Interferon receptors and the caspase cascade regulate the antitumor effects of interferons on human pancreatic cancer cell lines

BACKGROUND: Interferons (IFNs) have antiproliferative effects on tumor cells. The apoptotic effects and sensitization to chemotherapy conferred by IFN therapy, however, are not clearly understood. The aims of the present study were to explore the apoptotic effects of IFNs in human pancreatic cancer cell lines and to attempt to define their ability to synergistically enhance sensitivity to 5-fluorouracil (5-FU) and gemcitabine, a mechanism that depends on the expression of IFN receptors. METHODS: Human pancreatic cancer cells were cultured alone or in combination with the chemotherapeutic agents 5-FU and gemcitabine. Differential dosages of IFN-alpha, -beta, and -gamma were also added to the cell lines concomitantly during a period of 24 to 96 hours. The cell line viability and effects of treatment were examined using the methylthiazol tetrazolium assay and single-stranded DNA apoptosis assay. The expression of IFN receptors was determined using immunohistochemistry. Caspase-8 inhibitor was used to block the caspase cascade. RESULTS: The antiproliferative and apoptotic effects of IFNs were most profoundly demonstrated on those cells that expressed the respective IFN receptor. The apoptotic effects provided by the interferons, however, were blocked by caspase-8 inhibition. The addition of IFNs significantly enhanced the cytotoxic effects of 5-FU and gemcitabine in those cell lines that expressed the corresponding IFN-alpha, -beta, or -gamma receptors. CONCLUSIONS: This study on pancreatic cancer cell lines has demonstrated that IFNs mediate apoptosis through IFN receptors and the caspase cascade. Enhanced cytotoxicity occurred when IFNs were combined with 5-FU and gemcitabine.     

胰腺星形细胞在胰腺癌中的作用

胰腺癌是常见的消化道恶性肿瘤之一,因早期诊断困难,恶性程度高,手术切除率低,并对化放疗均不敏感,故预后极差.其病理特征之一是肿瘤中有大量的结缔组织形成反应.而胰腺星形细胞(PSCs)在这一反应中起重要作用,并通过与胰腺癌细胞的相互作用,对胰腺癌细胞的增生、侵袭和转移有重要作用.本文就PSCs在胰腺癌发展中的作用及机制作一综述.     

竞争性内源RNA在胰腺癌中的作用

胰腺癌是消化系统恶性程度较高的肿瘤之一,如何早期发现、诊断及提高疗效是目前临床迫切需要解决的问题.近年来竞争性内源RNA假说的提出为阐明包括胰腺癌在内的多种肿瘤的发生发展机制提供了重要线索及新的研究方向.微小RNAs (miRNAs)和长链非编码RNAs (lncRNAs)均为竞争性内源RNA假说的重要组成部分,研究发现,miRNAs的过度表达和沉默,以及部分lncRNAs的异常表达均与胰腺癌的发生发展有密切关系.本文分别从竞争性内源RNA假说的内容及机制,竞争性内源RNA成员在胰腺癌等肿瘤中的作用作系统综述.     

The role of pancreatic resection in the treatment of pancreatic pseudocysts

Complicated pancreatic pseudocysts, including multiple pseudocysts, those that have failed prior internal or external drainage, those with associated biliary or pancreatic duct strictures and those where the diagnosis of cystic neoplasm cannot be excluded, pose unique problems in terms of treatment by standard internal or external drainage techniques. In the series reported herein, pancreatic resection (pylorus-sparing pancreaticoduodenectomy or distal pancreatectomy) was used to treat patients with these complicated pseudocyts resulting in a 59% morbidity rate, 3% mortality rate, and 6% recurrence rate. Results from a collective series of 152 patients from the literature support these findings. Although pancreatic resection has a limited role in the management of patients with uncomplicated pancreatic pseudocysts, it is the treatment of choice in patients with complicated pancreatic pseudocysts.     

The role of neurolytic celiac plexus block in the treatment of pancreatic cancer pain

Pancreatic carcinoma, an important leading cause of cancer death, has increased steadily in incidence and still has a poor prognosis. Pain is one of the most frequent symptoms, affecting more than 75% of patients. It is often present in the early stages of disease and may be severe and difficult to treat. Abdominal viscera, including pancreas, liver, gallbladder, adrenal, kidney, and the gastrointestinal tract from the level of the gastroesophageal junction to the splenic flexure of the colon are innervated, at least in part, via the celiac plexus. Thus, painful tumors in these viscera may have pain relieved through the use of a neurolytic celiac plexus block (NCPB). Although some investigators questioned the role and the efficacy of NCPB in the treatment of upper abdominal cancer pain, most of them have suggested that it may represent the optimal treatment, especially for pancreatic cancer pain. In this report we have reviewed the techniques, results, and complications of NCPB for the treatment of pancreatic cancer pain.     

Fundamental studies on intravesical instillation of interferons in the treatment of bladder cancer

The cytotoxic effect of interferons on T24 cells, the established cell line from human urinary bladder cancer, the distribution of the drugs in blood, urine and tissues of various organs and histopathological change in the bladder mucosa in dogs following intravesical instillation of the drugs, were studied. These studies were conducted to investigate the possible application of each type of interferons to intravesical treatment of superfitial bladder cancer. 1) The cytotoxicity of Ro22-8181 (recombinant human interferon alpha), GKT-beta (recombinant human interferon beta) and KW2202 (recombinant human interferon gamma) on T24 cells was examined by colony formation method and growth inhibition assay. Cytocidal effects of interferons were dependent on dose and exposure time, and GKT-beta is most effective (GKT-beta greater than Ro22-8181 greater than KW2202). Cytostatic effects of GKT-beta were also dependent on dose and exposure time. 2) The interferon levels in blood, urine and tissues were measured by FL-Sindbis system following bladder instillation of GKT-beta or KW2202 in beagle dogs with bilateral cutaneous ureterostomy. No interferons were detected in blood and urine. Bladder mucosa and submucosal layer were observed through a microscope 6 and 10 hours after bladder instillation of GKT-beta or KW2202 in beagle dogs with bilateral cutaneous ureterostomy. Degeneration of bladder mucosa and submucosal layer was scarcely observed. The above results suggest that GKT-beta is a suitable drug for intravesical treatment of bladder cancer.     

Blunt pancreatic injuries in children: the role of percutaneous external drainage in the treatment of pancreatic pseudocysts

During the past 10 years, 26 cases of blunt pancreatic trauma were diagnosed in our institution. In 42.3% (11/26) the accident was bicycle-related. Seventy-three percent of patients were seen within 48 hours of injury. The most frequent clinical presentations included abdominal pain, tenderness and vomiting. Diagnosis of pancreatic injury was suggested by hypermylasemia in most cases. Associated trauma was seen in seven patients (26.9%) and it was intraabdominal in four (15.3%). Computerized tomography (CT) scan is the single most useful radiologic investigation in evaluating pancreatic trauma. Ultrasound, although less accurate than CT scan in determining the severity of the initial injury, is useful in the evaluation and treatment of pancreatic pseudocysts. Pancreatic pseudocysts developed in ten patients. Spontaneous resolution occurred in five (50%). In three patients, percutaneous external drainage (PED) was successful in treating pancreatic pseudocysts without complications or recurrence at 11, 19, and 31 months. PED is a suitable form of treatment in selected cases of pancreatic pseudocysts. Results in children are better than in the adult population, probably due to the absence of primary pancreatic pathology. We believe that PED should be considered the primary therapeutic procedure for traumatic pancreatic collections prior to more invasive surgical treatment, when there is no evidence of pancreatic duct transection on CT scan.     

Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)

Introduction Pancreatic ductal adenocarcinoma (i.e., pancreatic cancer) is an almost universally lethal disease. The identification of precursor lesions of pancreatic cancer provides an opportunity for early detection and potential therapeutic intervention before the development of invasive cancer. Discussion It is now established that pancreatic cancers do not arise de novo but rather exhibit a sequential histological and genetic progression of precursor lesions culminating in frank, invasive neoplasia. Pancreatic intraepithelial neoplasia (PanIN) is the most common non-invasive precursor lesion of pancreatic cancer. The development of a consensus nomenclature scheme for PanINs has facilitated research into pancreatic cancer precursors and enabled standardization of results across institutions. Conclusion PanINs harbor many of the molecular alterations observed in invasive pancreatic cancer, confirming their status as true non-invasive precursor lesions. Recently developed genetically engineered mouse models of pancreatic cancer also demonstrate the stepwise PanIN progression model, underscoring the commonalities in pancreatic neoplasia between mouse and man.     

胰腺癌外科治疗的进展

作为2013年西方国家第四大癌症死亡原因,胰腺癌在新发癌症病例中已上升至女性第9位和男性第10位.由于早期检出率低,胰腺癌患者确诊时仅20%可手术,30%～40%为局部晚期,50%已全身转移,总体5年生存率仅6%.为提高早期检出率,内镜超声引导下穿刺活检是获得组织诊断的最佳方式,但准确率不高,故国际诊疗指南建议如有以下几点即可考虑外科手术：①囊性肿物直径〉2～3cm;②MRI和内镜超声中检出可疑结节;③导管内乳头状黏液瘤（IPMN）和黏液性囊腺瘤等癌前病变.1995年至2004年美国国家癌症数据库研究显示,手术患者的5年生存率为24.6%,而非手术患者仅为2.9%.因此,手术切除是患者获得长期生存和潜在治愈的唯一机会.外科手术技术和围手术期管理进步使胰腺手术更加安全,特别是围手术期疗效的进展,外科医生可以实施更加复杂的手术切除.因此,可切除标准亦有所放宽：①血管切除：过去视为不可切除,如今只要适合重建,肿瘤侵犯肝动脉、门静脉和肠系膜上静脉均可行边界性切除,但若肿瘤完全包绕腹腔干或者肠系膜上动脉则视为不可切除;②多脏器切除：对于侵犯了邻近器官（例如结肠系膜、结肠、胃）的局部浸润肿瘤均可行多脏器切除术;③扩大的淋巴结清扫术：扩大的淋巴清扫术并不能提高生存率,反而增加并发症率,因此,不推荐常规施行胰腺癌扩大的淋巴结清扫术;④腹腔镜胰腺切除术在胰腺癌中的应用：腹腔镜胰体尾切除术是可行且安全的,但目前仍缺乏腹腔镜胰头部切除术的肿瘤学长期效果的数据.研究报道,胰腺术后并发症发生率在小规模医院为16.3%,大规模医疗中心为3.8%,但病死率却控制在5%以下.最主要的并发症是术后胰瘘（POPF）,在此基础上,POPF增加了其他并发症的发生率,如腹腔脓肿、胰腺切除术后出血（PPH）和胃排空延迟（DGE）.对此,胰腺手术国际研究小组（ISGPS）认为减少POPF发病率的外科策略包括选择最安全的胰肠吻合或胰腺残端闭合技术、胰肠吻合的支架和通过生长激素抑制剂来减少胰腺外分泌,具体如下：①胰腺吻合：主要是胰空肠吻合和胰胃吻合,目前两种方式仍然没有结论 性的数据显示有差异,大多数大规模的胰腺外科中心采用胰空肠吻合术,但对于规模较小的机构而言,技术不太复杂的胰胃吻合术可能是更好的选择.②远端胰腺切除术的残端处理：为减少POPF的发生,已经探讨了若干项治疗策略,包括薄壁组织横断、胰腺残端闭合、胰腺残端额外覆盖和胰肠吻合的不同技术,但仍然是一个尚未解决的难题.③胰腺吻合时支架管的应用：不支持常规放置支架.④生长激素抑制剂：理论上会降低POPF的风险,但有研究报道生长抑素类似物尚不能有效治疗POPF.此外,术前胆汁引流显著增加了术后并发症率,而在病死率、住院时间和生存效果方面没有效果.故不推荐常规地施行术前胆道支架植入术,但以下患者除外：与凝血功能障碍有关的高胆红素血症患者,需要行新辅助治疗或姑息性化疗的局部浸润性肿瘤或者出现转移的患者.对于不可行手术切除的患者,有一种可以选择的方法 是施行新辅助治疗并尝试在肿瘤降期后行手术切除.原则上讲,放化疗可以更加有效地使局部降期,研究表明,吉西他滨（Gemcitabine）是辅助治疗的金标准,可增加术后生存率,但单独应用化疗还是放化疗联合应用仍存在争议.然而,由于大多数患者在手术切除后两年内发生了全身性的疾病进展,胰腺癌患者的长期疗效仍然不理想,故即便是可切除的胰腺癌也要视为一种全身性疾病.因此,将来手术技术发展可能不会给长期疗效带来可观的效果.为了提高长期效果,我们迫切地需要新的和更加有效的系统性治疗.     

溶瘤病毒与胰腺癌

胰腺癌是常见的消化道恶性肿瘤之一．晚期胰腺癌预后极差，治疗手段匮乏，至今人们仍在不断探索新的介入治疗手段，期望延长病人的生存期。溶瘤病毒（oncolytic virus）治疗是利用具复制活性的基因且经改造的病毒选择性感染癌细胞．使之溶胀死亡从而起到抗肿瘤效应的方法。本文就溶瘤病毒的原理及其在胰腺癌治疗中的临床应用作一概述。     

Operative management in the treatment of pancreatic cancer

The carcinoma of the pancreas is one of the 10 leading causes of death in the Western countries. Because of the resistance of pancreatic cancer against radiation and/or chemotherapy surgery is still the only possibility for cure. However, about 80 % of patients with the diagnosis of pancreatic cancer are no more suitable for curative resection at the time of diagnosis because of local tumor infiltration or the presence of distant metastases. This is one reason for the unsatisfactory situation in terms of 5-year-survival rate of 3 to 24 %. In resectable tumors of the pancreas head the standard Whipple dominates still as the surgical method of choice. However, the pylorus preserving Whipple has been established as a surgical alternative to the classical Whipple. Other surgical procedures like extended or regional pancreatic resections, predominantly done by Japanese surgeons seem to fit the concept of radical resection. But compared to the classical Whipple or the pylorus preserving Whipple resection there is still no clear advantage in terms of long term survival. The prospective European multicenter study ESPAC-1 firstly demonstrated a survival advantage for adjuvant chemotherapy (5-FU and folic acid) but no gain for radiochemotherapy in the treatment of patients with R0 or R1 resected pancreatic cancer in terms of prolongation of mean survival (19.7 months vs. 14.0 months).     

High dose intravenous immunoglobulin treatment: mechanisms of action.

Intravenous immunoglobulin (IVIg) treatment was introduced as replacement therapy for patients with antibody deficiencies, but evidence suggests that a wide range of immune-mediated conditions could benefit from IVIg. The immunoglobulins are precipitated from human plasma by fractionation methods. In conclusion, the differences in basic fractionation methods and the addition of various modifications for purification, stabilization, and virus inactivation result in products significantly different from each other.     

铁死亡在胰腺癌中的作用研究及进展

胰腺癌是一种恶性程度极高的消化系统肿瘤,侵袭性强,早期诊断困难,大多数患者因确诊时已处于晚期而无法接受根治性手术治疗,亦无其他有效治疗手段,故预后极差。铁死亡是一种铁依赖性新型细胞程序性死亡方式,以细胞内铁过载、脂质过氧化物增多和活性氧异常蓄积为特征。近年研究发现铁死亡在抑制胰腺癌细胞生长、增殖方面具有重要作用,并能够提高化疗药物疗效,有望成为胰腺癌治疗的潜在靶点。笔者对铁死亡在胰腺癌发生发展及治疗中的作用研究进展作一综述。     

胰腺癌的综合治疗

我国胰腺癌的发病率有上升趋势 ,手术切除率亦可望提高 ,然而 5年生存率则仍在 5 %左右。因此 ,在胰腺癌早期诊断方法尚未有突破的情况下 ,对胰腺癌中晚期病人 ,采用合理的综合治疗 ,提高病人的生存期和改善生活质量是现阶段临床外科医生应关注的问题。一、胰腺癌的手术治疗胰腺癌的手术治疗在目前仍是救治胰腺癌病人的重要措施 ,胰腺癌肿瘤能否被切除的可行性同手术医生的临床经验和技能有直接关系。胰十二指肠切除术在外科手术中有其难度和复杂性。最近临床调查发现 ,众多胰腺癌病人往往在就诊时 ,当阅读CT片 ,只要肿瘤累及邻近血管 ,往…     

Surgical treatment of pancreatic cancer

From 1964 to 1982, there were 782 patients treated for carcinoma of the pancreas. In 174 patients pancreaticoduodenal resection was possible (22%). Until 1977 we performed Whipple procedures, while from 1978 to 1982 total pancreatectomy was preferred. Comparing the results of both methods, we did not find any advantages of total pancreatectomy. Operative mortality did not decrease, survival time did not extend, and the higher resection rates (up to 26%) for more advanced tumor stages were accompanied by greater morbidity. With respect to the patients with inoperable cancer of the pancreas, we found over the last 5 years that the rate of those not undergoing surgery has climbed from 8% to 25%, while the rate of exploratory laparotomies was reduced from 28% to 5%. With the advent of preoperative percutaneous transhepatic cholangio-drainage (PTCD), the mortality rate of our palliative procedures dropped to 12%. Biliodigestive anastomosis of choice is the hepaticojejunostomy.

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Resumen En la República Federal de Alemania la frecuencia de carcinoma del páncreas ha venido en ascenso; en los últimos 20 años ha llegado a más del doble, con alrededor de 7,000 nuevos casos adicionales por año. Un total de 782 pacientes con carcinoma de páncreas fueron tratados por nosotros entre 1964 y 1982; en 174 casos fué posible hacer la resección pancreaticoduodenal (22%). Hasta 1977 preferimos el procedimiento de Whipple, en tanto que la pancreatectomía total fué el procedimiento de escogencia entre 1978 y 1982. Al comparar los resultados de ambos métodos no hallamos ventaja alguna por parte de la pancreatectomía total. La mortalidad operatoria no disminuyó, el período de supervivencia no se prolongó y las mayores tasas de resectabilidad (hasta 26%) para estados tumorales más avanzados se acompañaron de un mayor riesgo quirúrgico.Respecto a los pacientes con cáncer inoperable del páncreas, hemos observado que en los últimos cinco años la tasa de pacientes que no son sometidos a cirugía ha ascendido de 8% a 25%, mientras la tasa de laparotomías exploratorias pudo ser reducida de 28% a 5%. Con el advenimiento del drenaje biliar percutáneo transhepático preoperatorio se ha reducido la mortalidad de nuestros procedimientos quirúrgicos paliativos de 23% a 12%. La anastomosis biliodigestiva de escogencia es le hepaticoyeyunostomía termino-lateral por la técnica de Roux-en-Y. Se realiza gastroenterostomía sólo si hay indicación clínica de alteraciones en el vaciamiento del estómago.

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Résumé De 1964 à 1982, 782 malades ont été traités pour cancer du pancréas. Chez 174 d'entre eux il fut possible de pratiquer une duodénopancréatectomie (22%). Jusqu'à 1977 l'exérèse consista en une opération de Whipple. Elle fut remplacée de 1978 à 1982 par la duodénopancréatectomie totale. La comparaison des résultats obtenus par les deux méthodes permet d'affirmer que la seconde ne présente pas d'avantages substantiels par rapport à la première. La mortalité opératoire n'a pas diminué, la survie n'a pas augmentée alors que l'élévation du taux des résections (supérieur à 26%) pour des tumeurs plus avancées s'est accompagnée d'un risque chirurgical plus important.En ce qui concerne les malades atteints de cancers avancés il a été constaté qu'au cours des cinq dernières années le taux d'inopérabilité s'est élevé de 8 à 23% pendant que le taux de la laparotomie exploratrice s'est réduit de 28 à 5%. Depuis l'introduction du drainage biliaire transpariétal préopératoire le taux de mortalité des méthodes palliatives est tombé à 12%. L'anastomose biliodigestive de choix est l'hépaticojéjunostomie.

     

miR-519d在胰腺癌细胞中的表达及其作用

目的:探讨miR-519d在胰腺癌细胞中的表达及作用。方法:用qRT-PCR检测miR-519d在胰腺癌细胞系AsPC-1、BxPC-3、Capan-2、Panc-1及正常胰腺导管上皮细胞系HPDE6-C7中的表达。将Panc-1细胞分别转染miR-519d过表达质粒(miR-519d组)与阴性对照质粒(阴性对照组),以无处理的Panc-1细胞为空白对照组,用MTT法、Transwell实验、Western blot分别检测转染后细胞的增殖和侵袭能力、凋亡情况以及X连锁凋亡抑制蛋白(XIAP)的表达。结果:各胰腺癌细胞系中miR-519d相对表达量均明显低于正常胰腺导管上皮细胞系HPDE6-C7(均P0.05);与空白对照组比较,miR-519d组细胞增殖能力降低(培养72 h后明显降低)、凋亡率明显升高、侵袭能力明显减弱、XIAP蛋白表达量明显降低(均P0.05);阴性对照组各项指标与空白对照组差异均无统计学意义(均P0.05)。结论:miR-519d在胰腺癌细胞中表达下调,miR-519d表达下调有增强胰腺癌细胞增殖和侵袭能力、降低凋亡的作用,该作用可能与其调节XIAP蛋白的表达有关。