Vascular Vessel Invasion Research Articles

P1.05-059 Factors Associated with Recurrence and Survival in Patients with Curatively Resected Stage IA Adenocarcinoma of the Lung

Even when meticulously clinically and pathologically studied, completely resected stage IA adenocarcinoma of the lung does recur. However, there are few data regarding the patterns of recurrences and their risk factors in this population. Therefore, this study characterizes cancer recurrence and its risks and assesses recurrence-free survival in patients with curatively resected stage IA adenocarcinoma. Between January 1990 and December 2005, a total of 214 patients were given a final diagnosis of pathologic stage IA (UICC-7) adenocarcinoma of the lung. The medical records of these patients were retrospectively reviewed with regard to patient characteristics, tumor pathologic findings and follow up status. Survival was analyzed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards analysis. The median follow up after curative resection was 83 months. Cancer recurred in 28 patients (13%). Among them, local recurrence occurred in 10 patients (5%), whereas distant recurrence occurred in18 patients (8%). Recurrence earlier and later than 5 years after surgery was in 15 patients (7%) and in 13 patients (6%), respectively, with nearly constant risk. At 5 years after index resection, 175 patients (82%) were alive without evidence of cancer recurrence, 11 patients (8%) had experienced recurrence of cancer but still alive and 11 patients (5%) had died with non-cancer causes. Recurrence-free 5- and 10-year survival rates were 92.5 and 70.0%, respectively. Univariate analysis revealed five significant prognostic factors: gender (p=0.0177); lepidic component (p =0.0007); tumor location (p=0.0099); pleural invasion (p=0.0274) and lymphatic or vascular vessel invasion (LVI) (p< 0.0001). Multivariate analysis revealed lepidic component, tumor location, and LVI as significant factors. Hazard ratios for recurrence were 0.381 for having lepidic component (95% CI, 0.147-0.979; p= 0.0451), 0.361 for right sided tumor (95% CI, 0.188-0.692; p= 0.0022), and 2.785 for having LVI (95% CI, 1.392-5.555; p= 0.0038). Surgically “cured” stage IA adenocarcinoma of the lung recurs. Our analyses indicate no-lepidic component, tumor location, LVI as an independent indicator for cancer recurrence. Identifying high-risk patients for recurrence will simplify decision making for postoperative treatment strategies.

Multivariate survival analysis of patients with stage I NSCLC

背景与目的Ⅰ期患者尤其是Ⅰb期术后非小细胞肺癌(non-small cell lung cancer, NSCLC)患者能否从辅助化疗中获益备受争议。2009年第7版肺癌TNM分期发表。本研究的目的是明确新版TNM分期对Ⅰ期NSCLC患者的价值, 以及评估术后辅助化疗是否能提高早期肺癌患者的生存率。方法研究纳入了上海市胸科医院1998年6月-2010年6月早期NSCLC完全切除术的433例患者, 按照新的分期标准重新分期。把新分期的参数与其它已被证明与肺癌预后相关的因子结合起来, 进行多因素分析。研究纳入变量包括年龄、性别、吸烟史、病理类型、手术切除方式(叶切、双叶切、袖切和全切)、肿瘤大小(肿瘤最长径)、T分期、淋巴管血管癌栓和辅助化疗。结果女性患者3年生存率优于男性(89.22% vs 77.53%, P=0.001, 8)。老年患者预后不佳, ≥70岁的NSCLC患者3年生存率为70.64%, < 70岁为85.85%, P=0.000, 1)。肿瘤最长径≤2 cm患者的3年生存率优于 > 2 cm且≤3 cm患者(95.15% vs 85.71%), 肿瘤最长径 > 3 cm且≤5 cm及 > 5 cm且≤7 cm者3年生存率为74.80% vs 60.47%(P < 0.000, 1)。多因素分析显示年龄、性别、血管癌栓、病理类型、胸膜侵犯是影响生存期的预后因素。结论对Ⅰ期NSCLC患者而言, 肿瘤最长径及病理类型是独立的预后因素。腺癌患者的生存期优于其它病理类型。女性和非吸烟患者结局较好。Ⅰb期患者可能从术后辅助化疗中获益。

Study on the expression and significance of prostate stem cell antigen in perineural invasion of pancreatic carcinoma

Objective To investigate the role of the expression of prostate stem cell antigen(PSCA)in the development of perineural invasion in pancreatic carcinoma.Methods The histopathologic and immunohis-tochemical(SABC)studies were performed on 80 patients with pancreatic carcinoma.The overall incidence of PSCA expression,perineural,lymphatic and vascular vessel invasion were counted to investigate the relationships among them.Results Perineurel invasion was positively correlated with lymphatic and vascular vessel invasion (P<0.01).A positive corelation Was found between tumor PSCA expressioa(53 cases)and the perineurel in-vasion(66 cases).A definite correlation Was also found between cancer differentiation and PSCA tyxplres-sion.Conclusion PSCA is one of the most important molecules and may play a role as a navigating and docking molecule in the developmeat of perineural invasion. Key words: Pancreatic neoplasms; Prostate stem cell antigen

The Prognostic Significance of Tryptophanyl-tRNA Synthetase in Colorectal Cancer

Tryptophanyl-tRNA synthetase (TrpRS) is an aminoacyl-tRNA synthetase involved in protein synthesis and regulation of RNA transcription and translation and is an inhibitor of angiogenesis. TrpRS has been shown to be differentially expressed in colorectal cancer (CRC) and has thus been identified as a potential prognostic marker. The aim of this study was to analyze the correlation of TrpRS to the prognosis of patients diagnosed and treated for CRC within a defined population. With a polyclonal, monospecific IgG antibody, TrpRS expression was assessed by immunohistochemistry on tissue microarrays with tumors from a population-based CRC cohort (n = 320). Staining intensity and fraction of positive tumor cells were recorded. A Cox multivariate model including TrpRS expression, carcinoembryonic antigen, age, stage, tumor differentiation, and lymphatic and vascular vessel invasion was used to calculate the hazard ratio and 95% confidence interval (95% CI) for time to recurrence, disease-free survival, and overall survival. Low expression of TrpRS correlated to increased risk for lymph node metastasis (P = 0.025) and a more advanced tumor stage (P = 0.001). Patients with tumors and increased levels of TrpRS expression had better survival than patients with low expression levels. Multivariate analyses revealed significantly better disease-free survival (relative risk, 0.59; 95% CI, 0.38-0.95) for patients with high expression than for patients with low expression of TrpRS. For colon cancer patients, a reduced risk for recurrence was seen in patients with increased TrpRS expression (relative risk, 0.23; 95% CI, 0.07-0.80). Low expression of TrpRS in tumor tissue correlates with increased risk for recurrence and worse survival in patients with CRC. This can be related to its antiangiogenic properties and could aid in the future selection of new drugs in the treatment of CRC.

The prognostic significance of tryptophanyl-tRNA synthetase (trpRS) in colorectal cancer

4137 Background: Tryptophanyl-tRNA synthetase (trpRS) is an aminoacyl-tRNA synthetase involved in protein synthesis, regulation of transcription and translation of RNA and an inhibitor of angiogenesis. TrpRS has in the Swedish Human Protein Atlas program (www.proteinatlas.org) been identified as a possible prognostic marker for colorectal cancer (CRC). The aim of this study was to analyze the correlation of trpRS to the prognosis of patients treated for CRC. Methods: Immunohistochemistry (IHC) on tissue microarray (TMA) was done with a polyclonal, monospecific IgG tryptophanyl-tRNA synthetase (trpRS) antibody, on 320 consecutive patients with colorectal cancer, diagnosed 2000–2003. Staining intensity and fraction of positive tumor cells were recorded. Cox multivariate model including age, stage, differentiation and lymphatic and vascular vessel invasion was used to calculate hazard ratio and 95% confidence interval for overall and disease-free survival. Results: Patients with tumours that showed increased levels of trpRS protein expression had better survival compared to patients with low expression levels. Multivariate analyses revealed significantly better overall survival (HR 0.53; 95%CI 0.30–0.92) and disease-free survival (HR 0.41; 0.22–0.74) for patients with high expression compared to low expression. No recurrences were seen in stage II when more than 12 lymph node were analysed in patients with high trpRS (n=28) compared to 9 recurrences in patients with low expression (n=66) (p=0.026). Conclusion: Low IHC expression of TrpRS in tumor biopsies correlates to increased risk for recurrence and worse survival in patients with CRC. This can be related to its anti-angiogenic properties and could aid in the future selection of new drugs in the treatment of CRC. No significant financial relationships to disclose.

Independent prognostic value of plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) in colorectal cancer: A prospective validation study

11072 Background: Introduction of independent prognostic markers may play a significant role in future treatment of colorectal cancer (CRC). Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a glycoprotein, which acts as an inhibitor of all active matrix metalloproteinases. TIMP-1 can be measured in plasma, and it has previously been shown to carry independent prognostic value in patients with primary CRC. The purpose of the present study was to validate TIMP-1 as a prognostic marker in patients undergoing operation for primary CRC. Methods: In the present prospective study plasma samples were collected before surgery from 323 patients with primary CRC between 2000 and 2003. After collection of all samples TIMP-1 was determined using a thoroughly validated, in-house ELISA method. Recurrence and survival were registered and the association to plasma TIMP-1 levels was studied in a Cox multivariate model including age, disease stage, differentiation, lymphatic and vascular vessel invasion calculating hazar...

MATRIX METALLOPROTEINASE-7 IS A USEFUL MARKER FOR PREDICTING AGGRESSIVE BEHAVIOR OF SUBMUCOSAL GASTRIC CANCER

To elucidate the process of metastasis in submucosal gastric cancer (SM-GC), we examined the immunohistochemical expression of matrix metalloproteinases (MMPs: MMP-2, MMP-7, and MMP-9) and tissue inhibitors of metalloproteinases (TIMPs: TIMP-1, and TIMP-2) in 66 cases of SM-GC, and compared them with clinicopathological findings of the cases. The positive rates for MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 were 42.4%, 33.3%, 9.1%, 0%, and 48.5%, respectively. There was a significant correlation between MMP-7 positive rate and the degree of tumor invasion. Moreover, only MMP-7 positive rate was significantly higher in cases with lymphatic invasion, vascular vessel invasion, and lymph nodes metastasis than in cases without them. MMP-2 positive rate was significantly higher in cases with massive submucosal invasion (sm2) and intestinal-type carcinoma. There were no significant correlations between clinicopathological findings and positive rates for MMP-9, TIMP-1, and TIMP-2. In logistic regression, MMP-7 immunoreactivity was found to be an independent risk factor of lymphatic invasion, vascular vessel invasion, and lymph nodes metastasis. These data suggest that MMP-7 is an important factor implicated in local invasion and metastasis, and would be a useful marker for predicting aggressive behavior of SM-GC.

Discrepancy of computed tomographic image between lung and mediastinal windows as a prognostic implication in small lung adenocarcinoma

Background There have been no proven preoperative indicators for postoperative survival of patients with an adenocarcinoma, the incidence of which has been increasing lately. Methods Of 952 consecutive patients operated on for primary lung cancer between 1995 and 2002, 167 patients with a proven adenocarcinoma 3 cm or less in diameter underwent complete removal of the primary tumor. We examined their computed tomographic scans to estimate tumor shadow disappearance rate (TDR), which was defined as the ratio of the tumor area of the mediastinal window to that of the lung window, reviewed the clinical records, and evaluated their relation to prognosis. Results On univariate analyses, size of the tumor ( p = 0.0380), TDR ( p = 0.0018), carcinoembryonic antigen ( p = 0.0001) pathologic stage ( p < 0.0001), nodal involvement ( p < 0.0001), lymphatic invasion ( p = 0.0001), and vascular invasion ( p = 0.0017) were significantly associated with prognosis. Also, the outcomes of multivariate analyses for preoperative factors indicated that TDR ( p = 0.0340) and carcinoembryonic antigen ( p = 0.0047) are significant independent prognostic determinants. The 5-year survival was 48% in cases with a TDR of 0% to 25%, 87% in those with a TDR of 26% to 50%, 97% in those with a TDR of 51% to 75%, and 100% in those with a TDR of 76% to 100%. The incidence of lymphatic, vascular invasion, and nodal metastases was lower in patients with a higher TDR. Conclusions Small-sized adenocarcinomas with a higher TDR showed less lymphatic, vascular vessel invasion, or nodal involvement, and demonstrated longer survival, suggesting that TDR was associated with clinical-pathologic characteristics and tumor aggressiveness. Preoperative assessment of TDR may be useful to identify an appropriate candidate for a lesser pulmonary resection.

Prognostic impact of tissue inhibitor of matrix metalloproteinase-1 in esophageal carcinoma

Tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the activity of matrix metalloproteinase, which may play an important role in carcinoma invasion and metastasis. TIMP-1 is thus considered to inhibit carcinoma invasion and metastasis. However, TIMP-1 possesses another important function, cell growth promotion. The clinical significance of TIMP-1 expression has not been fully determined in esophageal carcinoma. We thus examined the expression of TIMP-1 mRNA in tumor (T) and corresponding normal (N) tissues of 85 esophageal carcinoma cases by RT-PCR. The T:N ratio of TIMP-1 mRNA expression in each case was evaluated semi-quantitatively with adjustment by an internal control gene. The mean T:N ratio was 2.0 (range 0.2-6.5). When comparing high-expression cases (T:N > 2.0, n = 37) with low-expression cases (T:N < or = 2.0, n = 48), the former showed a significantly higher frequency of lymph vessel invasion, vascular vessel invasion, lymph node metastasis and advanced-stage disease. The former cases showed a poorer prognosis than the latter. Multivariate analysis disclosed that TIMP-1 expression status was an independent determining factor for prognosis. Our findings suggest that TIMP-1 expression correlates with tumor extension of esophageal carcinoma and might, if validated, prove useful as a novel prognostic marker for esophageal carcinoma.

Expression of ornithine decarboxylase mRNA in gastric carcinoma

BACKGROUND Ornithine decarboxylase (ODC) is a key rate-limiting enzyme in polyamine biosynthesis. Several studies using an enzyme assay revealed that the ODC activity was higher in tumor tissue than in normal tissue. However, there is little information on the mRNA status of ODC in surgical specimens. ODC is a transcriptional target gene of c-myc. METHODS cDNA was obtained by reverse transcription (RT) from fresh specimens of 56 surgical pairs of primary gastric carcinomas and corresponding normal tissue specimens. The ODC and c-myc mRNAs were subsequently detected by means of the polymerase chain reaction. The tumor/normal (T/N) ratio of ODC expression was calculated after correcting for glyceraldehyde-3-phosphate dehydrogenase as an internal control. The T/N ratio of ODC was plotted against that of c-myc. RESULTS The corrected expression levels of ODC mRNA in the tumor were greater than those of the normal mucosa in 36 of 56 cases (64%). The cases of tumor with vascular vessel invasion showed a higher T/N ratio than those without vascular invasion (P < 0.01). Similarly, female patients showed a higher T/N ratio than male patients (P < 0.01). There was a significant correlation between the expressions of both ODC and c-myc genes (P < 0.05). CONCLUSIONS The findings imply that (1) overexpression of ODC mRNA in tumor tissue may correlate with aggressive biologic behavior, such as vascular vessel invasion, and (2) there is an intimate correlation between ODC and c-myc genes. Cancer 1996;77:1634-8.

Expression of ornithine decarboxylase mRNA in gastric carcinoma

Ornithine decarboxylase (ODC) is a key rate-limiting enzyme in polyamine biosynthesis. Several studies using an enzyme assay revealed that the ODC activity was higher in tumor tissue than in normal tissue. However, there is little information on the mRNA status of ODC in surgical specimens. ODC is a transcriptional target gene of c-myc. cDNA was obtained by reverse transcription (RT) from fresh specimens of 56 surgical pairs of primary gastric carcinomas and corresponding normal tissue specimens. The ODC and c-myc mRNAs were subsequently detected by means of the polymerase chain reaction. The tumor/normal (T/N) ratio of ODC expression was calculated after correcting for glyceraldehyde-3-phosphate dehydrogenase as an internal control. The T/N ratio of ODC was plotted against that of c-myc. The corrected expression levels of ODC mRNA in the tumor were greater than those of the normal mucosa in 36 of 56 cases (64%). The cases of tumor with vascular vessel invasion showed a higher T/N ratio than those without vascular invasion (P < 0.01). Similarly, female patients showed a higher T/N ratio than male patients (P < 0.01). There was a significant correlation between the expressions of both ODC and c-myc genes (P < 0.05). The findings imply that (1) overexpression of ODC mRNA in tumor tissue may correlate with aggressive biologic behavior, such as vascular vessel invasion, and (2) there is an intimate correlation between ODC and c-myc genes.

Macroscopic intraoperative diagnosis of serosal invasion and clinical outcome of gastric cancer: risk of underestimation.

Data on 715 Japanese patients with gastric cancer were studied retrospectively with regard to the relationship between macroscopic and microscopic diagnoses of serosal invasion and clinicopathological factors affecting the accuracy of the macroscopic diagnosis. Although there was no macroscopic evidence of serosal invasion intraoperatively (S0 or S1), there was histological evidence of cancer cells on the serosal surface in 69 patients (9.7%). In these serosal invasion-positive cases, the tumors were larger; were located more commonly in the upper third, lesser and greater curvatures of the stomach; were Borrmann type 3 or type 4 tumors, and of an undifferentiated histologic type with an infiltrative growth pattern more commonly, and had more extensive lymphatic and vascular vessel invasion and lymph node metastasis (P < 0.01). Total gastrectomy was done more often for the serosal invasion-positive group, but the extent of lymph node dissection was comparable. Cases of a noncurative resection because of a positive surgical margin were more frequent in the serosal invasion-positive group (8/69 vs. 14/646, P < 0.01), and most had undifferentiated and infiltrative cancers. The 10-year survival rates were 49.2% and 85.5% for patients with and without serosa invasion, respectively. These findings clearly show that the serosal surface, especially in cases of the undifferentiated or infiltrative type of gastric cancer, must be closely inspected intraoperatively.

内視鏡的ポリペクトミー6年6カ月後に局所再発をきたした大腸粘膜下浸潤癌の1例

The patient was a 53-year-old woman. She received colonoscopic polypectomy 6.5 years ago for sigmoid colon polyp. The resected specimen revealed well differentiated adenocarcinoma invading massively into the submucosal layer with vascular vessel invasion. She was recommended for an additional surgical resection but she refused. She was followed up by barium enema and colonoscopy and serum CEA. No evidence of recurrence was detected until 6.5 years after the polypectomy, when she had bloody stool and barium enema revealed submucosal tumor-like protrusion with depression at the site of the previous lesion. Resection of the sigmoid colon was carried out successfully, and no lymph node metastasis was observed. The tumor was well differentiated adenocarcinoma invading to the serosal surface, mainly located in the submucosal layer, suggesting local recurrence of the tumor. This is the case having the longest period of local recurrence after polypectomy, by the review of the Japanese literature. The authors suggest that long term follow up would be necessary after polypectomy of colonic carcinoma invading into submucosal layer.

P53 nuclear overexpression: an independent predictor of survival in lymph node--positive colorectal cancer patients.

This study was performed to determine the prognostic significance of p53 gene overexpression in a homogeneous group of node-positive colorectal cancer patients. Paraffin sections from the primary tumors in 107 colorectal cancer patients who had preoperative serum carcinoembryonic antigen (CEA) levels less than five were examined for the expression of p53 nuclear protein by immunohistochemical staining using the monoclonal antibody PAb 1801. The nuclear p53 overexpression was compared with clinicopathologic variables and follow-up data. Positive staining was not observed in normal colorectal mucosal cells. Specific p53 nuclear staining was detected in primary tumor from 50 patients (46.7%). p53 nuclear overexpression was not significantly correlated with patients' sex, age, tumor location, differentiation, T stage, N stage, and lymphatic and/or vascular vessel invasion. With a median follow-up of 61.7 months, 60% of the p53-positive patients have had disease recurrence, versus only 35% of the p53-negative group (P = .02). Forty-two percent of the p53-positive patients died of colorectal cancer compared with 21.1% of the p53-negative patients (P = .03). By multivariate analysis, p53 overexpression was found to be an independent predictor for disease-free and disease-specific survival. In node-positive colorectal cancer patients with low preoperative CEA levels, nuclear p53 overexpression as determined by immunohistochemistry on archived tissue is an independent predictor for prognosis.