Treatment Of Gallbladder Carcinoma Research Articles

Research progress of emodin anti-gallbladder carcinoma

Emodin is an effective active ingredient extracted from Chinese herbal medicine, which has the function of antimicrobial, anti-inflammatory, antioxidant and scavenging oxygen free radicals, inhibiting platelet aggregation, improving microcirculation, protecting various organs and tissues as well as a wide range of anti-tumor effect. Primary biliary gallbladder is a common malignant tumor resection rate and lack of effective adjuvant treatment. It has been confirmed that emodin has broad spectrum antitumor effect, whereas, whether it has curative effect in the treatment of gallbladder carcinoma there is no reliable clinical trials confirmed that its resistance to gallbladder carcinoma function needs further experimental research. In this review, we report the research progress of emodin anti-gallbladder carcinoma.

Effects of autophagy on 5-fluorouracil cytotoxicity for gallbladder carcinoma GBC-SD cell

To explore the effects of autophagy on 5-fluorouracil (5-FU) cytotoxicity for gallbladder carcinoma GBC-SD cell and discuss a novel and promising strategy of autophagy inhibitor for increasing the clinical efficacy of 5-FU in the treatment of gallbladder carcinoma. After a pre-treatment of autophagy inhibitors, such as chloroquine (CQ) and 3-methyladenine (3-MA), or silencing the autophagy-related genes (autophagy-related gene 5, autophagy-related gene 7), the inhibition of 5-FU to proliferation and the viability of GBC-SD cell were measured. And the apoptotic rate and cell cycle of GBC-SD cell were analyzed. Blocking of autophagy by pharmacological (CQ, 3-MA) or genetic (siRNA) means induced cell death in GBC-SD cell pre-treated with 5-FU.Furthermore, 5-FU treatment resulted in a general increase of apoptotic rate and G0/G1 arrest of GBC cells. And such an effect was potentiated by a pre-treatment of CQ. Autophagy in GBC-SD cell is induced by DNA damaging agent 5-fluorouracil.While in combination with CQ pre-treatment, the cytotoxicity of 5-fluorouracil becomes potentiated.

Abstract 3432: HSP90 expression and antitumoral activity of geldanamycin and its analog 17-AAG in gallbladder cancer.

Abstract Background. Gallbladder carcinoma (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. In Chile, it has an extremely high incidence and is the second cause of death by cancer among women. Heat shock protein 90 (HSP90) is a molecular chaperone and is one of the most abundant proteins expressed in cells. Many oncogenic proteins responsible for the transformation of cells to cancerous forms are client proteins of HSP90. Two molecules have shown to inhibit the action of HSP90, geldanamycin (GA) and its analog 17-allylamino-17-des-methoxygeldanamycin (17-AAG) and hence a potential target for adjuvant therapy. HSP90 expression and antitumoral activity of GA and 17-AAG have not been studied in GBC. Methods. Expression of HSP90 was analyzed in 47 selected GBC cases by immunohistochemical staining using a monoclonal mouse HSP90 antibody (clone JPB24, dilution 1:200, Novocastra, Newcastle upon Tyne, UK). A positive case was interpreted if at least 50% of the tumor showed cytoplasmic staining. HSP90 expression was also evaluated in 6 GBC cell lines by Western blot analysis. A viability assay was performed in GB-d1 cells to determine the median lethal dose (LD50) of GA and 17-AAG. After treatment with different concentrations of each inhibitor for 48 h, the percentage of viable cells was assessed with a colorimetric MTS cell proliferation assay (Promega, Madison, WI). Treatment with 0.1% of DMSO as solvent was used as control. We tested the change of migration capability of GB-d1 cells by Transwell chambers after 24h with GA (15μM) and 17-AAG (12μM) treatment. Western blotting of GB-d1 cells before and after treatment with each inhibitor was done to evaluate the expression of HSP90, EGFR, ERK1/2, Cyclin B1 and ACTB. Results. HSP90 was frequently overexpressed in GBC primary tumor and cell lines. The staining intensity ranged from weak to strong, with 35 cases (74%) showing moderate intensity. Average expression was 78%. The MTS cell viability demonstrated that both GA and 17-AAG elicited cytostatic and cytotoxic effects on GB-d1 cells. After 24h treatment with GA or 17-AAG, the migration rates of GB-d1 cells decreased drastically up to 5% together with the down-regulation of EGFR and Cyclin B1. Conclusions. Our results showed that HSP90 is highly expressed in GBC making it a good candidate for targeted therapy. HSP90 inhibition with GA or 17-AAG induces cytotoxicity and significantly reduces in vitro cell migration and the expression of oncogenic client proteins of HSP90. Our results suggest that the inhibition of HSP90 function by GA and 17-AAG may provide a promising therapeutic strategy for the treatment of GBC. However, these results must be complemented with in vivo assays and clinical trials. Grant Support: FONDECYT 1090171 Citation Format: Jose R. Valbuena, Juan C. Roa, Pamela A. Leal, Patricia A. Garcia, Alejandro Corvalan. HSP90 expression and antitumoral activity of geldanamycin and its analog 17-AAG in gallbladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3432. doi:10.1158/1538-7445.AM2013-3432

Role of adjuvant chemoradiotherapy and chemotherapy in patients with resected gallbladder carcinoma: a multi-institutional analysis (KROG 19-04).

Objective:The effectiveness of adjuvant treatments for resected gallbladder carcinoma (GBC) has remained unclear due to lack of randomized controlled trials; thus, the aim of present study was to evaluate the role of adjuvant treatments, including chemoradiotherapy (CRT) and/or chemotherapy (CTx), in patients with resected GBC.Methods:A total of 733 GBC patients who received curative-intent surgical resection were identified in a multi-institutional database. Of 733 patients, 372 (50.8%) did not receive adjuvant treatment, whereas 215 (29.3%) and 146 (19.9%) received adjuvant CTx and CRT, respectively. The locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS) of the adjuvant treatment groups were compared according to tumor stage (stage II vs. stage III–IV).Results:In stage II disease (n = 381), the 5-year LRFS, RFS, and OS were not significantly different among the no-adjuvant therapy, CTx, and CRT groups, and positive resection margin, presence of perineural invasion, and Nx classification were consistently associated with worse LRFS, RFS, and OS in the multivariate analysis (P < 0.05). For stage III–IV (n = 352), the CRT group had significantly higher 5-year LRFS, RFS, and OS than the no-adjuvant therapy and CTx groups (67.8%, 45.2%, and 56.9%; 37.9%, 28.8%, and 35.4%; and 45.0%, 30.0%, and 45.7%, respectively) (P < 0.05).Conclusions:CRT has value as adjuvant treatment for resected GBC with stage III–IV disease. Further study is needed for stage II disease with high-risk features.

MIS5-4 - Stromal Cell-Derived Factor-1α is Associated with Gallbladder Carcinoma Progression and is a Novel Independent Poor Prognostic Factor

ABSTRACT Background Although recent studies have suggested that stromal cell-derived factor-1α (SDF-1α) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated SDF-1α expression in GBC, and its biological and prognostic role in GBC tumorigenesis. Methods We examined SDF-1α expression in tumor specimens from 72 GBC patients by immunohistochemistry and analyzed the correlation between SDF-1α expression and clinicopathologic factors or survival. The functional significance of SDF-1α expression was investigated by SDF-1α treatment; suppression of CXCR4, which is a major receptor of SDF-1α; and SDF-1α overexpression in both in vitro and in vivo studies. Results SDF-1α was differentially expressed in GBC tissues. The expression of SDF-1α was significantly associated with a high histologic grade (P = 0.042) and nodal metastasis (P = 0.015). Multivariate analyses showed that SDF-1α expression (hazard ratio [HR] 8.675; P = 0.014) was an independent risk factor for patient survival. SDF-1α significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of SDF-1α significantly promoted tumorigenicity of GBCs in a xenograft model. Conclusions Our results indicate that GBC cells express both SDF-1α and its receptor, and SDF-1α may have a role in GBC progression through an autocrine mechanism. In addition, SDF-1α is a novel independent poor prognostic factor in patients with GBC. Thus, targeting SDF-1α and the SDF-1α receptor CXCR4 may provide a novel therapeutic strategy for GBC treatment.

Chemokine (C-X-C Motif) Ligand 12 Is Associated with Gallbladder Carcinoma Progression and Is a Novel Independent Poor Prognostic Factor

Although recent studies have suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated CXCL12 expression in GBC and its biologic and prognostic role in GBC tumorigenesis. We examined CXCL12 expression in tumor specimens from 72 patients with GBC by immunohistochemistry and analyzed the correlation between CXCL12 expression and clinicopathologic factors or survival. The functional significance of CXCL12 expression was investigated by CXCL12 treatment and suppression of CXCR4, a major receptor of CXCL12, as well as by CXCL12 overexpression in in vitro and in vivo studies. CXCL12 was differentially expressed in GBC tissues. CXCL12 expression was significantly associated with a high histologic grade (P = 0.042) and nodal metastasis (P = 0.015). Multivariate analyses showed that CXCL12 expression (HR, 8.675; P = 0.014) was an independent risk factor for patient survival. CXCL12 significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of CXCL12 significantly promoted GBC tumorigenicity in a xenograft model. Our results indicate that GBC cells express both CXCL12 and its receptor CXCR4, and CXCL12 may have a role in GBC progression through an autocrine mechanism. In addition, CXCL12 is a novel independent poor prognostic factor in patients with GBCs. Thus, targeting CXCL12 and CXCR4 may provide a novel therapeutic strategy for GBC treatment.

Prognosis and Management for Gallbladder Cancer with Hepatic Invasion: Long-term Results of 139 Patients from a Single Center in China

To improve the diagnosis of primary gallbladder carcinoma (GBC) with/without hepatic metastases by analyzing our experience of different GBC treatment in our patients. A retrospective study was carried out to analyze the clinical data of the 139 patients with GBC who underwent hepatic resection in our unit from January 2003 to December 2007. Patients were divided into two groups according to whether they demonstrated hepatic invasion. Tumor presentation, surgical modes, and prognosis of each patient were retrospectively reviewed. Kaplan-Meier curves and log-rank tests were employed to compare the survival rates of those patients undergoing different surgical procedures. Of the 139 patients, 46 were men and 93 were women with the male to female ratio of 1:2.0. Their ages were ranged from 35 to 86 years with a mean age of 62.8±10.4 years. There were 73 patients complicated with hepatic invasion (group A), and no hepatic invasion occurred in the other 66 patients (group B). Compared with the group B, the patients with hepatic invasion suffered lower differentiation of tumor (p=0.000), more advanced Nevin staging (p=0.008) and poorer prognosis (p=0.013). Radical resection were more frequently performed in group B (75.76%) than in group A (45.20%) with better outcomes (p=0.000). GBC patients complicated with hepatic invasion had poorer prognosis than those without invasion in long-term follow-ups. Radical resection might result in a satisfied prognosis in patients without hepatic invasion, but appears less favorable than palliative resection in those who were complicated with hepatic invasion.

The cell adhesion molecule L1 promotes gallbladder carcinoma progression in vitro and in vivo

Recent studies have demonstrated that the cell adhesion molecule, L1, is expressed in several malignant tumor types and its expression correlates with tumor progression and metastasis. However, the role of L1 in gallbladder carcinoma (GBC) remains unclear. Here, we demonstrate that L1 is expressed in GBC cells and plays an important role in the growth, motility, invasiveness, and adhesiveness of GBC cells. Specific depletion or overexpression of L1 in the GBC cell lines JCRB1033 and SNU-308, respectively, was achieved by lentivirus-mediated transduction and expression of an L1 mRNA-specific short hairpin RNA or full-length human L1. Stable depletion of L1 led to a significant decrease in GBC cell proliferation, migration and invasion, as well as decreased intracellular signaling through AKT and FAK. Overexpression of L1 in GBC cells enhanced these cellular activities. In a GBC xenograft nude mouse model, suppression of L1 markedly reduced tumor growth and increased the survival of tumor-bearing mice whereas L1 overexpression stimulated tumorigenicity. Taken together, these results suggest that L1 plays a crucial role in GBC progression and may be a novel therapeutic target in GBC treatment.

Comparative proteomic analysis of human gallbladder carcinoma

To find out potential molecular targets for gallbladder carcinoma diagnosis and treatment by analyzing and comparing the proteins expressed in human gallbladder carcinoma tissue and benign gallbladder tissue. Proteomic analysis of 6 human gallbladder carcinoma tissues and 6 benign gallbladder tissues was carried out. Total proteins of the carcinoma tissue and benign gallbladder tissue were separated by two-dimensional gel electrophoresis (2-DE). The differentially expressed proteins were analyzed and identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Immunohistochemistry was used to examine the expression of PEBP1 protein in an independent series of samples. Protein extracts of individual samples in each type of tissues were separated on two-dimensional gels. There were forty six differentially expressed proteins in the gallbladder carcinom tissues. Seventeen proteins were successfully identified by MS, in which nine proteins were overexpressed in tumors while the other eight proteins were underexpressed. The increased level of PEBP1 protein in gallbladder carcinoma was further confirmed by immunohistochemical analysis. Seventeen differentially expressed proteins were successfully characterized by comparative proteomic analysis. Those results may provide scientific foundation for screening the molecular biomarkers which can be used in diagnosis and treatment of gallbladder carcinoma, as well as to improve its prognosis and provide a new clue for carcinogenesis research of gallbladder carcinoma.

The role of HER3 on HER2-driven gallbladder carcinogenesis and possible HER2/HER3 targeting therapy by pertuzumab for gallbladder canrcinoma

e22083 Background: ErbB2 has been known to be important for gallbladder carcinogenesis. Supporting this, the gene amplification of HER2 was found in ca. 20% of human gallbladder carcinoma (GBC) (Kawamoto, et al. Gastrointest Cancer Res 2007). Following these results, a Phase II study of trastuzumab for treatment of GBC (NSC 688097) is being conducted. Although the mechanism of HER2 activation is not well understood, the role of HER3 in HER2-driven tumorigenesis has been discussed and we have concluded that HER2/HER3 heterodimerization might be important for GBC cell proliferation (ASCOGI 2009, ab#155). In this study, we determined HER family expressions in human GBC and examined the effect of pertuzumab against human GBC cell lines. Methods: Tissues from 47 GBCs and 6 non-cancerous gallbladders were examined. All cases were screened for HER1, HER2, HER3 expressions by immunohistochemistry (IHC) and those HER family gene amplification by fluorescence in situ hybridization (FISH) were performed. 6 human GBC cell lines were also analyzed by Western blotting and FISH as well and their growth assays were investigated with heregulin stimulation to confirm the existence of HER2/HER3 heterodimerization. Then, GBC cells were cultured with heregulin and various doses of pertuzumab for 72 hours and CCK-8 assay was performed. Results: HER3, HER2 and HER1 overexpression by IHC was found in 34%, 32% and 19% of GBCs, respectively. Phosphorylated (p-) HER2 and p-HER1 were found in 23% and 11% of GBCs, respectively. FISH analysis was considered successful in the same serial sections. HER3, HER2 and HER1 FISH (+) was found in 26%, 19% and 4% of GBCs, respectively. Three of 6 GBC cell lines were recognized their growth curves with heregulin were increasing. These 3 cell lines showed good responses to the treatment with pertuzumab. Conclusions: More than 20% of GBC over-expressed either HER2 or HER3. These HER2 and HER3 may form heterodimer, which in turn results in the activation of HER2. The cell lines proliferating with the administration of heregulin showed good responses to the pertuzumab treatment. Therefore, HER2/HER3 heterodimerization may be an ideal biomarker for the treatment by pertuzumab and this agent may be a new therapeutic regimen for GBC. No significant financial relationships to disclose.

Laparoscopic cholecystectomy only could be an appropriate treatment for selected clinical R0 gallbladder carcinoma

Laparoscopic cholecystectomy (LC) for gallbladder carcinoma still is controversial except for the early stages of gallbladder carcinoma (Tis). This study was designed to evaluate and revisit the role of LC in treating gallbladder carcinoma. Available medical records of patients with surgeries for gallbladder carcinoma were retrospectively investigated from August 1992 to February 2005. Among 219 patients treated for gallbladder carcinoma, 57 (26%) underwent LC. A total of 16 patients (28.1%) underwent subsequent radical cholecystectomy (LC-RC), and 41 (71.9%) were only followed up without radical surgery (LC). Tis was found in 11 patients (19.3%), T1a in 3 patients (5.3%), T1b in 8 patients (14%), T2 in 19 patients (33.3%), and T3 in 16 patients (28.1%). The findings showed R0 in 14 cases of the radical cholecystectomy group, and clinical R0 was noted in 30 cases of the LC-only group. No survival differences were noted between LC and LC-RC (p = 0.2575), especially in the case of T2 lesions (p = 0.6274), nor between the R0 and clinical R0 (p = 0.5839). However, significant survival differences were noted between the R2 and R0 groups, and between R2 and clinical R0, respectively (p < 0.001). The findings show that LC could be appropriate treatment for gallbladder carcinoma only in selected cases of clinical R0 lesions.

Surgical Treatment of pT2 Gallbladder Carcinoma: A Reevaluation of the Therapeutic Effect of Hepatectomy and Extrahepatic Bile Duct Resection Based on the Long-term Outcome

The clinical indications for hepatectomy and extrahepatic bile duct resection (EBDR) for pT2 gallbladder carcinoma (GBC) remains controversial. The aim of this study is to elucidate the therapeutic effect of hepatectomy and extrahepatic bile duct resection on the surgical treatment of pT2 GBC. Ninety-four patients with pT2 GBC who underwent a potentially curative resection were retrospectively analyzed regarding their pathological findings, surgical procedures, and survival. The most powerful predicting factor for the survival is the nodal status. The 5-year survival rate was 87.1% for the pN0 patients and 55.7% for the pN1 patients. With respect to surgical procedures, the 5-year survival rate was 73.3% for the 51 patients with hepatectomy, and 87.2% for the 43 patients without hepatectomy. In addition, the 5-year survival rate was 66.7% for the 11 patients with EBDR, and 81.1% for the 83 patients without EBDR. When restricting the patients to those with pN1 disease, the 5-year survival rate of the patients who received these procedures did not surpass that of the patients who did not. There is no positive therapeutic effect besides providing surgical margins in hepatectomy and EBDR in the surgical treatment of pT2 GBC whereas lymph node dissection is most effective procedure for improving survival. Provided that the negative surgical margins are secured, a hepatectomy and an EBDR can therefore be withheld in the surgical treatment for the pT2 GBC.

Thinking process for treatment of gallbladder carcinoma

1976年,Nevin等首先提出了原发性胆囊癌的临床病理分期和分级方案,其依据是胆囊癌组织浸润生长和扩散的范围以及细胞的分化程度.由于其简便实用,很快为广大外科学者认同并广泛采用.具体分为5期3级,分期和分级与预后单独相关,分期和分级的相加值与预后有明显的相关性,数值越高,预后越差[1]。

Significance of Extensive Surgery Including Resection of the Pancreas Head for the Treatment of Gallbladder Cancer—From the Perspective of Mode of Lymph Node Involvement and Surgical Outcome

The present study aimed to clarify the efficacy of extensive surgery, including pancreas head resection, for more complete lymphadenectomy in the treatment of gallbladder carcinoma. The study involved retrospective analyses of 65 consecutive patients with gallbladder carcinoma who underwent surgical resection between 1982 and 2003. Of these 65 patients, 41.5% displayed node-positive disease and among them 23.1% had positive para-aortic nodes. Of six node-positive 5-year survivors, five underwent pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy. The 5-year survival rates were 76.2% for pN0, 30.0% for pN1, 45.8% for pN2, and 0% for pM1[lymph], respectively. Significant differences existed in survival rates. Postoperative recurrence was observed in 24.1% (13/54) of patients who underwent R0 resection. Of the four patients who displayed lymph node recurrence, two had pericholedocal and/or posterior pancreatoduodenal lymph node metastasis at the time of surgery and underwent pancreas-preserving regional lymphadenectomy. These results suggest that extensive resection, including resection of the pancreatic head, is effective in selected patients with up to pN2 lymph node metastasis, as long as complete removal of the cancer can be achieved. Pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy should be considered when lymph node metastasis is obvious and the patient is in good condition.

Direct lymphatic spreading route into the liver from the gallbladder: an animal experiment using pig.

In the special occasion that the physiological lymphatic flow is obstructed, gallbladder carcinoma (GBC) may spread into the liver via lymphatic route. Therefore, this study was conducted to find out the direct lymphatic route draining into the liver from the gallbladder using pigs with ligated cystic ducts. After injecting the carbon particle suspension (CH40) or the contrast medium (Lipiodol) into the subserosal layer of the gallbladder, the lymphatic route into the liver was examined both macroscopically and histologically. In controls, CH40 or Lipiodol drained along the cystic duct toward the hepatoduodenal ligament. After occlusion of cystic duct, CH40 was interrupted at the ligated point, and then spread into the liver nearby the gallbladder bed, running off to the liver hilus, toward the hepatoduodenal ligament. This route was confirmed by the Lipiodol drainage into the right median lobe of the liver, equivalent to the segments V and IV a in humans. We presented for the first time the emergence of lymphatic drainage from the gallbladder into the liver after the occlusion of physiological lymphatic route using pigs. This implies that the direct spread into the segments V and IV a of liver should be considered in the surgical treatment of advanced GBC.

Occult gallbladder carcinoma diagnosed by a laparoscopic cholecystectomy.

A laparoscopic cholecystectomy (LC) has become a common treatment modality. The incidence of occult gallbladder carcinoma (GC) diagnosed by LC has increased; however, the effects of a radical second operation after LC have not yet been demonstrated. In this study we examine the outcome of such further surgical intervention. We clinicopathologically studied occult GC diagnosed by LC. We analyzed the results to establish a therapeutic protocol for repeated surgical intervention, and to determine whether the incidence of occult GC has increased. GC, which invaded the mucosa and exhibited a noninvading biliary wedge (m+/bm-), did not recur during the follow-up. GC, which invaded the subserosa (ss)+/bm- and thus required a second operation, did not recur, and the patients had a satisfactory prognosis, both short-term and long-term. One of the patients with ss+/bm+ developed peritoneal dissemination after secondary surgical intervention. After evaluating the clinical outcome of a second operation for the treatment of GC, we concluded that, even for advanced stage patients, repeated surgical intervention may improve the prognosis of GC and thus should be considered, when encountering such patients.

Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients

The long-term effects of initial laparoscopic cholecystectomy on the prognosis of patients with GBC remain unknown because of the limited numbers of patients reported from single institutions. This study was designed to determine the long-term prognosis of patients with gallbladder carcinoma (GBC) who had undergone laparoscopic cholecystectomy (LC), and to clarify the role of LC for the treatment of GBC and the benefit of aggressive additional excision. The clinical courses and outcomes of 498 patients with laparoscopically removed GBC registered in a nationwide survey were examined. Written questionnaires sent to members of the Japanese Society of Biliary Surgery included questions on Preoperative diagnosis, timing and methods to obtain final diagnosis, depth of invasion, second surgical procedure, prognosis of patients, and type of recurrence, if any. The 5-year survival rates of patients after LC according to the depth of invasion were as follows: 99% in those with pT1a (limited to the mucosa), 95% in those with pT1b (muscularis), 70% in those with pT2 (subserosa), 20% in those with pT3 (serosa), and 0% in those with pT4 (serosa with invasion to adjacent organs). Perforation of the gallbladder during LC was found in 20% of the patients. Patients with gallbladders perforated during LC showed a significantly lower survival rate than did those without perforated gallbladders ( P < 0.01). Additional excision during or after LC was carried out in 48% of the patients, and the frequency of additional excision increased in accordance with the depth of invasion. Compared with patients who underwent LC only, additional excision resulted in better survival in patients with pT2 or pT3 tumors ( P = 0.051 and P < 0.05, respectively), but this difference was not found in patients with pT1 or pT4 tumors. LC is not likely to worsen the survival rate of patients with GBC compared with the survival rate of patients undergoing a standard open radical procedure, as long as additional excision is conducted for patients with laparoscopically removed pT2 or pT3 GBCs. Special attention should be paid to prevention of bile spillage during LC.

Present status of the diagnosis and treatment of gallbladder carcinoma.

Because early carcinoma of the gallbladder causes no specific signs or symptoms, most patients with this disease are diagnosed with advanced-stage tumors. High-resolution ultrasonography and a low index of suspicion for polypoid masses or asymmetric gallbladder thickening represent the best method of early detection. Despite regular preoperative gallbladder imaging, many cancers are only detected intraoperatively or incidentally on pathologic examination. All known or suspected gallbladder cancers should be definitively treated with a laparotomy, not laparoscopic surgery. For early gallbladder cancers (Tis and T1 cancers), simple cholecystectomy is adequate therapy. More advanced-stage carcinomas without distant metastases should routinely be managed with a radical cholecystectomy, which includes partial hepatectomy and regional lymphadenectomy. Any adherent organs should be resected en bloc with the cancer. Pancreatoduodenectomy has been performed in several Japanese centers, but is rarely performed in the West for locally advanced gallbladder cancers. Most patients who undergo curative resection will develop recurrent disease, but there is currently no proven effective adjuvant therapy.

Role of Surgery for Gallbladder Carcinoma with Special Reference to Lymph Node Metastasis and Stage Using Western and Japanese Classification Systems

The role of radical resection in the treatment of gallbladder carcinoma was examined with special reference to lymph node metastasis using two classifications: one proposed by the American Joint Committee on Cancer (AJCC) and the other by the Japanese Society of Biliary Surgery (JSBS). Histologic evaluations for the depth of tumor invasion (T), lymph node metastasis (N), stage, and follow-up for a mean period of 38 months (range 4-185 months) were completed in 52 patients with gallbladder carcinoma who underwent surgical resection from 1982 to 1997. The definition of T was similar in the two classifications. The extent of nodal involvement (N, AJCC; n, JSBS), stage, and survival were examined. In the absence of lymph node metastasis, the 5-year survival rate reached 71%. The 5-year survival rate in patients with involved nodes confined to the hepatoduodenal ligament, posterosuperior pancreaticoduodenal region, or along the common hepatic artery (N1 and part of N2 by AJCC; nl and n2 by JSBS) approximated 28%. In contrast, postoperative survival was poor in the presence of more extensive nodal involvement (rest of N2 by AJCC; n3 and n4 by JSBS), with no 2-year survivors. The definition of stage I was the same in both classifications, and all patients in this stage are alive. The 5-year survival rates in stages II and III by the AJCC were 70.7% and 22.4%, respectively, and those by JSBS 61.9% and 23.1%, respectively. Thus the survival rates in stages I to III were essentially similar irrespective of the staging system. Stage IV showed significantly worse survival than stage III by the JSBS classification. In contrast, the differentiation of stage IV from III by the AJCC was not significant because of the better survival in stage IV that contained any T with nodal involvement in the posterosuperior pancreaticoduodenal region and along the common hepatic artery. Radical resection should be considered for patients with stage I to III disease defined by either classification and applied to the tumor invasion up to T3 with nodal involvement confined to the hepatoduodenal ligament, posterosuperior pancreaticoduodenal region, and along the common hepatic artery. The role of radical surgery seems to be limited in patients with more extensive tumor invasion or lymph node metastasis.

Author reply

The comments of Dr. Gallardo et al. are most welcome. Their early experience with gemcitabine in the treatment of gallbladder carcinoma gives hope that an effective treatment for this disease will emerge in the near future. If the efficacy of gemcitabine can be demonstrated in their clinical trial, we would have further proof that anecdotal observations do provide fertile ground for testing new hypotheses and should not be discounted as routinely occurs in medicine. The high rates of carcinoma of the gallbladder in Chile and other parts of Latin America constitute an opportunity for more accelerated treatment experience than exists in the U. S., thereby giving us an opportunity to learn from our southern neighbors. Hopefully, this opportunity will not be missed by practitioners, nor by would-be sponsors of clinical trials. Combination chemotherapy trials with gemcitabine already are underway, and also may be worthy of consideration for gallbladder carcinoma. Improvement on single agent results with concurrent use of gemcitabine and cisplatin in nonsmall cell lung carcinoma is a noteworthy example. The combination of doxorubicin and gemcitabine recapitulates the model of an anthracycline combined with cytarabine, the first major treatment success in acute myelogenous leukemia, and therefore also would be worthy of testing in solid tumors. The imminent availability of monoclonal antibodies such as Herceptin (Genentech, Inc.) and anticarcinoembryonic antigen antibody, and their synergistic combination with cytotoxic agents could be applicable to many patients with gallbladder carcinoma, representing yet another novel and promising idea for testing in the coming years. Finally, given the propensity of both gallbladder and pancreatic malignancies to spread to the peritoneal cavity, the feasibility and usefulness of intraperitoneal administration of gemcitabine should be explored as well. Clearly, much work remains to be done for this difficult disease, but perhaps the new and expanding array of tools in oncology gradually will allow our hopes to be translated into reality. Michael P. Castro M.D.*