Biological correlates of FDG uptake in non-small cell lung cancer

PURPOSE: Each pathological stage of non-small cell lung cancer (NSCLC) consists of a heterogeneous population containing patients at much higher risk than others. Noninvasive functional imaging modalities, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), could play a role in further characterization of NSCLCs. As many factors can influence the extent of FDG uptake, the underlying mechanisms for FDG accumulation in tumors, are still a matter of debate. The aim of the present study was to investigate these possible mechanisms in the primary site of early stage preoperatively untreated NSCLC. METHODS: 19 patients with early stage NSCLC, who had undergone both preoperative FDG-PET imaging and curative surgery, were enrolled in this study. Standardized uptake values (SUVs) were used for evaluation of primary tumor FDG uptake. Final diagnosis, tumor type, tumor cell differentiation and size of the primary tumors were confirmed histopathologically in resected specimens. Histologic sections were analyzed for amount of inflammation and necrosis. Expression of the glucose membrane transporters (GLUT-1 and GLUT-3); the isoforms of the glycolytic enzyme hexokinase (HK-I, HK-II and HK-III); and the cysteine protease caspase-3, was evaluated immunohistochemically. RESULTS: FDG uptake was significantly higher in squamous cell carcinomas (mean SUV 13.4+/-4.9, n=8) compared to adenocarcinomas (7.1+/-3.3, n=8, p=0.007), or large cell carcinomas (5.9+/-1.9, n=3, p=0.02). The degree of FDG accumulation seemed to depend especially on GLUT-1, GLUT-3 and tumor cell differentiation. The summed standardized values of these three parameters correlated significantly with the SUV (r=0.47, p=0.05). CONCLUSION: The present study supports the hypothesis that tumor cell differentiation in combination with overexpression of GLUT-1 and GLUT-3 determine the extent of FDG accumulation and that squamous cell carcinomas accumulate more FDG than adenocarcinomas or large cell carcinomas.     

Correlation between FDG uptake and glucose transporter type 1 expression in neuroendocrine tumors of the lung

Neuroendocrine (NE) lung tumors are subdivided into the following types; typical (TC) and atypical carcinoids (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). Moreover, the determinants of the FDG uptakes of NE lung tumors have not been elucidated. Thus, the aim of the present study was to investigate the relationships between FDG uptake and glucose transporter type 1 (Glut-1) expression in these NE tumors. Tissue-proven NE lung tumor patients (n=32; age, mean+/-S.D.=67.8+/-10 years; male:female=28:4) who had undergone F-18 FDG-PET before treatment were enrolled in this study. There were 1 TC, 3 AC, 5 LCNEC, and 23 SCLC patients. FDG uptakes were quantified using maximum standardized uptake values (maxSUV). Paraffin sections of tumor tissues were immunostained using anti-Glut-1 antibody (Neomarkers, 1:50). Levels of Glut-1 expression are presented as percentages of tumor cells positively immunostained (%Glut-1). Relations between FDG uptakes and Glut-1 expression were assessed using Pearson correlation analysis. The maxSUVs of all NE lung tumors ranged from 0.6 to 29.5 (mean+/-S.D.=7.7+/-5.4) and %Glut-1 expression ranged from 0 to 100% (18+/-24%). The maxSUVs of all NE lung tumors were found to be significantly correlated with %Glut-1 expression (r=0.6471, p=0.0001). By subgroup analysis, maxSUV was also found to be significantly correlated with %Glut-1 expression in SCLC (n=23, r=0.6189, p=0.0016). FDG uptake was found to be highly correlated with Glut-1 expression in NE lung tumors. This result suggests that Glut-1 plays a crucial role in determining FDG uptake in these tumors.     

Expression of p16INK4a and MIB-1 in relation to histopathology and HPV types in cervical adenocarcinoma

A total of 101 primary cervical adenocarcinomas were analyzed for the presence of p16INK4a and MIB-1 expression in correlation with the presence of 'high-risk' types of human papillomavirus (HR-HPV) and clinical outcome.We found that adenocarcinoma grading showed a significant negative correlation to p16INK4a levels (p=0.001): i.e. we found less intense p16 staining in poorly differentiated tumors than in more highly differentiated tumors as well as a highly significant correlation between HPV infection and higher levels of p16INK4a staining (p=0.00), which was similar for different HPV-types. Tumor suppressor protein p16INK4a levels were higher in HPV positive than in HPV negative tumors. Higher levels of the proliferation marker MIB-1 were associated with poorer outcome. Higher MIB-1 levels were seen in tumors with a lower grade and higher stage at diagnosis. Moreover, MIB-1 levels seem to be higher in tumors due to infection with HPV 16 and 18 compared with HPV 45. MIB-1 may be a helpful marker in grading adenocarcinoma: a high level of expression of MIB-1 indicates a low grade of tumor, whereas high expression of p16INK4a indicates a highly differentiated of the tumor. Thus, immunostaining for p16INK4a appears to be a useful diagnostic tool for cervical adenocarcinoma.     

(F-18) fluorodeoxyglucose positron emission tomography as a predictor of pathologic grade and other prognostic variables in bone and soft tissue sarcoma.

Positron emission tomography (PET) can be used to measure tumor metabolism in sarcomas by measuring the standard uptake value (SUV) of (F-18) fluorodeoxyglucose (FDG). FDG-PET SUV has been shown to correlate with histological grade. We compared FDG-PET SUV in 89 bone and soft tissue sarcomas with histopathological features, including tumor grade, as well as with markers of cell proliferation and cell cycle regulatory gene expression that may be prognostically or therapeutically important. All patients had undergone PET before biopsy. Features evaluated included grade (National Cancer Institute for soft tissue or Mayo Clinic for bone), cellularity, and the number of mitoses per 10 400x fields. Deparaffinized, formalin-fixed sections were immunostained with antibodies to Ki-67 (MIB-1), p53 (DO7), p21WAF1 (EA10), and mdm-2 (1B10). For Ki-67, results were estimated as a percentage of positive cells. For p53 and mdm-2, only cases with >20% positive cells were considered to be overexpressing these proteins. For p21WAF1, only cases with <10% positive cells were considered to have lost normal p21WAF1 expression. Tumor S-phase percentage and ploidy were determined by flow cytometry. FDG-PET SUV was associated with histopathological grade, cellularity, mitotic activity, MIB labeling index, and p53 overexpression. No association was seen with p21WAF1, mdm-2, S-phase fraction, or ploidy. Tumor metabolism data acquired by FDG-PET may help ensure accurate grading and prognostication in sarcoma by guiding biopsy toward the most biologically significant regions of large masses. Further follow-up will be necessary to determine whether FDG-PET provides independent prognostic information.     

Immunohistochemical study of fatty acid synthase in ovarian neoplasms

In order to evaluate the prognostic significance of fatty acid synthase (FAS), the key enzyme in fatty acid biosynthesis, in ovarian benign and malignant tumors 98 patients with ovarian masses were immunohistochemically evaluated. Histologic features of the lesions and expression for FAS were statistically associated with clinical data and disease-free survival over a 5-year follow-up period. The mean age of patients was 65 years. TNM surgical stages were I in 31.8%, II in 28.2% and III in 40% of cases. The 5-year disease-free survival of the 85 malignant common epithelial ovarian tumors was 47.1% while 35.3 of patients died with active disease. Seventy-eight (79.6%) out of 98 cases expressed FAS in the neoplastic epithelial cells and 42 (42.9%) in the non-neoplastic stromal cells. Statistical analysis revealed FAS expression and stage of the disease to be significantly correlated to recurrence and survival rates only in the malignant common epithelial tumors. Moreover, multivariate analysis showed FAS expression (p=0.05) and tumor stage (p=0.03) to be independent prognostic predictors. FAS is a reliable predictor of recurrence and disease-free survival in common epithelial ovarian tumors along with neoplastic stage. Clinical data, other histologic subtypes and grading were not statistically significant.     

Clinical characteristics of meningiomas assessed by 11C-methionine and 18F-fluorodeoxyglucose positron-emission tomography

The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including (11)C-methionine and (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on (11)C-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and (11)C-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, (11)C-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of (11)C-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of (11)C-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of (11)C-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P < 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that (11)C-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.     

Correlation of 18-F-fluorodeoxyglucose (FDG) accumulation with glucose transporter (Glut-1) expression in esophageal squamous cell carcinoma

BACKGROUND: We previously reported that positron emission tomography (PET) with 18-F-fluorodeoxyglucose (FDG) might be a useful tool for evaluating the stage of esophageal squamous cell carcinoma (SCC), and that FDG-PET shows greater accuracy in the diagnosis of lymph node metastasis than computed tomography. Further, we elucidated the relationships among FDG-PET performance, glucose transporter (Glut)-1 expression and serum levels of the tumor markers carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA) and squamous cell carcinoma antigen (SCC-Ag) in esophageal SCC. PATIENTS AND METHODS: We studied 44 patients with thoracic esophageal SCC who had undergone radical esophagectomy. Immunohistochemical analysis was used to detect the expression of Glut-1 in resected specimens and FDG accumulation was assessed by FDG-PET scan. RESULTS: FDG uptake in the primary tumor was found in 34 out of 44 (77.3%) patients. No significant correlation was observed between SUVs and the tumor markers CEA, CYFRA and SCC-Ag. The survival rate in patients with high FDG uptake (SUV > 3) was significantly lower than in cases with low FDG uptake (SUV < 3) (p < 0.01). A significant correlation was observed between SUV and Glut-1 expression (p < 0.05). The prognosis in patients with both low Glut-1 expression and low FDG uptake tended to be more favorable than in patients with high Glut-1 expression and/or high FDG uptake. CONCLUSION: Glut-1 expression was related to FDG uptake, and assessment of both FDG uptake and Glut-1 expression might be useful for providing prognostic information in patients with esophageal SCC.     

Prognostic significance of grading and staging systems using MIB-1 score in adult patients with soft tissue sarcoma of the extremities and trunk

BACKGROUND: The predictive value of histologic grading and staging systems for overall survival in different types of adult soft tissue sarcoma of the extremities and trunk is unclear. METHODS: Histologic slides from 193 patients with primary tumors were reviewed for diagnosis, and Ki-67 (MIB-1) immunostaining was performed for grading in all patients. Univariate and multivariate analyses were conducted to analyze the results from patients with soft tissue sarcomas as a group and among the six main histologic categories: malignant fibrous histiocytoma (n = 49 patients), liposarcoma (n = 48 patients), synovial sarcoma (n = 30 patients), spindle cell sarcoma (n = 24 patients), small round cell sarcoma (n = 15 patients), and others (n = 27 patients). The median follow-up was 50 months. RESULTS: Univariate analysis of soft tissue sarcomas showed that tumor size and depth, histologic type, MIB-1 score, grades based on three criteria (tumor differentiation/histologic type, necrosis, and either mitosis or MIB-1 score) and disease stage, as assessed by tumor size, depth, and grade, were associated with overall survival. Among these variables, grading and staging systems using the MIB-1 score had better predictive value compared with the MIB-1 score and standard grading and staging models in the main histologic categories. Because survival curves for the different tumor grades and stages showed similar trends between the different histologic types, multivariate analysis was conducted adjusting for age, gender, disease site, surgical margin, tumor size and depth, grade, stage, and histologic type. Consequently, Grade 3 emerged as the most significant adverse prognostic factor. Additional adverse prognostic factors were Stage III, Grade 2, a histologic type of spindle cell sarcoma, and patient age > 50 years at the time of presentation. The histologic type liposarcoma was identified as a favorable prognostic factor. CONCLUSIONS: The current results indicate that grading and staging systems using the MIB-1 score are very strong prognostic factors in patients with the main histologic types of soft tissue sarcoma. Specific assessment of histologic type should be carried out before deciding on treatment strategies.     

葡萄糖转运蛋白1在卵巢浆液性肿瘤中的表达及其意义

目的探讨葡萄糖转运蛋白1（GLUT-1）在卵巢浆液性肿瘤中的表达及其意义。方法收集100例卵巢浆液性肿瘤患者手术标本,采用多克隆抗体的GLUT-1免疫组织化学SP法进行染色,分析其异常表达与肿瘤临床分期及分型之间的相关性。结果正常组织中GLUT-1表达为阴性,GLUT-1在良性、交界性、恶性卵巢浆液性肿瘤中的表达呈增高趋势（P〈0．001）,GLUT-1的表达与卵巢浆液性囊腺癌临床分期呈正相关（P〈0．001）。结论GLUT-1的过度表达与卵巢浆液性肿瘤的组织学和分期相关。GLUT-1有望成为检测卵巢浆液性肿瘤恶变的标志物。     

Prognostic markers in chondrosarcoma: evaluation of cell proliferation and of regulators of the cell cycle

Purpose. The prognosis, treatment principles and prediction of clinical outcome of patients with chondrosarcoma currently rest on histologic grading which is somewhat ambiguous due to difficulty in pathologic interpretation of this neoplasm. Immunohistochemistry, flow cytometry and oncogene/tumor suppressor gene expression have been examined as alternative indices to predict the biologic behavior of these tumors. Because of partial successes obtained with flow cytometry and because of the improvement in predicting recurrence offered by examining the S-phase fraction, we undertook the current study to determine if expression of specific regulators of the cell cycle would act as prognostic indicators for these patients.Subjects/methods. We examined archival pathologic specimens from 39 patients with at least 2 years' clinical follow-up for the presence of p53, Rb, src and MIB-1 by immunohistochemistry and correlated this with clinical histories and incidence of recurrence.Results. While Rb, p53 and src gene products were identified to a variable extent in these specimens, there was no prognostic significance to their expression. In contrast, MIB-1, an epitope expressed only during semiconservative replication and an accepted marker of cell proliferation, served as a significant prognostic indicator. MIB-1 staining was present in 14.5% of tumor cells in all specimens (range 0-59%). When MIB-1 staining was examined with respect to disease recurrence, there was a statistically significant association between staining and histologic grade (p < 0.05) as well as event-free survival (p < 0.02). Comparing survival curves stratified by MIB-1 expression, there was a significant decrease in event-free survival associated with increasing MIB-1 indices (p < 0.003). Covariates that were associated with event-free survival include histologic grade (p = 0.025) and stage (Musculoskeletal Tumor Society) (p = 0.014). There was no statistical association with patient age (p = 0.15), tumor size (p = 0.47), tumor histology (p = 0.62) or anatomic location (p = 0.316).Discussion. These results indicate that determination of the proliferation index by MIB-1 immunostaining may serve as a useful adjunct to current histopathologic classification. Patients with a high proliferation index may benefit from established adjuvant therapies or experimental approaches including immunotherapy or biologic modulation.     

FDG uptake and glucose transporter type 1 expression in lymph nodes of non-small cell lung cancer.

AIMS: FDG uptake in NSCLC is related to glucose transporter type 1 (Glut-1) expression. Here, we investigated the direct causal relationship between FDG uptake and Glut-1 expression to determine the role of Glut-1 in FDG uptake by malignant and benign lymph nodes (LNs). METHODS: Fifty-five curative lung resections in 53 NSCLC patients (male:female=36:17, age=62.0+/-11.8 years) were included. Maximum standardized uptake values (maxSUVs) of LNs in preoperative whole body FDG-PET and Glut-1 immunostaining results were compared. RESULTS: Of 316 pathologically confirmed LNs, 12.3% (39/316) were malignant, and in malignant LNs, FDG positive LNs were no different from FDG negative LNs in terms of size (15.0+/-6.7 mm vs 10.0+/-6.1mm, p>0.05), or in terms of the proportion of LNs occupied by tumor (60.0+/-28.8% vs 39.2+/-38.4%, p>0.05), but had greater percentages of Glut-1 positive cells in tumors (74.1+/-31.8% vs 22.7+/-18.7%, p<0.01), and Glut-1 staining intensities (3.4+/-0.9 vs 1.8+/-1.3, p<0.01). FDG negative malignant LNs featured cytoplasmic Glut-1 expression and adenocarcinoma. Glut-1 staining intensities were found to be significantly correlated with the maxSUVs of malignant LNs (rho=0.516, p<0.05), but the percentages of Glut-1 positive cells in tumors were not (r=0.2072, p>0.05). Analysis of FDG positive benign LNs showed that maxSUV was not correlated with degree of follicular hyperplasia, or Glut-1 expression (p>0.05). CONCLUSIONS: Intense Glut-1 immunoreactivity was found to be proportionally related to the degree of FDG uptake by malignant LNs in NSCLC. However, the finding that Glut-1 expression in lymphoid hyperplasia showed no correlation with FDG uptake in benign LNs requires further investigation.     

Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: a study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion.

PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.     

P21WAF1/CIP1在卵巢上皮性肿瘤中的表达与临床意义的研究

目的 :探讨P2 1WAF1/CIP1在恶性卵巢上皮性肿瘤中的表达与临床意义。方法 :应用免疫组化S P检测P2 1WAF1/CIP1在 2 0例良性、10例交界性、5 5例恶性卵巢上皮性肿瘤中的表达 ,并分析P2 1WAF1/CIP1与恶性卵巢上皮性肿瘤临床病理指标的关系。结果 :P2 1WAF1/CIP1在良性、交界性与恶性卵巢上皮性肿瘤中的表达总阳性率及强阳性率均有显著性差异 (P =0 0 0 7,P强 =0 0 0 1) ,并随良性、交界性、恶性而降低表达 (P <0 0 1,P强 <0 0 0 1) ;与恶性卵巢上皮性肿瘤的临床分期、组织分化、淋巴转移、腹水及预后均有关 (P =0 0 11,0 0 0 0 ,0 0 14 ,0 0 11;P强 =0 0 37,0 0 0 3,0 0 16 ,0 0 0 2 ,P <0 0 5 )。结论 :P2 1WAF1/CIP1在恶性卵巢上皮性肿瘤的形成和发展中发挥重要作用 ,检测P2 1WAF1/CIP1蛋白表达情况对卵巢肿瘤的良恶性鉴别 ,判断预后 ,探索卵巢癌的发生过程 ,从而指导卵巢癌的基因治疗均有积极的意义。     

GLUT-1和DNA-PKcs在卵巢浆液性肿瘤组织中的表达及其意义

背景与目的:已知肿瘤细胞生长所需能量是通过葡萄糖转运体蛋白1(glucose transporter protein 1,GLUT-1)完成的葡萄糖代谢来提供的.另外,参与基因损伤修复的催化亚单位--DNA蛋白激酶(DNA-dependent protein kinase catalytic subunit,DNA-PKcs)在肿瘤形成中也起着非常重要的作用.本研究旨在探讨GLUT-1和DNA-PKcs在卵巢浆液性肿瘤组织中的表达及其与肿瘤生物学行为的关系和意义.方法:免疫组化方法检测80例卵巢浆液性肿瘤组织中GLUT-1、DNA-PKcs的表达,分析其异常表达与临床病理参数之间的相关性.以正常卵巢组织20例为对照.结果:正常卵巢组织GLUT-1表达全阴性,DNA-PKcs表达全阳性.GLUT-1在良性、交界性、恶性卵巢浆液性肿瘤中的表达呈增高的趋势,与卵巢浆液性肿瘤的发生发展呈正相关(rs=0.943,P＜0.01);在恶性肿瘤中的阳性率(100%)明显高于交界性(55%).DNA-PKcs在良性、交界性和恶性卵巢浆液性肿瘤中的阳性率分别为95%、90%、60%,差异有统计学意义(P＜0.01).GLUT-1与DNA-PKcs的表达呈负相关(rs=-0.270,P＜0.01).GLUT-1表达与临床分期、腹腔种植、腹水、淋巴结转移均相关(P＜0.05);DNA-PKcs仅与临床分期和淋巴结转移相关(P＜0.05),与腹水、腹腔种植无关(P＞0.05).结论:GLUT-1的异常表达和DNA-PKcs的丢失与卵巢浆液性肿瘤恶变相关.     

GLUT-1 expression in ovarian carcinoma: association with survival and response to chemotherapy

BACKGROUND: Cancer cell growth is an energy-related process supported by an increased glucose metabolism. The objective of this study was to investigate the association of GLUT-1 with response to chemotherapy and outcome in patients with ovarian carcinoma. METHODS: Histologic sections of formalin fixed, paraffin embedded specimens from 113 primary ovarian carcinomas were stained for GLUT-1 by using polyclonal GLUT-1 antibody (Dako Co., Carpinteria, CA) and the labeled streptavidin biotin procedure. Intensity of GLUT-1 staining was compared with disease free survival (DFS), chemotherapy response, and other clinicopathologic characteristics. RESULTS: GLUT-1 cytoplasmic membrane staining was observed in 89 of 104 (85.6%) malignant tumors. Poorly differentiated tumors showed a trend to overexpress the GLUT-1 protein compared with the more differentiated counterparts (27.6% vs. 8.7%; P = 0.08). Patients who experienced a complete clinical response to chemotherapy were more frequently GLUT-1 positive than GLUT-1 negative (80% vs. 51.5%; P = 0.036). In multivariate analysis of advanced stage disease, residual tumor (P = 0.0001) and high GLUT-1 expression levels (P = 0.028) were the only independent variables that maintained a significant association with response to chemotherapy (P = 0.0001; chi-square = 38.13). In the subgroup of Stage III-IV (International Federation of Gynecology and Obstetrics patients showing a complete clinical response, GLUT-1 overexpression was associated with a shorter DFS. The median time to progression was 30 months in GLUT-1 strongly positive cases (> 50% of cancer cells positive) versus 60 months in GLUT-1 weakly positive cases (< or = 50% of cancer cells positive; P = 0.024). CONCLUSIONS: GLUT-1 status is an independent prognostic factor of response to chemotherapy in advanced stage ovarian carcinoma. Moreover, patients overexpressing GLUT-1 show a significantly shorter DFS. These results suggest that the assessment of GLUT-1 status may provide clinically useful prognostic information in patients with ovarian carcinoma.     

Analysis of immunohistochemical expression of p53 and the proliferation marker Ki-67 antigen in skull base chordomas: relationships between their expression and prognosis

The prognosis of chordomas is difficult to predict based solely on histological findings. The purpose of this study was to assess the immunohistochemical expression of the proliferation marker Ki-67 antigen and the expression of p53 in skull base chordomas and to relate their expressions to the outcome. We examined the expression of p53 and the MIB-1 labeling index (LI), assessed by Ki-67 expression, in 19 tumors (initial, n = 11; recurrent, n = 8) from 11 patients. The correlation among the MIB-1 LI, p53 expression, and the clinical outcome was analyzed. The mean MIB-1 LI and p53 expression at the initial surgery were 5.6 ± 4.6% and 9.0 ± 9.4%, respectively. At the time of recurrence, the mean MIB-1 LI and p53 expression were 10.2 ± 7.4% and 16.5 ± 12.0%. The correlation between the MIB-1 LI and p53 expression at the initial and recurrent surgeries was highly significant (r = 0.948; P < 0.0001). The change in p53 expression from the initial to the recurrent chordomas was significantly greater in patients who died of tumor-related causes than in the surviving patients. In the surviving patients, the values for MIB-1 LI and p53 expression in the recurrent tumors were significantly higher in the disease-ongoing group than in the disease-free group. Our results suggest that determination of the immunohistochemical expression of p53 and Ki-67 antigen is helpful to predict tumor recurrence and prognosis in skull base chordomas.     

Prognostic significance of matrix metalloproteinase-7 in epithelial ovarian cancer and its relation to beta-catenin expression

We investigated the expression and prognostic significance of matrix metalloproteinase (MMP) -7, its relation to beta-catenin expression and clinicopathological factors in epithelial ovarian cancer. The expression of MMP-7 was analyzed immunohistochemically in a series of 284 primary epithelial ovarian cancers, their 36 metastases and 8 normal ovaries. In cancers with endometrioid histology, a high percentage area of MMP-7 expression and an intense MMP-7 signal was significantly associated with nuclear positivity of beta-catenin in cancer cells (p = 0.003, chi2 = 8.853 and p = 0.030, chi2 = 4.713, respectively). In all tumors and nonendometrioid subgroup, a low percentage area of MMP-7 positive tumor cells was significantly correlated with a high histological grade of the tumor (p = 0.003 and 0.005, respectively), in all tumors also with advanced stage of the tumor (p = 0.002) and large primary residual tumor (p = 0.005). A 10-year disease-related survival (DRS) was significantly better when the percentage area of MMP-7 expression in cancer cells was high, when compared to low (p = 0.0008). A high percentage area of intense MMP-7 signal in cancer cells predicted a significantly more favorable DRS and recurrence-free survival (RFS) (p = 0.0003 and 0.0052, respectively). In multivariate analysis, a high percentage area of intense MMP-7 signal in tumor cells was an independent prognostic factor, predicting favorable DRS and RFS. The present study showed that intense MMP-7 signal in tumor cells is an independent prognostic factor predicting better survival in epithelial ovarian cancer.     

Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma

BACKGROUND: Proliferative activity in tumors depends on regulation of the cell cycle. p27(Kip1) (p27) plays a pivotal role as a negative regulator of the cell cycle. A decrease in p27 expression has been reported in many kinds of tumors, but little is known regarding p27 in patients with renal cell carcinoma (RCC). METHODS: Expression of p27 and the related cyclins (cyclin A, cyclin E, and cyclin D1) was examined immunohistochemically in 67 patients with of clear cell RCC. The Ki-67 labeling index (MIB-1 LI) and clinicopathologic parameters related to a poor prognosis also were analyzed. To determine their prognostic significance, univariate and multivariate survival analyses were performed. RESULTS: In tumors, there was considerable immunoreactivity for cyclin A, cyclin D1, and MIB-1, and the mean values for each were 1.08%, 16.1%, and 1.5%, respectively. Cyclin E expression was rare. The expression of p27 was correlated strongly with the expression of cyclin A (correlation coefficient, 0.432; P < 0.0004) and cyclin D1 (correlation coefficient, 0.476; P < 0.0004). Also, an inverse correlation was present between p27 expression and tumor size (P = 0.0377). In univariate analysis, the unfavorable prognostic factors were high TNM stage (P < 0.0001), large tumor size (P = 0.0016), high histologic grade (P = 0.0104), and low p27 expression (P < 0.0001). In multivariate analysis, high TNM stage (P = 0.0035) and low p27 expression (P = 0.0235) were independent prognostic factors for disease specific survival in patients with RCC. CONCLUSIONS: The results of this study suggest that low p27 expression may be a significant and independent, unfavorable prognostic factor in patients with renal cell carcinoma.     

Prognostic relevance of p53 protein expression in glioblastoma

TP53 plays a key role in cellular response to DNA-damaging agents, and mutation of this gene, which is associated with immunohistochemically detectable p53 protein accumulation, may influence response to chemo- and radiotherapy. We investigated immunohistochemically the influence of p53 protein accumulation in 114 consecutive cases of primary glioblastoma treated by surgery and adjuvant radio- and chemotherapy. In addition, we determined cellular proliferation index using the antibody MIB-1 and apoptotic index of tumor cells using the TUNEL-assay. Twenty-nine patients (25.4%) were considered as positive with regard to p53 protein expression (>50% p53 immunostained tumor cells). Patients with p53 positive glioblastomas were significantly younger (mean age 54.4+/-2 years) than those with p53 negative tumors (mean age 61.4+/-1.1 years) (p=0.002, Mann-Whitney test). While no significant difference in apoptotic index was found, we observed a significantly higher MIB-1 labeling index (LI) in patients with p53 positive tumors (median LI: 36.4%) compared to p53 negative ones (median LI: 23.8%) (p=0.005, Mann-Whitney test). p53 protein expression was associated with significantly longer survival in univariate analysis (p=0.0399, log-rank test). In multivariate analysis of overall survival (Cox regression) only postoperative Karnofsky performance status remained as independent prognostic factor. We conclude that glioblastoma patients with immunohistochemically detectable p53 protein expression, who received adjuvant radio- and chemotherapy, have a significantly better overall survival, possibly due to increased sensitivity to this adjuvant treatment.     

F-18]Fluorodeoxyglucose positron emission tomography can predict pathological tumor stage and proliferative activity determined by Ki-67 in clinical stage IA lung adenocarcinomas

OBJECTIVE: To predict a malignant grade of lung cancer by fluorodeoxyglucose positron emission tomography (FDG-PET) scanning, we investigated the correlation between FDG uptake and pathological tumor stage, proliferative activities determined by Ki-67 and cyclin D1, and an alteration of p53, in clinical stage (c-stage) IA lung adenocarcinomas. METHODS: FDG-PET was performed for 71 patients with c-stage IA lung adenocarcinomas. FDG uptake was measured by a contrast ratio (CR) between the tumor and contralateral lung. Ki-67, cyclin D1 and p53 staining scores were examined by immunohistochemistry. RESULTS: The lesions with ground-glass opacity were found in 26 patients, and solid lesions in 45 by computed tomography. The pathological tumor stages (p-stage) were stage IA in 59 and more advanced stages in 12. The latter had significantly higher CR value than the former (P < 0.001). Patients with CR > or = 0.55 could be predicted to be at advanced tumor stages, with a sensitivity of 0.83 and a specificity of 0.82. The CR and staining scores of Ki-67 were significantly correlated with each other (P < 0.0001), and both the values were significantly higher in advanced tumor stages than in p-stage IA, and were also significantly higher in tumors with intratumoral lymphatic, vascular and pleural involvements than in those without such features (P < 0.05-0.0001). CONCLUSIONS: In c-stage IA lung adenocarcinomas, the FDG uptake can predict p-stage and tumor proliferative activity determined by Ki-67. For c-stage IA lung adenocarcinomas showing CR > or = 0.55, mediastinoscopy or neoadjuvant chemotherapy is indicated.