CD44 variant 6 expression predicts response to treatment in advanced colorectal cancer

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. CD44 variant 6 (CD44v6) has been postulated to be involved in both carcinogenesis and tumor progression. Therefore, we have examined CD44v6 expression in tumors from 57 patients with advanced colorectal cancer who received one of two chemotherapy regimes (either irinotecan alone or irinotecan and 5-flurouracil with folinic acid). CD44v6 expression was determined immunohistochemically in 57 paraffin-embedded primary tumor sections and assessed using image analysis software. Strong expression levels of CD44v6 were seen in 24/57 (42%) of tumors, moderate levels in 17/57 (30%), weak levels in 9/57 (16%) and no expression was seen in 7/57 (12%). The pattern of staining was predominantly cytoplasmic, 7/57 tumors also exhibited membrane specific expression. A significant association was found between tumor CD44v6 expression and treatment response (Fisher's exact test p=0.01). Only 1/12 patients with no or weak tumor expression of CD44v6 showed a response to treatment whereas 20/41 (49%) patients with moderate or strong CD44v6 expression responded to treatment. Evaluation of CD44v6 expression of locally advanced and metastatic colorectal tumors may enable the clinician to identify and select patients that will show the best response to irinotecan based chemotherapy.     

Evaluation of CD44 variant 6 expression and clinicopathological factors in pulmonary metastases from colon carcinoma

Although relatively little is known about the molecular mechanisms underlying tumor progression, recently CD44 glycoproteins and the c-Met receptor tyrosine kinase have been identified as potentially important components of the metastatic cascade. CD44 is a family of transmembrane receptors generated from a single gene by alternative splicing and differential glycosylation. Important biological processes involving CD44 glycoproteins include cell adhesion, lymphocyte homing, hematopoiesis, tumor progression and metastasis. The precise mechanism via which CD44 promotes tumorigenesis have not yet been elucidated. We evaluated the expression of adhesion molecule CD44 variant 6 in pulmonary metastases from colorectal carcinomas and its correlation with clinicopathological parameters. Twenty patients were randomly selected from the patients who had undergone a resection of pulmonary metastasis from colorectal cancer. Formalin-fixed, paraffin-embedded archival specimens of tumor tissues and adjacent normal mucosa from these patients were the subjects of the present study. Immunoreactivity for CD44 was quantified. Specimens were considered positive if almost 25% of the neoplastic cells were stained. CD44 v6 expression was related to the interval between colon resection and metastases diagnosis, the number of pulmonary metastases, and the survival after lung resection. No statistical correlation was found between CD44 v6 positivity and disease-free interval after colon resection, number of metastases or 2-year survival after lung resection. Probably CD44 v6 is necessary and sufficient to confer metastatic potential to carcinoma cells increasing the migration capacity and participating in invasion via changes in adhesion to the extracellular ligands, but is not necessary to modify the clinical history of the metastases. Therefore the evaluation of CD44 v6 expression in lung metastases does not influence the therapeutic scheme.     

Clinical significance of extrahepatic bile duct resection for advanced gallbladder cancer

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the clinical significance of extrahepatic bile duct (EHBD) resection during surgery for advanced gallbladder cancer. METHODS: Among 110 patients with pT2 or higher grade gallbladder cancer, 58 patients without microscopic invasion to the EHBD were reviewed. Prognostic factors of the 58 patients were evaluated by multivariate analysis. The impact of EHBD resection on survival was assessed in relation to two prognostic determinants: (i) lymph node metastasis: positive (n = 23) and negative (n = 35); (ii) perineural invasion: positive (n = 25) and negative (n = 33). RESULTS: Hepatic metastasis and perineural invasion were found to be independently significant prognostic factors. (i) No survival benefit of additional EHBD resection could be confirmed in each group of patients with or without nodal metastasis. (ii) In 25 patients with perineural invasion, 14 patients who underwent EHBD resection showed better survival as compared to the 11 patients who did not undergo EHBD resection (5-year survival rate, 46% vs. 0%, P = 0.009). In the remaining 33 patients without perineural invasion, the additional EHBD resection did not yield significant improvement of survival (P = 0.28). CONCLUSIONS: Resection of EHBD may offer prognostic advantage when perineural invasion exists, even in the absence of biliary infiltration.     

A case of adenosquamous carcinoma of lower extrahepatic bile duct

We report a 83-year-old female with bile duct cancer who underwent subtotal stomach preserving pancreatoduodenectomy. Pathologically, her tumor was diagnosed as adenosquamous carcinoma of the lower extrahepatic bile duct with final stage IVb[pT3pN3M(-)].The prognosis of patients with adenosquamous carcinoma of the bile duct is very poor, and the reason is thought to be its tendency to invade the pancreas.Although she was an aged patient, we performed adjuvant chemotherapy using gemcitabine.No recurrence has occurred until this day, 30 months after the operation.This is thought to be an effect of the adjuvant chemotherapy, considering its poor prognosis.     

肝外胆管癌预后因素分析

目的分析肝外胆管癌患者的预后因素.方法单因素按不同水平分层的人时死亡率计算方法和多因素Cox模型分析预后因素.结果:手术方式和术后生存期的关系最为密切,行切除术的患者术后生存期明显延长,其次是病理类型、术后并发症和术后生存期关系亦非常密切,建立了肝外胆管癌术后生存危险状态函数.在此基础上比较了不同术式的1、3、5年生存率.探查术的1、3、5年生存率分别为11.48%、0.06%、0.003%;外引流术的1、3、5年生存率30%、16.12%、0.31%,切除术的1、3、5年生存率分别为69.23%、28.10%、17.04%.结论: 手术切除是治疗肝外胆管癌患者的最佳方案.     

Ultrasound directed extrahepatic bile duct intraluminal brachytherapy.

Intraluminal brachytherapy with a transcatheter Iridium-192 (Ir-192) wire, as a method to deliver a boost to patients with tumors of the extrahepatic bile ducts, has been well described. A major limitation of current imaging techniques is the inability to accurately define the proximal, distal, and most importantly the lateral extent of the tumor. We have found endoluminal ultrasound, which to this date has been used primarily to measure arterial wall layers, can successfully determine tumor volume in the bile ducts. The small diameter of these ultrasound probes allows easy insertion into a biliary duct drainage tube. Given the uncertainties in the determination of tumor size in the bile ducts, ultrasound is an ideal method by which to obtain the measurements. We present a case of recurrent islet cell carcinoma treated with external beam radiation therapy and an Ir-192 intraluminal brachytherapy boost in which the ultrasound probe was used to determine the tumor volume and response to therapy.     

Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response

BACKGROUND AND OBJECTIVES: Tumor-infiltrating lymphocytes form an important aspect of the host defense against an expanding neoplasm. CD8+ T cells have been identified as a prognostic factor in several cancers. Here, we investigate that the influence of CD8+ T cells on extrahepatic bile duct carcinoma (EBDC) patient survival. METHODS: CD8+ T cell immunoreactivity in 58 surgically resected EBDC specimens was investigated. The relationship between CD8+ T cell immunoreactivity and clinical and histopathologic features was analyzed. RESULTS: Thirty-two tumors (55%) possessed intratumoral CD8+ T cells. The degree of intratumoral CD8+ T cell immunoreactivity demonstrated a significant relationship to lower numbers of lymph node metastasis, reduced venous invasion, decreased perineural invasion, and better pTNM staging. Intratumoral CD8- T cells were also associated with increased patient survival. Multivariate analysis indicated that the presence of intratumoral CD8+ T cells was an independent prognostic factors. CONCLUSIONS: The infiltration of a cancer cell nest by CD8+ T cells is a reliable marker predicting increased survival of patients with EBDC.     

Prognostic value of CD44 variant expression in primary breast cancer.

CD44 is a family of cell surface transmembrane glycoproteins members which differ in the extracellular part by sequences derived by alternative splicing of 10 variant exons (v1-v10). CD44 proteins containing such variant sequences have been implicated in tumor metastasis formation. Here, we have evaluated the expression of CD44 variants by immuno-histochemistry in primary breast cancer samples of 237 node-negative and 230 node-positive patients. For the analysis of samples derived from node-negative patients, the exon-specific antibodies used were DIII, vff7 and vff18 (v6), vff17 (v7/v8), fw11.24 (v9) and vff16 (v10). With the different antibodies which recognize v6 epitopes, the majority of tumors were positively stained (> or = 65% of the tumors) with varying intensities. Thirty-nine percent of the tumors were positively stained with the antibody vff16, and approximately half of the tumors with the antibodies vff17 and fw11.24. The expression of CD44 v6 epitopes in tumors from node-negative patients was associated with a favorable prognosis, both upon univariate and multivariate analysis. The expression of CD44 v7/8, v9 or v10 epitopes was not significantly related with relapse-free survival. Samples from node-positive patients were only examined with the antibodies vff7, vff17 and vff18. The staining with none of these antibodies was correlated with the length of relapse-free survival of the patients. Our data suggest that, generally, the usefulness of knowledge of CD44 variant expression is of limited value for assessing the risk of relapse in patients with primary breast cancer. However, the expression of exon v6 of CD44 may be a marker to identify patients with a relatively favorable prognosis in node-negative patients.     

肝外胆管癌影像学诊断与手术病理对照分析

目的 通过肝外胆管癌的影像学诊断,探讨MR胆胰管造影（MRCP）对肝外胆管癌的诊断价值。地65例经手术病理证实的肝外胆管癌,其中行超声波检查（US）60例,电子计算机断层扫描（CT）52例,逆行胰胆管造影（ERCP）20例,经皮肝穿刺胆管造影（PTC）9例,磁共振胆胰管造影（MRCP）20例。根据各种检查方法显示的影像学表现和诊断,与手术病理结果进行对照分析。结果 定位诊断准确率US为81．7％,CT为84．6％,ERCP为75．0％,PTC为88．9,MRCP为100％;定性诊断准确率US为73．3％,CT为82．7％,ERCP为75．0％,PTC为88．9％,MRCP为95．0％。结论 MRCP对肝外胆管癌诊断定位和定性优于US、CT、ERCP及PTC。     

肝外胆管癌外科治疗的远期疗效评价

目的 分析影响肝外胆管癌远期疗效的因素,探讨不同的治疗方法对其预后的影响,总结诊治经验。方法 对84例肝外胆管癌临床病理资料进行回顾分析,应用SPSS10．0统计软件包进行统计学分析。结果 胆管癌患者的总体5年生存率为13．1％。胆管癌根治切除组的1,3,5年生存率分别为76.8％、52．6％和30．5％。根治切除组与姑息手术组、剖腹探查组、非手术组间差异有统计学意义（P〈0.01）。Cox多因素分析显示,淋巴结转移、组织学分级、远处转移与胆管癌的预后显著相关。结论 肝外胆管癌患者扩大切除范围有望改善预后,但总体疗效有限。早期诊治及综合治疗是改善预后的关键。     

Endoscopic diagnosis of extrahepatic bile duct carcinoma: Advances and current limitations

The accurate diagnosis of extrahepatic bile duct carcinoma is difficult, even now. When ultrasonography (US) shows dilatation of the bile duct, magnetic resonance cholangiopancreatography followed by endoscopic US (EUS) is the next step. When US or EUS shows localized bile duct wall thickening, endoscopic retrograde cholangiopancreatography should be conducted with intraductal US (IDUS) and forceps biopsy. Fluorescence in situ hybridization increases the sensitivity of brush cytology with similar specificity. In patients with papillary type bile duct carcinoma, three biopsies are sufficient. In patients with nodular or infiltrating-type bile duct carcinoma, multiple biopsies are warranted, and IDUS can compensate for the limitations of biopsies. In preoperative staging, the combination of dynamic multi-detector low computed tomography (MDCT) and IDUS is useful for evaluating vascular invasion and cancer depth infiltration. However, assessment of lymph nodes metastases is difficult. In resectable cases, assessment of longitudinal cancer spread is important. The combination of IDUS and MDCT is useful for revealing submucosal cancer extension, which is common in hilar cholangiocarcinoma. To estimate the mucosal extension, which is common in extrahepatic bile duct carcinoma, the combination of IDUS and cholangioscopy is required. The utility of current peroral cholangioscopy is limited by the maneuverability of the "baby scope". A new baby scope (10 Fr), called "SpyGlass" has potential, if the image quality can be improved. Since extrahepatic bile duct carcinoma is common in the Far East, many researchers in Japan and Korea contributed these studies, especially, in the evaluation of longitudinal cancer extension.     

CD44V6在乳腺癌中的表达及其临床意义

目的探讨乳腺癌中CD44v6蛋白的表达及临床意义.方法用免疫组织化学方法对乳腺癌CD44v6蛋白送行检测,并与患者临床病理指标进行分析.结果乳腺癌CD44v6蛋白阳性反应率为58.4%(28/48),与肿瘤大小、腋淋巴结转移成正相关.结论CD44v5参与了乳腺癌的发生、发展过程,可能是评估乳癌生物学行为的不良指标.     

Altered p21(WAF1/CIP1) expression is associated with poor prognosis in extrahepatic bile duct carcinoma

This study was designed to determine the clinical implications of p21(WAF1/CIP1) expression and the relationship between p21(WAF1/CIP1) expression and p53 status in extrahepatic bile duct carcinoma (EBDC). Low p21(WAF1/CIP1) expression was immunohistochemically detected in 23 (67.6%) of 34 EBDCs, moderate in six (17.7%), and high in five (14.7%). Kaplan-Meier curves showed that low and high p21(WAF1/CIP1) expressions were significantly associated with shortened disease-free survival (low vs. moderate, P=0.02; high vs. moderate, P=0.01). There was no correlation between p21(WAF1/CIP1) and p53 expression. These findings suggest that altered p21(WAF1/CIP1) expression exerts an adverse influence on the prognosis of EBDC.     

The prognostic significance of CD44s and CD44v6 expression in stage two breast carcinoma: an immunohistochemical study.

AIMS: Expression of the v6 variant isoform of CD44 has been causally associated with the development of metastases. This study, using immunohistochemical techniques, examined the prognostic significance of CD44s and CD44v6 expression. METHODS: A cohort of 109 women presenting with stage 2 breast cancer, with a minimum follow-up of 5 years, were assessed. RESULTS: Eighty percent of patients demonstrated CD44v6 expression on immunohistochemical studies. CD44v6 expression in tissue sections was found to be independent of age, tumour size, grade, and lymph-node status. No significant association was demonstrated between CD44v6 expression and either disease-free or overall survival. Similar findings were observed for CD44s. CONCLUSIONS: CD44s and CD44v6 do not appear to be useful as prognostic indicators in early breast cancer. The increased expression of variant CD44 isoforms seen in breast neoplasia may merely be a marker for loss of control of alternative splicing within tumour tissue.     

Analysis of failure following curative irradiation of gallbladder and extrahepatic bile duct carcinoma

Twenty patients with carcinoma of the gallbladder (GB-4 patients) or extrahepatic bile ducts (EHBD-16 patients) received radiation therapy with curative intent between January, 1980 and December, 1982. All 20 received 4500–5000 rad in 180–200 rad fractions to the tumor and regional lymph nodes. A 1000 to 1500 rad external beam boost was delivered in 180–200 rad fractions in 10 patients who received external beam alone or concomitant 5-Fluorouracil (5-FU). Three of the four GB and 5 of the 16 EHBD patients received a transcatheter boost with 192-Iridium (¹⁹²Ir) to a dose of 2000–2500 rad calculated at a 0.5-0.1 cm radius. An additional 2 patients with EHBD lesions received an intraoperative electron (IORT) boost of 1500–2000 rad in one fraction calculated to the 90% isodose. Survival and patterns of failure were analyzed by site and treatment method. All four patients with GB carcinoma are dead of disease at 5$\text{1}\text{2}$, 6, 9 and 10 months from the date of diagnosis respectively. Three of the four developed diffuse peritoneal carcinomatosis. Five of the 16 patients with EHBD carcinoma are alive with a median follow-up of 18 months (range 6–23 months). Four of the 5 patients received a transcatheter ¹⁹²Ir or IORT boost and all are without evidence of disease. Four of 9 patients who had a subtotal resection with transection of tumor, dilatation of the bile ducts with probes or curettement of the bile ducts developed either diffuse peritoneal carcinomatosis (3 patients) or a recurrence in the surgical scar (2 patients). Local failure was documented in 3 of the nine patients treated with external beam alone ±5-FU, and has been documented in one of the seven patients who received an IORT or transcatheter ¹⁹²Ir boost. Further experience is necessary to determine whether this aggressive treatment will result in long-term disease-free survival in these patients.     

Development and clinical pathology of carcinoma of the gallbladder and extrahepatic bile duct

We reported the causes of cancer development and clinical pathology of the gallbladder and extrahepatic bile duct carcinoma. Gallstone, secondary bile acid, and congenital malunion between the bile duct and the pancreatic duct are considered as causes of intestinal metaplasia of the mucosa of the biliary tract. The intestinal metaplasia has closely relationship with development of dysplasia and carcinoma. We treated 101 patients with gallbladder carcinoma and 85 patients with bile duct carcinoma. Sex ratios of the patients with gallbladder carcinoma and bile duct carcinoma were 1:1.8 and 1.7:1. Fifty-one of 101 patients with gallbladder carcinoma had gallstones, and 17 of them had congenital malunion between the bile duct and the pancreatic duct. In four of 23 patients with gallbladder carcinoma and 10 of 64 patients with bile duct carcinoma, superficial cancer spread was seen and it was very important for surgical operation clinically.     

Two cases of advanced extrahepatic bile duct cancer successfully treated by S-1 monotherapy

Biliary tract cancers, including extrahepatic bile duct cancer, are often diagnosed at an advanced stage; however,no standard therapies have been established as yet for this disease,and new,effective chemotherapeutic agents are being sought. Recently, a late phase II study of S-1, an oral fluoropyrimidine, in 40 patients with advanced biliary tract cancer yielded a good response rate of 35.0%. In this article,we report two patients with advanced extrahepatic bile duct cancer enrolled in the study who showed a partial response to S-1 monotherapy.