胆囊癌外科治疗的争议与思考

胆囊癌恶性程度高,易侵犯邻近脏器和发生淋巴结转移,且对放化疗不敏感,是预后最差的胆道恶性肿瘤。根治性手术切除仍然是目前唯一有可能治愈胆囊癌的手段,但是关于胆囊癌的手术方式、肝脏切除范围、淋巴结清扫范围、意外胆囊癌的处理等方面仍存在诸多争议。此外,当前免疫治疗和靶向治疗在多种实体瘤中取得巨大成功的背景下,未来外科手术在进展期胆囊癌治疗中的地位是否会发生改变,亦值得我们进一步思考。     

Successful treatment of advanced gallbladder cancer with an anticancer drug S-1: assessment based on intratumoral gene

While surgical resection is the most effective treatment for gallbladder cancer, most of these cancers are not resectable at the time of diagnosis, and therefore, chemotherapy serves as the primary therapy in many cases. However, to date, there is no standard chemotherapy for this cancer. We report a case of advanced gallbladder cancer for which the anticancer drug S-1 was effective. The patient was a 53-year-old woman who presented with a huge ovarian tumor. On workup, all abdominal images revealed the presence of advanced gallbladder cancer that had invaded the liver. Because the gallbladder formed a relatively hard and swollen mass involving the omentum, as revealed during exploration, the surgical resection of the gallbladder was not possible at that time, and only hysterectomy and bilateral salpingo-oophorectomy were performed. She started on the anticancer drug S-1 just after this operation. S-1 is a prodrug of 5-fluorouracil (5-FU), and contains 5-chloro-2-4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase (DPD) that rapidly degrades 5-FU. Eight months after the first operation, radical cholecystectomy was performed. Pathologically, the tumor was diagnosed as an adenocarcinoma of the gallbladder, and no evidence of liver invasion was found. Intratumoral gene expression analysis of the resected gallbladder revealed significantly elevated DPD expression. We suggest that the rapid degradation of 5-FU mediated by this high DPD in our patient was significantly blocked by the CDHP in S-1, and that the efficacy of 5-FU was consequently maintained at the maximum level.     

胆囊癌综合治疗的研究进展

胆囊癌是一种常见的胆管恶性肿瘤，因早期临床缺乏典型表现，晚期治疗效果差，导致该疾病总体预后不良。目前针对胆囊癌的手术治疗、放疗、化疗等治疗方式仍在不断更新。本文就近年来国内外相关文献，对胆囊癌的手术治疗、放疗、化疗等综合治疗手段作一综述，以期望提高对胆囊癌治疗的认识。     

Gallbladder cancer: a subtype of biliary tract cancer which is a current challenge in China

Biliary tract cancers, broadly described as malignancies that arise from the biliary tract epithelia, are usually divided into two major clinical phenotypes: cholangiocarcinoma and gallbladder cancer, differing in etiopathogenesis, risk factors, and perhaps molecular and genetic signatures. Atypical symptoms and lack of tumor biomarkers make it difficult to diagnose in early stages. At the time of presentation, few patients are candidates for potentially curative surgical resection. We here assessed and compared features of a total of 150 cases divided into extra- and intrahepatic cholangiocarcinomas and gallbladder cancers (GBC). Althought there were no significant differences in serum tumour marker levels, GBC patients had the poorest prognosis. Furthermore, gallbladder cancer respond poorly to chemotherapy or radiation therapy and approximately half of untreated patients died within 10 months. Therefore, treatment for patients with gallbladder cancer is still in challenge. Outcomes and survival of these patients had improved little over the past three decades - a period in which new successful treatments have greatly contributed to the prolonged patient survival for many other cancers.     

Inhibitory effect of Survivin promoter-regulated oncolytic adenovirus carrying P53 gene against gallbladder cancer

Gene therapy has become an important strategy for treatment of malignancies, but problems remains concerning the low gene transferring efficiency, poor transgene expression and limited targeting specific tumors, which have greatly hampered the clinical application of tumor gene therapy. Gallbladder cancer is characterized by rapid progress, poor prognosis, and aberrantly high expression of Survivin. In the present study, we used a human tumor-specific Survivin promoter-regulated oncolytic adenovirus vector carrying P53 gene, whose anti-cancer effect has been widely confirmed, to construct a wide spectrum, specific, safe, effective gene-viral therapy system, AdSurp-P53. Examining expression of enhanced green fluorecent protein (EGFP), E1A and the target gene P53 in the oncolytic adenovirus system validated that Survivin promoter-regulated oncolytic adenovirus had high proliferation activity and high P53 expression in Survivin-positive gallbladder cancer cells. Our in vitro cytotoxicity experiment demonstrated that AdSurp-P53 possessed a stronger cytotoxic effect against gallbladder cancer cells and hepatic cancer cells. The survival rate of EH-GB1 cells was lower than 40% after infection of AdSurp-P53 at multiplicity of infection (MOI) = 1 pfu/cell, while the rate was higher than 90% after infection of Ad-P53 at the same MOI, demonstrating that AdSurp-P53 has a potent cytotoxicity against EH-GB1 cells. The tumor growth was greatly inhibited in nude mice bearing EH-GB1 xenografts when the total dose of AdSurp-P53 was 1 × 10⁹ pfu, and terminal dUTP nick end-labeling (TUNEL) revealed that the apoptotic rate of cancer cells was (33.4 ± 8.4)%. This oncolytic adenovirus system overcomes the long-standing shortcomings of gene therapy: poor transgene expression and targeting of only specific tumors, with its therapeutic effect better than the traditional Ad-P53 therapy regimen already on market; our system might be used for patients with advanced gallbladder cancer and other cancers, who are not sensitive to chemotherapy, radiotherapy, or who lost their chance for surgical treatment.     

Systemic therapy for biliary tract cancers

Biliary tract cancers (BTCs) are invasive carcinomas that arise from the epithelial lining of the gallbladder and bile ducts. These include intrahepatic, perihilar, and distal biliary tree cancers as well as carcinoma arising from the gallbladder. Complete surgical resection offers the only chance for cure; however, only 10% of patients present with early-stage disease and are considered surgical candidates. Among those patients who do undergo "curative" resection, recurrence rates are high; thus, for the majority of BTC patients, systemic chemotherapy is the mainstay of their treatment plan. Patients with unresectable or metastatic BTC have a poor prognosis, with a median overall survival time of <1 year. Despite a paucity of randomized phase III data, a consensus on first-line systemic therapy is emerging. In this review, we discuss the clinical experience with systemic treatment of BTC, focusing on the rationale for a first-line regimen as well as future directions in the field.     

Gallbladder carcinoma

Although it is the most common cancer of the biliary tree, gallbladder carcinoma remains an uncommon disease. As a result, many clinicians rarely encounter it and there is uncertainty regarding proper management. Resection is the most effective and only potentially curative treatment. Early stage tumors are often curable with a proper resection; however, many patients present late in the course of the disease when surgical intervention is no longer effective. While other treatment modalities are used in patients with advanced disease, there is limited data on efficacy. In many cases, the diagnosis is made after a cholecystectomy has been performed and an incidental tumor is identified in the specimen. In such cases, reoperation and definitive resection is appropriate and effective for patients with invasive lesions.     

胆囊癌的早期诊断及治疗

目的探讨胆囊癌的早期诊断和治疗效果。方法回顾性分析我院近6年收治的18例胆囊癌患者。结果18例胆囊癌患者术前均行B超检查,其中诊断为胆囊癌10例,确诊率为55.5％。18例均行手术治疗,6例行胆囊切除术,余均行姑息手术。病理诊断胆囊腺癌17例.鳞癌1例。结论我们认为B起检查是早期诊断胆囊癌的有效方法,对胆囊癌的治疗应力争行根治性手术,以期提高生存率。对无法行根治手术患者,可行姑息手术改善症状。     

Multidisciplinary treatment of biliary tract cancers

Ninety-six patients referred for radiation therapy to Washington University affiliated institutions with tumors of the extrahepatic biliary tree form the basis of this report. Patients were examined with regard to demographic factors, tumor primary site, presenting symptoms, methods of diagnosis, and methods of management. The median survival of all 96 patients in this series was 11 months. There was no significant difference between patients with gallbladder cancer and patients with cancer of the biliary ductal system. There was a statistically significant improvement in survival in those patients undergoing resection as management or as a component of the management of their tumors (P = 0.02). Patients receiving >4,000 cGy of radiation therapy had an improved survival compared to those patients receiving ≤4,000 cGy of radiation therapy (P = 0.003). While surgical resection improved survival for those patients undergoing removal of all gross tumor, this effect was noted especially in patients with gallbladder cancer. © Wiley-Liss, Inc.     

原发性胆囊癌基因诊断现状

 原发性胆囊癌（PGC）是胆道系统常见的恶性肿瘤,恶性程度高、预后差。因其临床表现不典型,常与胆囊炎、胆囊结石的症状相似,早期诊断比较困难。而且随着腹腔镜胆囊切除术（LC）在临床上的普及,术后诊断胆囊癌的病例也逐渐增多。因此,如何提高PGC的早期诊断水平,为其早期治疗创造条件一直是人们所关注的问题。现代医学在基因学水平上研究PGC的生物学行为,有助于提高其早期诊断率。就近年来国内外有关PGC基因诊断的研究状况进行综述。     

Chemotherapy for pancreatic cancer: from metastatic disease to adjuvant therapy

Pancreatic cancer remains a significant therapeutic challenge in oncology as the 21st century begins. Currently available cytotoxic chemotherapeutic agents provide only a modest survival benefit for patients with advanced disease. Recent efforts to improve survival in the setting of locally advanced and metastatic disease have focused on combinations of cytotoxic agents and the integration of newer molecular agents. To date, these strategies have been somewhat disappointing, prompting some experts to consider changes in clinical trial design with more rigorous patient eligibility criteria. In the adjuvant therapy setting, investigation of newer agents has lagged behind studies in more advanced disease, but recent results suggested some evidence of incremental advance. However, just as in advanced pancreatic cancer, without a more disciplined approach to patient selection for surgical intervention and subsequent adjuvant therapy, progress can be expected to remain very slow. This review will provide a brief summary of the history of chemotherapy in the treatment of pancreatic cancer and focus on its current and future role in adjuvant therapy.     

Surgical strategies in patients with gallbladder cancer: nihilism to optimism

INTRODUCTION: Gallbladder cancer is an aggressive disease with dismal results of surgical treatment and a poor prognosis. However, over the last few decades selected groups have reported improved results with aggressive surgery for gallbladder cancer. METHODS: Review of recent world literature was done to provide an update on the current concepts of surgical treatment of this disease. RESULTS: Long-term survival is possible in early stage gallbladder carcinoma. Tis and T1a gallbladder carcinoma can be treated with simple cholecystectomy only. However, in T1b and beyond cancers, aggressive surgery (extended cholecystectomy) is important in improving the long-term prognosis. Laparoscopic cholecystectomy should not be performed where there is a high index of suspicion of malignancy due to the frequent association with factors (such as gallbladder perforation and bile spill) which may lead to implantation of cancer cells and dissemination. Surgical resection for advanced carcinoma gallbladder is recommended only if a potentially curative R0 resection is possible. Aggressive surgery with vascular and multivisceral resection has been shown to be feasible albeit with an increase in mortality and morbidity. However, the true benefit of these radical resections is yet to be realized, as the actual number of long-term survivors of advanced gallbladder carcinoma is few. CONCLUSIONS: Surgery for gallbladder carcinoma, like other malignancies, has the potential to be curative only in local or regional disease. Pattern of loco-regional spread of disease dictates the surgical procedure. Radical surgery improves survival in early gallbladder carcinoma. The long-term benefit of aggressive surgery for advanced disease is unclear and may be offset by the high mortality and morbidity.     

Polyps of the gallbladder

One of the unusual problems associated with gallbladder disease is a polyp discovered by either ultrasonography or by oral cholecystogram. We report a recent experience of two cases of polyps of the gallbladder removed by cholecystectomy. The incidence of gallbladder polyps of any type is quite varied in the medical literature. Eighty percent of polyps occur in females, and these occur after the third decade of life. The polyps can either be cholesterol or inflammatory polyps that are not really benign tumors but just reactions of the gallbladder wall. The true mucosal benign lesions are either adenomyomas or papillomas. The adenomyomas and papillomas have malignant potential. There are case reports of carcinoma in situ and cancer arising from these lesions. The treatment for a gallbladder polyp is a cholecystectomy.     

Strategies for gastric cancer in the modern era

Gastric cancer is one of the most common neoplasms in Japan, and it is also the second leading cause of cancer-related deaths worldwide. Nowadays, infection with Helicobacter pylori (H. pylori) is a known risk factor for the development of gastric cancer. Therefore, gastric cancer should be considered as an infectious disease, and in fact, prophylactic eradication of H. pylori may prevent the development of metachronous gastric carcinoma. Before the role of H. pylori was understood, a different approach was used. Recently even after the cancer has developed, some newer therapeutic approaches have been pursued. These newer treatments have been summarized as "minimally invasive therapies" and use endoscopic or laparoscopic techniques. In addition, robotic approaches are being developed that seem to hold a great potential to change the surgical approach. Since basic understanding and treatment of the disease have both changed significantly over the last decade, we present a review of current advances in gastric cancer research and therapy.     

2009—2015年甘肃省肿瘤登记地区胆囊癌流行特征及变化趋势分析

目的 分析甘肃省肿瘤登记地区2009—2015年胆囊癌发病与死亡的流行特征,为制定胆囊癌防治策略提供依据。方法 按照全国肿瘤登记中心制定的审核方法收集甘肃省11个肿瘤登记点上报的数据作为样本数据,描述甘肃省肿瘤登记地区胆囊癌发病和死亡情况,计算胆囊癌粗发病率(死亡率)、中国人口标化率(中标率)、世界人口标化率(世标率)、累积率(0~74岁)等,采用Joinpoint 4.7.0.0软件计算年度变化百分比(Annual percentage change,APC)。结果 2009—2015年甘肃省肿瘤登记地区胆囊癌新发病例1 782例,胆囊癌粗发病率为4.70/10万(男性3.91/10万,女性5.54/10万),中标率为4.50/10万,世标率为5.34/10万;死亡病例1 123例,胆囊癌粗死亡率为2.96/10万(男性2.38/10万,女性3.59/10万),中标率为2.68/10万,世标率为3.07/10万。城市地区发病和死亡中标率(4.93/10万,2.94/10万)均高于农村地区(1.93/10万,1.66/10万)。胆囊癌发病率和死亡率随着年龄的增长呈上升趋势,在85+岁年龄组达到高峰,呈现出城市高于农村、女性高于男性的特点。甘肃省2009—2015年胆囊癌发病中标率呈下降趋势(APC=-10.9%,t=-3.0,P＜0.05),死亡中标率时间变化趋势不明显(APC=-10.6%,t=-0.8,P=0.4)。结论 胆囊癌已成为甘肃省常见的恶性肿瘤之一,其中城市老年女性为胆囊癌防治的重点人群,应针对其开展早期筛查、早期诊断和早期治疗工作,提高胆囊癌早期检出率,降低胆囊癌发病率、死亡率和疾病负担。     

Aggressive Therapy is Warranted for Gallbladder Cancer

Untreated gallbladder cancer is a rapidly fatal disease. Over the years, however, the benefit of aggressive surgical therapy for this disease has been debated. This debate stems from the fact that gallbladder cancer is often metastatic to regional nodes and invasive of the liver at the time of discovery. Complete resection of this tumor, therefore, requires extensive procedures that, until recently, were associated with a very high morbidity and mortality. In this issue Maibenco et al. summarize the changing attitudes about this cancer. Their major message that radical resection of gallbladder cancers can provide long-term survival and cure deserves emphasis.     

The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer – A systematic review

BackgroundNeoadjuvant chemotherapy for advanced gallbladder cancer (GBC) has recently been proposed as an alternative to adjuvant chemotherapy, with potential increase in resectability rate and overall survival.AimTo undertake a systematic review and critical appraisal of available literature on the use of neoadjuvant chemotherapy (NACT) or chemoradiotherapy (NACRT) in the treatment of advanced GBC.MethodsSystematic review carried out in line with the Meta-analysis Of Observational Studies in Epidemiology guidelines. Primary outcomes were clinical benefit rate (CBR) of neoadjuvant therapy, defined as percentage of complete response, partial response and stable disease, resectability rate and R0 resection. Secondary outcomes were overall and disease-free survival.Results8 studies met the inclusion criteria (n = 474), of which 398 (84.0%) received NACT and 76 (16.0%) received NACRT. 133 of 434 patients (30.6%) had progressive disease despite NACT or NACRT. The CBR was 66.6%. 17% of the patients who responded to chemotherapy did not proceed to surgery. 50.4% of the patients were considered suitable for surgical resection, of which 191 (40.3%) underwent curative resection. The R0 rate for the whole cohort was 35.4%. Overall survival ranged from 18.5 to 50.1 months for those who underwent curative resection versus 5.0–10.8 months for non-resected group.ConclusionsThere is insufficient data to support the routine use of NACT or NACRT in advanced GBC, as this has only benefited a third of whole cohort, who eventually achieved a R0 resection. Future studies should be in the form of randomized controlled trials to investigate the role of neoadjuvant therapy in advanced GBC.     

原发性胆囊癌的螺旋CT分期及手术预后评价

目的探讨原发性胆囊癌的螺旋CT分期和手术预后评价效果。方法选择2010年2月至2013年2月间收治的经手术病理证实的45例胆囊癌患者，均进行64排螺旋CT检查，并进行相关手术与穿刺细胞学检查。结果经过观察，所有患者均表现为胆囊壁不均匀增厚，17例表现为胆囊肿块边界不清晰，21例表现为胆囊壁向腔内突出。侵犯肝脏30例，侵犯十二指肠22例，侵犯结肠5例，侵犯胆管18例。根据螺旋CT分期，Ⅰ期16例，Ⅱ期15例，Ⅲ期6例，1W8例。通过CT分期与手术结果比较发现，只有3例患者因为侵犯十二指肠只进行了细胞穿刺学检查。结论螺旋CT能清晰显示原发性胆囊癌的形态学分型与对邻近器官侵犯，为胆囊癌术前分期提供重要信息，并以此可评估其手术可切除性，对改善患者预后有重要价值。     

Adjuvant and neoadjuvant therapy in prostate cancer

While surgery and radiation therapy remain the only definitive treatments for prostate cancer, single modality therapy has been associated with high failure rates in patients with aggressive disease. Although hormonal therapy has been effective in cases of metastatic disease, the timing of treatment with respect to definitive therapy remains controversial. This review will explore the efficacy of hormonal and chemotherapy in both the adjuvant and neoadjuvant settings. A MEDLINE search was performed to identify pertinent articles regarding both adjuvant and neoadjuvant therapy in prostate cancer. Articles of historical relevance in addition to those using large patient numbers with a randomized design were reviewed preferentially. Since hormonal therapy has been considered standard treatment at the time of cancer progression after definitive therapy, many of the randomized trials essentially compared adjuvant therapy to delayed therapy. Historical trials using adjuvant hormonal therapy have been limited due to difficulties in clinical staging, as well as toxicities attributed to the formulations used. More recently, hormonal therapy has been found to delay disease progression, increase disease-free survival, and decrease mortality when given immediately after prostatectomy or radiation therapy in selected patients. Neoadjuvant hormonal therapy can improve disease-free survival and local control when given before radiation therapy; it has only decreased positive surgical margins when given prior to radical prostatectomy. Although hormonal therapy given immediately after either radical prostatectomy or radiation therapy is highly effective, the side effects of persistent long-term use must be weighed for each patient. While the use of chemotherapy has been limited by the lack of active agents, newer combinations have shown effectiveness in patients with hormone refractory disease, raising the possibility of their use in the adjuvant setting.     

The evolving role of radiation therapy in the management of malignant melanoma

The incidence of melanoma is rising in the United States, leading to an estimated 68,720 new diagnoses and 8,650 deaths annually. The natural history involves metastases to lymph nodes, lung, liver, brain, and often to other sites. Primary treatment for melanoma is surgical excision of the primary tumor and affected lymph nodes. The role of adjuvant or definitive radiation therapy in the treatment of melanoma remains controversial, because melanoma has traditionally been viewed as a prototypical radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, there may be a significant role for radiation therapy in melanoma treatment. Stereotactic radiosurgery for brain metastases has shown effective local control. High dose per fraction radiation therapy has been associated with a lower rate of locoregional recurrence of sinonasal melanoma. Plaque brachytherapy has evolved into a promising alternative to enucleation at the expense of moderate reduction in visual acuity. Adjuvant radiation therapy following lymphadenectomy in node-positive melanoma prevents local and regional recurrence. The newer clinical data along with emerging radiobiological data indicate that radiotherapy is likely to play a greater role in melanoma management and should be considered as a treatment option.