具有重要作用。放疗作为术前、术后综合治疗的一部分发挥作用,也可以采用单纯放疗的形式缓解症状、控制病变生长,从而延长生存期,起到姑息治疗的目的。     

分化型甲状腺癌再次手术临床分析

目的：探讨分化型甲状腺癌再次手术的原因、时机及对策。方法：对5年来收治的甲状腺手术后病理证实为分化型甲状腺癌,需要再次手术治疗的30例临床病理资料进行回顾性分析。结果：24例再次手术的原因为将分化型甲状腺癌误诊为甲状腺良性病变,手术切除范围不够,4例原因为分化型甲状腺癌术后复发,2例原因为131I治疗前的甲状腺清除。结论：分化型甲状腺癌的误诊是造成甲状腺癌再次手术的主要原因,应强调术中快速冰冻病理检查在甲状腺手术中的常规应用。     

分化型甲状腺癌再次手术临床分析

目的:探讨分化型甲状腺癌再次手术的原因、时机及对策。方法:对5年来收治的甲状腺手术后病理证实为分化型甲状腺癌,需要再次手术治疗的30例临床病理资料进行回顾性分析。结果:24例再次手术的原因为将分化型甲状腺癌误诊为甲状腺良性病变,手术切除范围不够,4例原因为分化型甲状腺癌术后复发,2例原因为131I治疗前的甲状腺清除。结论:分化型甲状腺癌的误诊是造成甲状腺癌再次手术的主要原因,应强调术中快速冰冻病理检查在甲状腺手术中的常规应用。     

促甲状腺激素受体在分化型甲状腺癌组织中的表达及意义

目的 探讨促甲状腺激素(TSH)受体在分化型甲状腺癌中的表达及意义.方法 采用免疫组化染色检测74例分化型甲状腺癌患者和28例结节性甲状腺肿患者甲状腺组织中TSH受体的表达,分析其与分化型甲状腺癌患者TNM分期和淋巴结转移的关系.结果 TSH受体在结节性甲状腺肿组织中的阳性表达率为89.3％,明显高于分化型甲状腺癌组织(55.4％;x2=10.21,P＜0.05).TSH受体在Ⅰ期、Ⅱ期、Ⅲ期和Ⅳ期分化型甲状腺癌组织中的阳性表达率分别为75.9％、47.8％、38.9％和25.0％,随着临床分期的升高,阳性表达率逐渐下降.统计学分析的结果显示,TSH受体的表达与分化型甲状腺癌的TNM分期相关(P＜0.05),而与淋巴结转移无关(P＞0.05).结论 TSH受体在分化型甲状腺癌组织中的阳性表达率较低,且随着TNM分期的增加,TSH受体的阳性表达率逐渐下降.TSH受体表达水平的检测可为分化型甲状腺癌患者术后进行TSH抑制治疗提供依据.     

分化型甲状腺癌的超声表现及与颈部淋巴结转移的关系研究

目的 探讨分化型甲状腺癌的超声表现及与颈部淋巴结转移的关系.方法 收集108例分化型甲状腺癌患者的临床资料,患者术前均接受超声检查,分析分化型甲状腺癌患者术前临床特征、超声表现与颈部淋巴结转移的关系.结果 年龄﹤45岁、结节最大径﹥1 cm、边缘不规则、侵犯甲状腺被膜的转移组分化型甲状腺癌患者比例分别高于未转移组,差异均有统计学意义(P﹤0.05).转移组与未转移组分化型甲状腺癌患者血流丰富程度比较,差异有统计学意义(P﹤0.05).多因素分析结果显示,年龄﹤45岁、侵犯甲状腺被膜、丰富血流均是分化型甲状腺癌患者颈部淋巴结转移的独立危险因素(P﹤0.05).结论 分化型甲状腺癌术前超声表现及临床特征能一定程度上预测颈部淋巴结转移风险,临床针对具有颈部淋巴结转移高危因素的患者,应仔细检查,为临床治疗提供更可靠的参考依据.     

BRAF基因突变及其对分化型甲状腺癌钠碘同向转运体功能影响的研究进展

目的:总结分化型甲状腺癌中鼠类肉瘤滤过性毒菌(V-raf)致癌同源体B1(BRAF)基因突变与钠碘同向转运体(NIS)国内外研究进展,阐述BRAF和NIS基因结构表达与调控及BRAF基因突变对NIS功能的影响。方法:应用PubMed、Sciencedirect和万方检索系统,以"分化型甲状腺癌、钠碘同向转运体、BRAF、131I"为关键词,检索1998-2010年相关文献95篇。纳入标准:1)NIS结构与功能;2)NIS与分化型甲状腺癌的关系;3)BRAF结构与功能;4)BRAF突变与分化型甲状腺癌的关系;5)BRAF突变与NIS表达在分化型甲状腺癌中的关系。根据纳入标准分析文献23篇。结果:甲状腺癌131I治疗通过NIS介导。NIS的表达可以预测复发DTC131I的聚集和131I疗效评价。BRAF突变在PTC中可作为不良影响因子,影响PTC的发生、侵袭及预后。BRAF基因突变能引起NIS表达下降(20%～80%),病灶摄碘能力降低。NIS的表达水平在含有BRAF V600E突变的PTC中明显降低。结论:BRAF基因突变能引起NIS表达下降,降低病灶碘治疗疗效。因此,BRAF基因突变有望成为预测甲状腺癌放射性碘治疗疗效的指标。     

The medically important dematiaceous fungi and their identification

Dematiaceous fungi include a large group of organisms that are darkly pigmented (dark brown, olivaceous, or black). In most cases the pigment is melanin, and specifically, dihydroxynaphthalene melanin. The diseases produced include chromoblastomycosis, eumycotic mycetoma, and phaeohyphomycosis. Phaeohyphomycosis is a new classification for a diverse group of previously known entities grouped together on the basis of finding dematiaceous hyphal and/or yeast-like forms in tissue; tissue involvement may be superficial, cutaneous and corneal, subcutaneous, or systemic. Identification of these fungi is based mostly upon morphology. Important structures include annellides (Phaeoannellomyces, Exophiala), phialides (Phialophora, Wangiella), adelophialides (Phialemonium without collarettes, Lecythophora with collarettes), differentiation of conidiophores (Xylohypha versus Cladosporium) and conidial hilum, septation and germination (Bipolaris, Drechslera, Exserohilum). Useful laboratory tests include the 12% gelatin test (controversial), nitrate assimilation (W. dermatitidis is negative, most other species are positive), and determination of temperature maxima (especially 37 degrees C for E. jeanselmei, 40 degrees C for W. dermatitidis and B. spicifera, 42 degrees C for X. bantiana, and 45 degrees C for Dactylaria constricta var. gallopava and Scedosporium inflatum).     

Orale Langzeitbehandlung von Onychomykosen mit Ketoconazol

Zusammenfassung: An der Studie zur Wirksamkeit und Anwendungssicherheit von Ketoconazol nahmen 27 Männer im Alter von 20 bis 80 (Median: 57) Jahre, davon 18 mit Onychomykosen und 9 als KontroUen bei den Laborwertbestimmungen, teil. Während des ersten Behandlungsmonats erhielten je 9 Patienten 200 mg und 400 mg Ketoconazol täglich. Danach wurden beide Gruppen 6 Monate mit 200 mg/d weiterbehandelt. Die klinische Beurteilung sowie hämatologische, biochemische und Plasmaspiegeluntersu-chungen erfolgten mindestens monafich, mykologische Untersuchungen wurden vor Aufnahme und bei Beendigung der Therapie vorgenommen. Erne letzte klinische Unter-suchung erfolgte 1 Jahr nach Beginn der Studie. Nach 7 Monaten Behandlung wurden 23 von 30 Nägeln mit “gebessert” bis “stark gebessert” beurteilt, nach dem behandlungsfreien Intervall galt dies für 28 von 30 Nägeln. Die Plasmaspiegel waren mit 200 mg/d ausreichend und uber den Behandlungszeit-raum konstant. Dies spricht für gute orale Resorption und Abwesenheit von Enzyminduktion. Die Laborwerte zeigten im Vergleich zu den Kontrollen und den Werten vor Behandlung keine signifikanten Abweichungen, so daß myelo-, nephro- und hepatotoxische Wirkungen von 400 bzw. 200 mg/d ausgeschlossen werden können. Der Lipidhaushalt wurde nicht beeinfluat und es trat unter Therapie als Folge der Ketoconazolwirkung lediglich Lanosterin im Serum auf. Nach Beendigung der Therapie ging der Lanosteringehalt schnell zurück. Damit erweist sich Ketoconazol in den angewandten Dosen als ein gut verträgliches und zur Langzeitbehandlung von Onychomykosen geeignetes Antimykotikum. Summary: Twenty-seven males with a median age of 57 (range: 20 to 80) years took part in this study on the efficacy and safety of ketoconazole. Eighteen men suffered from onychomycosis; nine served as controls in the safety evaluation. During the first month of treatment, nine patients received 200 mg and the nine other 400 mg ketoconazole daily. Then the treatment was uniformly continued with 200 mg/d for 6 months. Clinical evaluation and haematological, biochemical and plasma level investigations were carried out at least at monthly intervals; mycological controls were performed at the start and end of therapy. A final clinical evaluation was carried out one year after the start of the study. After 7 months of treatment, moderate or definite clinical improvement was obtained in 23 out of 30 nails. After 5 more months without antimycotic treatment this was the case in 28 of 30 nails. Plasma levels obtained with 200 mg ketoconazole daily were adequate and constant during the entire treatment period. This indicates a good oral resorption as well as the absence of induction of hepatic enzymes. The laboratory values did not show significant deviations as compared with the controls or with the pretreatment values. This excludes myelo-, nephro- and hepatotoxic effects of 400 and 200 mg ketoconazole daily. The lipid metabolism was not influenced, the only difference was the occurrence of lanosterol in the serum, which is a result of the mechanism of action of ketoconazole. After the medication period the lanosterol levels subsided rapidly. In the applied doses ketoconazole is a well-tolerated and effective drug for the systemic long-term treatment of onychomycosis.     

Laboratory Techniques Alternative to In Vivo Experiments for Studying the Liberation, Penetration and Fungicidal Action of Topical Antimycotic Agents in the Skin, Including Ciclopiroxolamine

Summary: Short-term experiments on excised skin (human, pig) gave the following results: 1. In the tissue activity test with direct inoculation (D-TAT) commercial preparations of the non-azole antimycotics ciclopiroxolamine, tolnaftate and naftifine, produced higher inhibitory activity against Trichophyton mentagrophytes (standard strain) in various levels of the horny layer than were produced by the azole antimycotics econazole, miconazole, clotrimazole, oxiconazole and bifonazole. Fast drying solutions of antimycotics invariably gave higher inhibitory activities than creams. In the ultrafiltration tissue activity test (UFT- TAT) against Candida albicans (2 strains), antimycotic agents ranked in order of effectiveness as follows: ciclopiroxolamine – most of the azole antimycotics – bifonazole and naftifine. 2. In tests of fungicidal activity against T. mentagrophytes (2 strains) and Microsporum gypseum (1 strain) the first step was to inoculate the skin surface. After the horny layer had been penetrated by fungal mycelia, antimycotic agents of documented fungicidal potency, chiefly in the form of creams, were applied to the skin surface and left to act for up to 18 hours. The horny layer and epidermis were then scraped off and the concentration of viable fungi was determined. Ciclopiroxolamine cream and lotion produced by far the greatest diminution in viable fungi; creams containing oxiconazole and naftifine were moderately effective and those containing tioconazole and bifonazole produced a relatively small decrease in viable fungi. To avoid erroneous results it is important to homogenize and dilute the skin scrapings; if this is not done certain antimycotics will give misleadingly high fungal killing rates. At this early stage the scatter of results is still wide and minor differences in efficacy cannot as yet be detected with certainty. 3. From the results of various comparative tests it is evident that pig skin can be used as a substitute for human skin in the tests listed under 1. and 2. above. This discovery may make a valuable contribution towards limiting the need for experiments on living animals and trials on human beings. Zusammenfassung: In Kurzzeitversuchen an exzidierter Haut (Mensch, Schwein) wurde gefunden: 1. Im Gewebeaktivitätstest mit direkter Inokulation (D-GAT) wurde mit Handelspräparaten der Nichtazol-Antimykotika Ciclopiroxolamin, Tolnaftat und Naftifin in verschiedenen Hornschichtniveaus eine höhere Hemmaktivität gegenüber Trichophyton mentagrophytes (Standard-Stamm) erzielt als mit solchen der Azol-Antimykotika Econazol, Miconazol, Clotrimazol, Oxiconazol und Bifonazol. Rasch trocknende Lösungen von Antimykotika ergaben durchweg höhere Hemmaktivitäten als Cremes. Im Ultrafiltrations-Gewebeaktivitätstest (UFT-GAT) gegenüber Candida albicans (2 Stämme) ergab sich nach erzielter Wirksamkeit die Rangfolge Ciclopiroxolamine – Mehrzahl der Azolantimykotika – Bifonazol und Naftifin. 2. In Fungizidie-Testen gegenüber T. mentagrophytes (2 Stämme) und Microsporum gypseum (1 Stamm) wurde zunächst die Hautoberfläche inokuliert. Nach Durchdringung der Hornschicht mit Pilzmyzelien wirkten auf die Hautoberfläche bis zu 18 Stunden lang überwiegend Cremes von als fungizid publizierten Antimykotika ein. Während sich in abgeschabter Hornschicht und Epidermis der so bearbeiteten Hautoberflächen mit Ciclopiroxolamin-Creme und -Lotion die weitaus höchste Verminderung lebensfähiger Keime ergab, bewirkten Cremes mit Oxiconazol und Naftifin eine mittlere und solche mit Tioconazol und Bifonazol eine relativ niedrige Keimeliminierung. Zur Vermeidung von fehlerhaften Ergebuissen mußten Homogenisierung und Verdünnung der Hautschabsel erfolgen, anderenfalls bei mehreren Antimykotika eine zu hohe Keimabtötung vorgetäuscht worden wäre. Wegen der vorerst noch hohen Streuung der Ergebnisse können kleinere Wirksamkeitsunterschiede noch nicht sicher erfaßt werden. 3. Nach dem Ergebnis verschiedener Vergleichstests kann in den Testen zu 1. und 2. Schweinehaut als Ersatz für Haut vom Menschen dienen und dürfte damit wesentlich zur Einschränkung von Versuchen am lebenden Tier und von Prüfungen am Menschen beitragen.     

Efficiency of crude and purified fungal antigens in serodiagnosis to discriminate mycotic from other respiratory diseases

Mycotic immunodiagnosis was performed in 186 hospitalized patients with different respiratory diseases, mostly considered as tuberculosis and others with a doubtful diagnosis. Crude histoplasmin, coccidioidin, paracoccidioidin, blastomycin, candidin, aspergillin, and sporotrichin, as well as purified polysaccharide-protein complexes (PPC) of Histoplasma capsulatum, Coccidioides immitis, and Paracoccidioides brasiliensis were used as antigens. Immune tests used included skin test (ST), gel immunodiffusion (ID), counterimmunoelectrophoresis (CIE), complement fixation (CF), and ELISA. A possible association with candidosis was observed in 17% of patients with tuberculosis and diabetes; one presumptive paracoccidioidomycosis, one confirmed aspergillosis, and six cases of active histoplasmosis were determined. Candidin ST showed 29% of positive reactions with an increased frequency in patients between 31 and 55 years of age. CF test showed the highest positivity percentages with crude antigens, specially for Candida antigen (26.3%) and histoplasmin (18.2%). Cross reactions were evident with crude antigens but decreased when PPC's were used in ELISA.     

Isoconazole nitrate in the treatment of tropical dermatomycoses

Summary. A total of 54 patients with culturally proven tropical dermatomycoses, comprising 23 with various types of dermatophytoses, one with foot infection due to Trichosporon beigelii and one with foot infection due to Geotrichum candidum , two with candidoses of the groin and 27 with pityriasis versicolor, were included in a clinical trial of efficacy of 1% isoconazole cream (Travogen^R, Schering, Berlin, Germany). Five patients were not evaluable. A clinical and mycological cure was achieved in 29 cases in 3–4 weeks. In 15 (31%) of the remaining patients treatment was required for 5–6 weeks, while another three patients required treatment for 8 weeks. In two patients the disease proved to be resistant to treatment with the drug.
Zusammenfassung. Insgesamt 54 Patienten mit kulturell gesicherter Dermatomykose, (23 unterschiedliche Dermatophytosen, eine Trichosporon beigelii - und eine Geotrichum candidum -Fußinfektion, 2 Candidosen der Leistengegend und 27 Pityriasis versicolor) wurden in einer klinischen Wirksamkeits-studie mit 1% iger Isoconazol-Creme (Travogen^R, Schering, Berlin, Deutschland) behandelt. Fünf Patienten waren nicht auswertbar. Eine klinische und mykologische Heilung wurde bei 47 von 49 Patienten (96%) erreicht. Bei 29 patienten (59%) wurde die Heilung bereits nach 3–4 Wochen Behandlung erreicht. Weitere 15 Patienten (31%) benötigten 5–6 Wochen und drei Patienten 8 Wochen Behandlungsdauer. Zwei Mykosesituationen erwiesen sich als therapieresistent.     

Large-scale molecular characterization and analysis of gastric cancer

The recent effort by The Cancer Genome Atlas （TCGA） Network has revealed that gastric cancer, which is a leading cause of cancerrelated deaths worldwide with a 5-year survival rate less than 25%, is a much more heterogeneous disease than previously thought. And yet, conventional treatment approaches and clinical trials have assumed it is a single disease. Although it is well known that under the microscope, gastric cancer cells appear quite different, the current classification scheme recognizes two main categories of gastric cancer： diffuse and intestinal.     

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma''s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.