c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases

Background

c-MET plays an important role in tumor proliferation, invasion and metastasis. In this study we examined the expression of c-MET in colorectal adenomas, primary adenocarcinomas and their corresponding lymph node, peritoneal and liver metastases. We correlated our findings with clinicopathological features.

Methods

Twenty three cases of colorectal adenoma and 102 cases of primary colorectal carcinoma and their corresponding metastases (44 lymph nodes, 21 peritoneal deposits and 16 liver metastases) were studied to evaluate c-MET expression by immunohistochemistry. For comparison, 12 sections of adjacent healthy colorectal mucosa were examined.

Results

Statistically significant differences were present among normal tissues, colorectal adenomas and primary colorectal carcinomas (P=0.011). Normal tissues showed a negative or weak reaction in 66.67% and 33.33% of cases respectively. Expression of c-MET was positive in 47.8% of adenomas. A significant positive association was identified between c-MET high expression and degree of dysplasia (P=0.024). c-MET was highly expressed in 66.7% of primary colorectal carcinoma. Significant positive correlations were detected between c-MET expression and TNM stage (P=0.036), lymph node metastasis (LNM), peritoneal deposits and liver metastasis (P=0.038, P=0.094 and P=0.045, respectively). c-MET expression in metastatic tissues was significantly higher than that of the primary tumor.

Conclusions

c-MET expression is gradually up-regulated in the development and progression of colorectal cancer (CRC) from normal epithelium to adenoma to colorectal carcinoma to metastases.     

Clinical significance of washing cytology in patients with advanced gastric cancer

Since 1988, we have performed intraoperative peritoneal washing cytology (CY) of the Douglas pouch in 1,255 patients (pts) with gastric cancer to diagnose latent peritoneal dissemination. Patients were classified as follows: 914 pts in P0, CY0; 100 pts in P0, CY1; 90 pts in P1; 53 pts in P2; and 98 pts in P3. Usually Papanicolaou's staining method was used and immunocytochemical staining of CEA and MOC-31 was carried out to make a definitive diagnosis. Prognostic factors were determined in 638 pts without liver metastasis by multivariate analysis. Curability, depth of tumor invasion, lymph node metastases, histological type and CY were independent prognostic factors. The survival of P0, CY1 pts who had undergone curative surgery was better than those with non-curative surgery. In conclusion, CY can serve as an independent predictor of prognosis, so immunocytochemical staining is important. P0, CY1 pts without residual cancer should be treated with multimodal therapy.     

复发转移性结直肠癌的外科治疗及预后分析

背景与目的:结直肠癌是常见恶性肿瘤之一,其发病率有逐渐增高的趋势.其主要的治疗方法是根治性手术,手术后的复发及转移是导致患者死亡的主要原因.目前复发性结直肠癌的再手术是提高患者生存率和生存质量的主要方法.本文探讨结直肠癌术后复发的原因、诊断和外科治疗方法.方法:回顾性分析2003-2006年35例复发与转移性结直肠癌的外科治疗及预后.结果:手术后1年内复发者9例 (26%),3年内复发者26例(74 %).本组35例复发或转移性结直肠癌均行再次手术,7例复发性直肠癌再切除4例,造瘘3例,28例复发性结肠癌中,根治性切除8例(包括5例肝转移灶切除),姑息性切除10例,盲肠或横结肠造瘘10例.总切除率为63 %(22/35),其中根治性切除率为55%(12/22),姑息性切除45%(10/22).术后随访6～36个月,2例失访,12例根治性切除组中,9例无瘤生存,1例肺转移,2例肝转移;23例姑息治疗组中,5例死亡,4例肝转移,其余14例带瘤生存.结论:结肠癌的手术治疗,应根据其生物学特点,采取规范的手术方式、彻底清除原发灶、转移的肠系膜及淋巴结,术中注意无瘤操作,术后酌情辅以化疗或放疗,定期随访,是预防结直肠癌术后复发的主要措施.而对复发和转移病例,应根据其部位、临床特征,选择以手术为主的综合治疗方案,酌情达到根治或姑息治疗的目的.     

Preoperative diagnostic laparoscopy with local anesthesia and lavage telomerase activity for advanced gastric cancer

A pretherapeutic staging system to design operative or neoadjuvant treatments in gastric cancer is needed. In this study, a simple staging system based on diagnostic laparoscopic findings under local anesthesia to define a treatment was developed. This study was conducted with 68 patients with advanced gastric cancer. All the patients had been diagnosed as more than T3, or were suspected to have peritoneal seeding. Preoperative diagnostic laparoscopy under local anesthesia was performed in the operation room. After insertion of the trocars, the abdominal cavity was inspected, and biopsy and/or abdominal lavage sampling was performed. Patients were allocated into three stages based on laparoscopic and histopathologic findings. Twenty-eight out of 68 patients were diagnosed as P1, 34 patients as P0CY0 and 6 as P0CY1. Based on these results, 57 patients underwent operation. The accuracy rate of diagnosis was 95% in the P category, and 93% in the CY category. Lavage telomerase activity was examined on 10 patients with P0CY0 gastric cancer. Two out of 10 were positive for this activity, and both of them had died due to peritoneal recurrence within a year after operation. In conclusion, the proposed diagnostic laparoscopic staging system is a simple and reproducible method for selection of a suitable therapy. It is considered that diagnostic laparoscopy under local anesthesia is a useful preoperative examination in cases of advanced gastric cancer. Moreover lavage telomerase activity may be a more sensitive predictor of peritoneal recurrence than lavage cytology.     

Prognostic significance of tumor markers in peritoneal lavage in advanced gastric cancer

OBJECTIVE: Predicting peritoneal dissemination of cancer is very difficult whatever method of examination is used. Recently, a cytological examination of peritoneal lavage has been shown to be a feasible measure to predict an early state of peritoneal seeding. The predictive value of the levels of tumor markers in peritoneal lavage for peritoneal metastasis from gastric carcinoma was thus studied. METHODS: In 229 patients gastric cancer tumor markers, CEA, CA 125, and CA 19-9, in peritoneal lavage were intraoperatively evaluated using a chemiluminescent enzyme immunoassay. RESULTS: CEA in peritoneal lavage at a cutoff level of 0.5 ng/ml showed overall a higher sensitivity of 75.8% at a specificity of 90.8% for a diagnosis of peritoneal dissemination including cytologically positive peritoneal lavage [CY(+)] than CA 125 or CA 19-9 in peritoneal lavage. The CEA level in peritoneal lavage as well as both serosal invasion and the CA 125 level in peritoneal lavage were significant factors for the prediction of peritoneal dissemination including CY(+) with a relative risk of 6.6, 14.1 and 9.4. In patients undergoing curative operations, the recurrence rate for peritoneal dissemination and liver metastasis in cases with CEA levels in peritoneal lavage of > or = 0.5 ng/ml was significantly higher than that in cases with CEA levels of < 0.5 ng/ml (p < 0.0001, p < 0.002). CONCLUSIONS: These finding suggest that the CEA level in peritoneal lavage is thus considered to be a predictor of peritoneal dissemination including CY(+).     

Resection made possible following hepatic arterial infusion in 2 cases of hepatic metastases from colorectal cancer

Of 66 examples of hepatic metastases from colorectal cancer, 30 cases in which resection was performed had 3- and 5-year cumulative survival rates of 66.7% and 56.8%, while in 36 cases in which resection was not possible, the percentages were 8.7% and 2.9%, respectively. In two of the latter cases, resection was possible following WHF (5-FU 1,000 mg/m2 5 h qw). Case 1: A 58-year-old male, with rectal cancer and multiple metastases (H3, synchronous). Arterial infusion was performed 21 times, with the total volume of 5-FU administered being 31.5 g. The size of the lesions was reduced and hepatic resection was performed. The patient later died due to local recurrence and intra-abdominal lymph node metastases. He had survived 2 years and 11 months following hepatic resection and was free from recurrence of hepatic metastases. Case 2: An 82-year-old female, with cancer of the ascending colon, sigmoidal colon and multiple hepatic metastases (H3, metachronous). Arterial infusion was performed 16 times, with the total amount of 5-FU administered being 20 g. A lowering of CEA levels and reduction of tumor size were achieved, and hepatic resection was performed. Seven months following hepatic resection, CEA levels are normal and no distant metastases or recurrence in the residual liver have been found: possibly a complete cure. Even among cases of unresectable hepatic metastases from colorectal cancer, there are some in which resection is possible following hepatic arterial infusion chemotherapy, with the possibility of complete cure.     

大肠癌术后腹腔低渗温热化疗

目的研究腹腔低渗温热化疗对大肠癌术后腹腔内及肝转移的预防效果.方法收集自1996年7月～1999年12月大肠癌手术病例,随机分为两组A组腹腔低渗温热化疗组.B组常规静脉化疗组.观察腹腔复发率、肝转移率、生存率.结果A组腹腔复发率7.5%(4/53),肝转移率5.7%(3/53),1年、2年生存率分别为96.8%(60/62)、88.7%(55/62).B组腹腔复发率11.8%(6/51),肝转移率15.7%(8/51),1年、2年生存率分别为82.8(48/58)、74.1%(43/58).结论腹腔低渗温热化疗对预防大肠癌术后腹腔内复发、肝转移、提高生存率有显著疗效.     

Radiofrequency ablation (RFA) in colorectal cancer with hepatic metastases

We considered the appropriateness of RFA, which was performed in three cases of colorectal cancer with hepatic metastases accompanied by liver cirrhosis. Case 1 involved a patient with sigmoid colon cancer ss, n1 (+) with severe hepatic dysfunction and synchronous hepatic metastases (S5, S6, S8) in which RFA was performed. After 1 year and 6 months, recurrence (S3, S4) was detected in the residual liver, and the patient is currently undergoing the IFL (CPT-11/5-FU/Leucovorin) treatment. In case 2, following a partial hepatic resection, RFA was performed for cecal cancer ss, n2(+) with synchronous hepatic metastases (S5, S6, S8). After 11 months, recurrence (S5, S6, S7) occurred in residual liver and again RFA was performed following a partial hepatic resection. Lung metastases have occurred and currently IFL (CPT-11/5-FU/Leucovorin) and WHF treatments are underway. In case 3, 4 years and 8 months after cancer of the descending colon ss, n1 (+), RFA was performed on asynchronous hepatic metastases (S5, S7, S8). The patient died of peritonitis carcinomatosa one year after RFA. In all three cases, metastases were identified by dynamic CT as low density masses with no blood flow. Necrosis in all three metastases and local control had been achieved. There were no severe complications. Under the current conditions, local coagulation methods including RFA are appropriate in those cases in which resection are not possible such as multiple metastases with severe hepatic dysfunction, etc.     

Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors

Regional recurrence of malignant tumors in the peritoneal cavity usually signifies a poor prognosis for the host and often results in gastrointestinal complications requiring surgical intervention. One hundred patients with nongynecological malignancies found with peritoneal carcinomatosis were followed prospectively. The most common primary tumors were colorectal (N = 45) and pancreatic (N = 20) carcinoma. When associated with pancreatic carcinoma, 65% of patients had liver metastases and 60% had ascites. The presence of ascites was associated with poor survival, with no patient surviving past 30 days. Ascites was also a sign of poor prognosis in patients with colorectal carcinoma. Among possible prognostic factors in colorectal carcinoma patients, only disease-free interval, presence of lung metastases, and ascites showed statistically significant correlations with survival. Peritoneal carcinomatosis in sarcoma (N = 7) and breast cancer (N = 6) patients had median survival of 12 and 7 months, respectively. Surgical intervention for gastrointestinal complications in peritoneal carcinomatosis can provide significant palliation, with a few exceptions such as in patients with pancreatic or gastric carcinoma, ascites, and poor performance status.     

Serum sialyl-Tn antigen in colorectal cancer and its relationship to prognosis]

Serum sialyl-Tn antigen level was studied in 117 cases of colorectal cancer. The positive rates for serum sialyl-Tn antigen were 23.1% in primary colorectal cancer. There is a significant correlation between the positive rates of serum sialyl-Tn antigen and liver metastases, peritoneal dissemination, or lymph node metastases. The survival rate for patients with sialyl-Tn antigen positive sera was lower than those with sialyl-Tn antigen negative. Among patients who underwent curative operation, patients with sialyl-Tn positive sera gave a recurrence rate of 35.7%, while those with sialyl-Tn negative sera recorded a recurrence rate of 14.7%. There is no correlation between the positive rates of serum sialyl-Tn antigen and DNA ploidy pattern. Serum sialyl-Tn antigen levels may be a useful indicator in projecting the prognosis of colorectal cancer.     

Liver fatty acid-binding protein is a new prognostic factor for hepatic resection of colorectal cancer metastases.

BACKGROUND AND OBJECTIVES: Liver fatty acid-binding protein (L-FABP) is reported as a biological marker for enterocytic differentiation. We evaluated the prognostic value of L-FABP expression for patients undergoing hepatic resection of colorectal cancer metastases. METHODS: The study group comprised 68 patients who underwent hepatic resection for colorectal cancer metastases between 1982 and 1996 at Niigata University Medical Hospital, Niigata, Japan. L-FABP expression was immunohistochemically studied in metastatic liver tumors and their primary colorectal cancers. The relationship between L-FABP expression and patient prognoses was statistically analyzed. RESULTS: L-FABP was positively stained in 56% (38/68) of liver metastases from colorectal cancers and in 56% (38/68) of their primary tumors. Of 68 cases, 54 (79%) showed similar immunohistochemical findings between primary and metastatic tumors. Patients with L-FABP-positive liver metastases showed better prognosis than patients with L-FABP-negative metastases (P = 0.046). L-FABP expression in primary colorectal cancers more significantly (P = 0.009) affected long-term survival after hepatic surgery. Multivariate analysis revealed that the prognostic effect of L-FABP expression in primary colorectal cancers was exerted independently and that its impact was larger than conventional pathological prognosticators. CONCLUSIONS: L-FABP expression is suitable for use as a new presurgical prognostic factor for patients undergoing hepatic surgery for colorectal cancer metastases.     

不同治疗方法对结直肠癌肝转移患者预后的影响

目的 探讨不同治疗方法对结直肠癌肝转移患者预后的影响.方法 对300例结直肠癌首发肝转移患者的诊治过程及肝转移后生存情况进行回顾性分析.结果 结直肠癌肝转移灶完全切除者、姑息切除者和无法切除者的肝转移后中位生存期分别为48、19和18个月(P=0.000).对于无法行肝转移灶完全切除的患者,肝转移后化疗联合局部治疗和不治疗患者的肝转移后中位生存期分别为23个月和6个月(P=0.000).一线治疗有效患者和无效患者的肝转移后中位生存期分别为24个月和16个月(P=0.000).单因素生存分析结果显示,原发肿瘤的治疗方式、肝转移灶的手术方式、肝转移后的综合治疗以及一线治疗的疗效均与预后相关(均P<0.05).多因素分析结果显示,肝转移灶的手术方式、肝转移后的综合治疗和肝转移后一线治疗的疗效是影响结直肠癌肝转移患者预后的独立因素(P<0.05).结论 肝转移灶完全切除、肝转移后进行综合治疗以及肝转移后一线治疗有效的结直肠癌肝转移患者预后好.     

The role of carcinoembryonic antigen monitoring in management of colorectal cancer

Carcinoembryonic antigen (CEA) is an important tool in the management of colorectal cancer. Its use as a prognostic indicator in resectable disease remains controversial but may be improved with molecular detection of the antigen. In monitoring patients after resection, CEA can be the first sign of a potentially curable recurrence. It can also be useful in assessing tumor response in patients being treated for metastases without easily measurable disease. CEA alone cannot dictate the type or duration of treatment but may be used in addition to standard monitoring tests.     

Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer.

PURPOSE: Recent studies have shown that cyclooxygenase (Cox)-2 may be involved in colorectal carcinogenesis. We aimed to determine whether Cox-2 expression in itself can predict outcome of colorectal cancer patient after surgery. In addition, the expression of Cox-1 was also evaluated. EXPERIMENTAL DESIGN: Tissue samples of primary and secondary tumors from 288 patients undergoing surgical resections for colorectal adenocarcinoma were immunohistochemically examined for Cox-2 and Cox-1 expressions. The specimens were graded based on the intensity and extent of staining; then, the correlations between Cox-2 and Cox-1 expressions with clinicopathologic parameters and survival time were analyzed. RESULTS: Expression of Cox-2 was positive in 70.8% of primary tumor, 92.0% of lymph node metastases, 100.0% of hepatic metastases, and was significantly associated with tumor size, depth of invasion, lymph node metastasis, vessels invasion, stage and recurrence. In contrast, Cox-1 was positive in 42.7% of primary tumor, 84.0% of lymph node metastases, 37.5% hepatic metastases, and was associated with only tumor size. Patients with Cox-2-positive tumors had a significant shorter survival time than those with negative tumors did (P = 0.0006 by log-rank test); and, in a multivariate analysis, Cox-2 was an independent prognostic factor (P = 0.0103; relative risk 4.114; 95% confidence interval, 1.397-12.120). Cox-1 status had no statistically effect on patient survival time. CONCLUSIONS: Elevated Cox-2 expression, but not that of Cox-1, was significantly associated with reduced survival and recognized as an independent prognostic factor in our cohort of colorectal cancer patients.     

Long-term prognostic value of conventional peritoneal cytology after curative resection for colorectal carcinoma

BACKGROUND: This study was undertaken to evaluate the long-term prognostic significance of conventional peritoneal cytology in patients with advanced colorectal carcinoma after curative resection. METHODS: A review was performed of 189 patients who underwent curative resection for pT3/T4 carcinoma of the colon and upper/middle rectum between March 1987 and December 1991. Patient outcomes were reviewed retrospectively. Peritoneal cytology was performed before manipulation of the tumor. Intraoperatively, 50 ml of saline were instilled and 20 ml were reaspirated for cytology. In all patients, Papanicolaou and Giemsa stainings were performed to detect intraperitoneal free tumor cells. RESULTS: The median follow-up was 103 months. Malignant cells were identified in peritoneal washings from 11 patients (5.8%). Of the 11 patients with positive cytology, six (54.5%) developed recurrence and peritoneal recurrence was observed in four (36.4%). In contrast, of the 178 patients with negative cytology, 46 (25.8%) developed recurrence and peritoneal recurrence was observed in four (2.2%). The peritoneal recurrence rate was significantly increased (P = 0.0004) in the patients with positive cytology. The cancer-specific 10-year survival rates for the patients with positive and negative cytology were 45.5 and 80.3%, respectively (P = 0.0051). Multivariate analysis (Cox proportional hazard model) revealed that peritoneal cytology (positive: P = 0.0256) and lymph node metastasis (pN2: P = 0.0004) were independent predictors of cancer-specific survival. CONCLUSION: Conventional peritoneal cytology serves as a new prognostic marker after curative resection in patients with advanced colorectal carcinoma. It appears to be a useful diagnostic procedure for predicting recurrence, especially peritoneal recurrence.     

Clinical significance of serum CYFRA 21-1 in gastric cancer.

We studied the clinical significance of the soluble cytokeratin 19 fragment detected with monoclonal antibody CYFRA 21-1 in the sera of patients with histologically proven gastric cancer. Sera of 110 patients with gastric cancer were analysed for CYFRA 21-1 levels by a two-step sandwich enzyme immunoassay. There were no significant differences between CYFRA 21-1 levels and the histotype, depth of invasion or vessel invasion. However, CYFRA 21-1 was significantly higher in the presence of peritoneal metastases, liver metastases and extensive nodal involvement. When the positive cut-off value was defined as 5 ng ml-1, the CYFRA 21-1 in the stage IV and recurrent cases was 55.6% and 66.7%, respectively, which was as high as carcinoembryonic antigen (CEA) and greater than carbohydrate antigen 19-9 (CA 19-9). The positivities in stage I/II and III were zero and 5.9%, respectively, and false-positive rate in 76 patients with benign gastrointestinal disorders was 2.6%. There appeared to be no correlation between CYFRA 21-1 and CEA or CA 19-9. The patients with above 5 n ml-1 of CYFRA 21-1 had a significantly poorer prognosis. Multivariate analysis indicated that CYFRA 21-1 was an independent prognostic factor, while CEA and CA 19-9 failed to be of prognostic value. In conclusion, CYFRA 21-1 is a reliable tumour marker for gastic cancer in predicting very advanced cases, recurrence of the disease and overall poor prognosis.     

Two case reports of complete regression of liver metastases from colorectal cancer after locoregional immunochemotherapy

Hepatic arterial infusion (HAI) with pharmacokinetic modulating chemotherapy (PMC) has been well known to be one of the most effective protocols for unresectable liver metastases from colorectal cancer. PMC is a combination of oral UFT and continuous hepatic arterial 5-FU infusion. We present herein the cases of two patients with multiple liver metastases from colorectal cancer in whom complete regression (CR) was achieved by HAI with PMC in combination with Lentinan (immunostimulator). These patients received HAI via an implantable port system with a 4-24-hour continuous perfusion of 5-FU at 1,000 mg/m2 plus Lentinan at 2 mg/body once a week, and oral administration of UFT at 200-300 mg/m2/day everyday. CR of all metastatic lesions in the liver was achieved 4 months after the initiation of the treatment in both patients. One patient maintained CR for 3 months, but he died due to a recurrence of liver metastases and peritoneal dissemination 19 months after the initiation of the treatment. The other patient has been well without recurrence for 21 months. Because the liver is the largest immunologic organ, Lentinan could have activated lymphocytes and macrophages in the liver. Judging from the clinical experience of these two cases, HAI with PMC in combination with Lentinan could be one of the most promising treatment strategies for unresectable liver metastases from colorectal cancer.     

Assessment of K-ras, Smad4 and p53 gene alterations in colorectal metastases and their role in the metastatic process

To date there is no genetic marker that gives accurate information on the prognostic impact for patients with colorectal cancer. A particular clone, not detected in the tumor, could be responsible for the metastatic process. To overcome this problem, genetic alterations were analyzed in metastatic tissues from 58 patients who developed metastases after curative surgery for colorectal cancer. K-ras, p53 and Smad4 alterations were observed in respectively 38, 60 and 27% of the metastases. These frequencies are similar to the ones reported in primary colorectal tumors. Thus, these genetic alterations cannot be used as prognostic biomarkers in patients with colorectal cancer. The metastases were stratified into 3 groups, according to the metastatic localization. K-ras mutations were detected in respectively 75, 26 and 11% of the distant, peritoneal and liver metastases. Loss of Smad4 expression was observed more frequently in the liver (62%) than in other metastases (13%). These results suggest that the genetic changes of the tumor cells indicate the location of the metastases and thus, the route of metastatic spread.     

Preoperative serum alpha-L-fucosidase activity as a prognostic marker in colorectal cancer

OBJECTIVES: The aim of this study was to examine the prognostic value of the preoperative serum alpha-L-fucosidase (AFU) activity in colorectal cancer and to assess whether it could add prognostic information that Dukes' stages do not give. METHODS: A postoperative follow-up of 137 colorectal cancer patients was performed, and survival analyses were carried out to evaluate the impact of AFU activity on disease-free survival. Dukes' stage classification, preoperative serum carcinoembryonic antigen levels and six other clinicopathological features of the patients were also analysed. RESULTS: In previous studies, we have stressed the diagnostic value of AFU activity in preoperatively obtained serum from colorectal cancer patients. In the present work, we have found that the enzymatic activity of serum AFU was not related to the Dukes' stage of the primary tumour, but it was associated with the type of metastasis and recurrence of the disease. The mean value of preoperative serum AFU activity was higher in patients with distant metastases than in those with lymph node or peritoneal metastases, or without metastasis (p = 0.034). After a mean postoperative follow-up period of 22 months, three groups of patients with different recurrence rates could be distinguished (p = 0.0014). Similar results were found when only patients in Dukes' stage B (p = 0.0439) or C (p = 0.0122) were considered. CONCLUSIONS: According to our findings, serum AFU activity appears to be a good prognostic factor of tumour recurrence in colorectal carcinoma. Furthermore, patients in Dukes' stage B or C at high or very high risk of tumour recurrence could be spotted.     

Diagnosis and management of peritoneal carcinomatosis arising from adenocarcinoma of the colon and rectum

Peritoneal carcinomatosis (the implantation of tumor cells throughout the peritoneal cavity) occurs in as many as 50% of patients with colorectal cancer and in up to 25% is the only site of recurrence. There is increasing evidence that aggressive debulking of peritoneal only disease followed by intraperitoneal chemotherapy can have significant impact on the patient's quality and sometimes quantity of life. This chapter will provide an overview of the biologic basis of pathogenesis and the treatment of peritoneal metastases from colorectal cancer.