Enhanced response of human head and neck cancer xenograft tumors to cisplatin combined with 2-deoxy-D-glucose correlates with increased 18F-FDG uptake as determined by PET imaging

PURPOSE: To determine whether the response of human head and neck cancer xenografts to cisplatin (CIS) could be enhanced with 2-deoxy-D-glucose (2DG); whether 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) uptake correlated with responses to this drug combination; and whether 2DG would enhance CIS-induced radiosensitization. METHODS AND MATERIALS: Clonogenic survival responses to CIS + 2DG were determined in FaDu and Cal-27 cells and reduced/oxidized glutathione levels were monitored as parameters indicative of oxidative stress. The efficacy of CIS + 2DG was determined in FaDu and Cal-27 xenografts, and FDG uptake was determined by using positron emission tomography. RESULTS: Use of CIS + 2DG enhanced cell killing of FaDu and Cal-27 cells compared with either drug alone while increasing the percentage of oxidized glutathione in vitro. Use of CIS + 2DG inhibited FaDu and Cal-27 tumor growth and increased disease-free survival compared with either drug alone. The Cal-27 tumors showed greater pretreatment FDG uptake and increased disease-free survival when treated with 2DG + CIS relative to FaDu tumors. Treatment with 2DG enhanced CIS-induced radiosensitization in FaDu tumor cells grown in vitro and in vivo and resulted in apparent cures in 50% of tumors. CONCLUSIONS: These results show the enhanced therapeutic efficacy of CIS + 2DG in human head and neck cancer cells in vitro and in vivo compared with either drug alone, as well as the potential for FDG uptake to predict tumor sensitivity to 2DG + CIS. These findings provide a strong rationale for evaluating 2DG + CIS in combined-modality head and neck cancer therapy with radiation in a clinical setting.     

Deoxyglucose uptake by a head and neck squamous carcinoma: influence of changes in proliferative fraction

PURPOSE: Positron emission tomography, using the glucose analogue fluorodeoxy-D-glucose (FDG), is proving to be useful in the early response detection of head and neck tumors. Presently mechanisms underlying changes in FDG uptake after therapy are poorly understood. Response of tumors to therapy is often accompanied by a decrease in tumor cell proliferation. The purpose of this study was to assess whether or not changes in the uptake of deoxyglucose (DG) may reflect differences in proliferative fraction independent of other metabolic changes induced by using therapeutic agents. METHODS AND MATERIALS: HN5 head and neck tumor cells were grown to different cell densities producing populations of cells with different proliferative indices without the need for exogenous agents to manipulate cell-cycle kinetics. (3)H-DG uptake, S-phase fraction (Spf), and lactate production were determined in each population of cells. RESULTS: Large differences in Spf between populations of cells were associated with differences in DG incorporation. Lactate production was also found to correlate strongly with DG uptake. CONCLUSION: Therapy-induced changes in FDG uptake by tumors may be partly due to changes in proliferation.     

Flow cytometric analysis of Ki-67 in invasive ductal carcinoma of the breast: correlation with tumor and patient characteristics.

Of all markers associated with cellular proliferation in breast carcinoma, Ki-67 has more often been correlated with prognosis in patients with these tumors than others. To investigate the relevance of Ki-67 determination at each phase of the cell cycle in the biological assessment of mammary carcinoma we applied bivariate Ki-67/DNA content analysis on samples from 154 resected primary lesions. Three Ki-67-derived indices including an overall and G1 and S+G2M indices were generated. These values were correlated with similar indices derived from flow cytometric DNA/RNA analysis and traditional clinicopathologic factors. The results show that overall Ki-67 indices do not correlate with flow cytometric values and clinicopathologic factors. Flow-derived Ki-67 and DNA S+G2M indices were positively correlated (p<0.0001, r=0.58). High indices for the S+G2M phase derived by both Ki-67 and DNA analysis were significantly correlated with DNA aneuploidy, high tumor grade, and negative hormonal status. We conclude that the proliferative fraction (S+G2M) by either Ki-67 or DNA analyses offers more practical and clinically relevant information in assessing the proliferative activity in mammary carcinoma.     

Expression of GLUT-1 glucose transfer, cellular proliferation activity and grade of tumor correlate with [F-18]-fluorodeoxyglucose uptake by positron emission tomography in epithelial tumors of the ovary

We evaluated whether tracer FDG uptake, quantified as an SUV by PET in ovarian epithelial tumors, correlates with clinical stage, tumor grade, cell proliferation and glucose metabolism, all of which are biomarkers for response to chemotherapy, prognosis and overall survival in ovarian cancer patients. Seventeen patients suspected of having ovarian cancer by physical examination, tumor marker analysis and anatomic imaging (such as sonography, CT and/or MRI) underwent whole-body FDG-PET within the 2 weeks prior to surgery. Seventeen epithelial ovarian tumor specimens (13 malignant tumors, 5 at stage I, 2 at stage II, 6 at stage III; 2 borderline tumors; and 2 benign lesions) were available for pathologic evaluation. They were graded histopathologically, and immunohistochemistry for MIB-1 (proliferation index marker) and GLUT-1 was performed. Correlation between FDG uptake and clinical stage, GLUT-1 expression, MIB-1 LI and histologic grading score was determined. No positive correlation was observed between FDG uptake and clinical stage (p=0.14). Intensity of GLUT-1 expression (r=0.76, p=0.001), MIB-1 LI (r=0.457, p=0.014) and histologic grading score (r=0.692, p=0.005) showed statistically significant positive correlations with FDG uptake. Stepwise logistic regression analysis revealed that expression of GLUT-1 transporters was the strongest parameter (r=0.760, p=0.0004) by which to predict positive FDG uptake. Therefore, glucose consumption, as determined by analysis of SUVs in FDG-PET, may be a noninvasive biomarker for ovarian epithelial tumors.     

Nuclear morphometry and DNA densitometry of human gliomas by image analysis

In 48 patients with gliomas in whom complete clinical follow-up was obtained, DNA ploidy was evaluated by using formalin-fixed paraffin-embedded tissues and by means of image analysis. The mean DNA indices, determined by averaging DNA indices of all tumor cells in a tumor, were mainly affected by mean DNA indices of the nuclei of SG2M phase tumor cell (including S phase and G2M phase cells) (SG2M DNA indices) and that mean DNA indices correlated with the SG2M phase fraction. The SG2M DNA indices and the percentage of tumor cells with S phase and G2M phase were higher in high grade gliomas including anaplastic glioma and glioblastoma multiforme than in low grade gliomas. Patients with G2M-hypertetraploid tumors demonstrated a shorter time to tumor progression than those with G2M-tetraploid in high grade glioma. Morphometrically, the nuclei of SG2M phase glioma cells were larger and more deformity than those of G0G1 phase (including G0 phase and G1 phase cells) cells. The G2M-hypertetraploid tumors were highly malignant and demonstrated large nuclei, greater nuclear deformity, and a higher proliferative potential. The G2M-tetraploid gliomas demonstrated a shorter time to tumor progression in cases whose the SG2M fraction was large. In contrast, G2M-hypotetraploid gliomas revealed an insignificant trend towards a longer time to tumor progression than those associated with tetraploid and hypertetraploid gliomas. We emphasize herein the prognostic importance of the SG2M phase cell, as well as other proliferation indices.     

The relationship between FDG uptake in PET scans and biological behavior in breast cancer

BACKGROUND: Positron emission tomography (PET) is a non-invasive imaging modality used in the diagnosis and staging of breast cancer. However, several factors can affect fluoro-deoxyglucose (FDG) uptake by a tumor. To clarify the parameters that most affect FDG accumulation in tumors, the relationship between standardized uptake values (SUVs) and clinicopathological factors and immunohistopathological analysis was investigated in breast cancer. MATERIAL AND METHODS: PET studies were performed preoperatively on 37 patients with breast carcinoma. SUVs were counted at one hour (early phase) and at two hours (delayed phase) after FDG injection. The relationships between SUVs and 13 clinical, pathological and immunohistchemical factors were studied. RESULTS: A significant association was found between FDG accumulation and early and delayed phase mitotic counts (p=0.0018 and 0.0010, respectively), Ki67 positive cell percentage (p=0.0098 and 0.0062, respectively), and nuclear grade (p=0.0232 and 0.0195, respectively). On the other hand, nodal status weakly correlated with the delayed phase (p=0.0907). However, other clinicopathological parameters and immunohistopathological status, which included tumor size, age, histology, estrogen receptor, progesterone receptor and Her2/neu overexpression, did not correlate significantly with FDG uptake. CONCLUSION: Mitotic count and Ki67 reflect cellular aggressiveness. These parameters were strongly correlated with tracer uptake. Thus our data suggested that the biological behavior of breast cancer is reflected in the variation of FDG uptake by the tumor. However, whether FDG uptake is a true prognostic and predictive factor remains to be confirmed in larger studies over an extended period of time.     

鼻咽癌HK-Ⅱ和VEGF表达与PET/CT 显像18F-FDG摄取的关系

 目的 探讨鼻咽癌的18F-FDG摄取与肿瘤组织己糖激酶-Ⅱ(hexokinase-Ⅱ, HK-Ⅱ)及血管内皮细胞生长因子（VEGF）表达的关系。方法 对2005年3月至2006年8月收治的40例鼻咽癌患者进行正电子发射体层显像（PET）检查,测定肿瘤最大和标准摄取值（SUVmax和SUVmean）;应用标准链霉菌抗生物素蛋白 过氧化物酶亲和（SP）免疫组织化学法检测40例患者肿瘤组织己糖激酶-Ⅱ 和血管内皮细胞生长因子（VEGF）的表达。结果 40例鼻咽癌组织的SUVmax与 SUVmean分别为（9.45±1.87）和（6.04±1.09）;40例鼻咽癌组织HK-Ⅱ阳性细胞率为68.33%,VEGF染色阳性细胞率为60.8%;鼻咽癌组织FDG摄取（SUVmax）和HK-Ⅱ表达的细胞阳性率呈显著相关（r=0.493,P＝0.001）,鼻咽癌组织FDG摄取（SUVmax）和VEGF表达的细胞阳性率相关（r=0.460,P＝0.03）。结论 鼻咽癌组织FDG摄取与HK-Ⅱ和VEGF过度表达相关。     

DNA/RNA content and proliferative fractions of colorectal carcinomas: a five-year prospective study relating flow cytometry to survival

In our prospective study, flow cytometric analysis of cellular DNA and RNA content was performed on unfixed fresh specimens of colorectal adenocarcinoma taken from 176 patients. Of the 176 tumors, 113 (64%) were aneuploid. There was no correlation between aneuploidy and tumor stage, grade, location, or size. After a median follow-up of 5.6 years, no correlation between DNA or RNA content and patient survival was found. DNA content alone was not an independent prognostic factor when the colorectal carcinomas were segregated by curable and incurable stages. However, normal mucosa, diploid tumors, and aneuploid tumors showed progressively higher proliferation and higher RNA and DNA indices. Proliferative fraction--defined as the percentage of cells in S + G2 and M phases of the cell cycle--was significantly related to ploidy and to Dukes' stage. Despite these correlations, we did not detect a significant influence of proliferative fraction on survival when patients were segregated above or below the mean proliferative fraction for all tumors. More accurate methods of identifying the proliferative fraction of tumor cells are currently being pursued. While the role of flow cytometry in the evaluation and management of patients with colorectal carcinoma is still undefined for a number of other cellular parameters, it seems unlikely that DNA index, RNA index, or the proliferative fractions calculated from the DNA histogram, will, of themselves, represent independent prognostic factors.     

Ploidy and proliferative activity of human brain tumors. A flow cytofluorometric study

Ploidy and proliferative characteristics were estimated by flow cytometry of the nuclear DNA content of 92 human brain tumors. Samples were frozen at -20 degrees C immediately after surgery and single cell suspensions were obtained with a mechanical dissociation technique. Propidium iodide was employed for nuclear DNA staining. Human normal brain tissue was used as internal diploid reference standard. 86% of benign tumors had unimodal DNA distribution with a DNA index (DNA I = modal channel of the G0/1 peak of the studied population/modal channel of the G0/1 peak of the normal brain) usually within the diploid or near-diploid range. 14.0% had aneuploidy, with an additional cell peak having a median DNA I of 1.60. Among malignant tumors, these figures were 61.2 and 38.8% (p less than 0.001). The percentage of S phase cells was higher in malignant (median = 3.6) than in benign tumors (median = 2.0, p less than 0.01), without correlation to histological tumor subtype. Flow cytometry appears to be a useful method for evaluating differences in DNA distribution in tumors of the central nervous system.     

Myeloid differentiation antigens identify leukemic cell subpopulations with different cell cycle characteristics.

In order to assess the proliferative capacity of leukemic subpopulations and to know whether it can be related to the stage of maturation, the expression of two surface antigens identifying distinct steps of leukocyte differentiation (CD15 and CD34) was studied by flow cytometry in correlation with DNA content in 16 cases of acute myeloid leukemia (AML). The surface markers were studied by indirect immunofluorescence, using the monoclonal antibodies VIMD5 (anti-CD15) and MY10 (anti-CD34). The percentage of cells stained by each antibody and the intensity of staining were heterogeneous. Double-staining showed that a small percentage of cells coexpressed both antigens. A correlation was found between the percentage of cells stained by MY10 and the percentage of cells in S + G2 + M in the whole population (p less than 0.05). The percentage of cells in S + G2 + M was significantly higher in MY10-positive than in MY10-negative cells (p less than 0.005), and also higher in VIMD5-positive than in VIMD5-negative cells (p less than 0.005). In the 14 cases expressing both antigens, the percentage of cells in S + G2 + M was higher in VIMD5-positive than in MY10-positive cells (p less than 0.05), whereas there was no difference between VIMD5-negative and MY10-negative cells. It is concluded that the phenotype heterogeneity observed in leukemic cell populations is associated with differences in proliferative capacities. The subset of leukemic cells with the more mature phenotype (CD15-positive) has the highest proliferative activity.     

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.     

(18)F and (18)FDG PET imaging of osteosarcoma to non-invasively monitor in situ changes in cellular proliferation and bone differentiation upon MYC inactivation

Osteosarcoma is one of the most common pediatric cancers. Accurate imaging of osteosarcoma is important for proper clinical staging of the disease and monitoring of the tumor's response to therapy. The MYC oncogene has been commonly implicated in the pathogenesis of human osteosarcoma. Previously, we have described a conditional transgenic mouse model of MYC-induced osteosarcoma. These tumors are highly invasive and are frequently associated with pulmonary metastases. In our model, upon MYC inactivation osteosarcomas lose their neoplastic properties, undergo proliferative arrest and differentiate into mature bone. We reasoned that we could use our model system to develop noninvasive imaging modalities to interrogate the consequences of MYC inactivation on tumor cell biology in situ. We performed positron emission tomography (PET) combining the use of both (18)F-fluorodeoxyglucose ((18)FDG) and (18)F-flouride ((18)F) to detect metabolic activity and bone mineralization/remodeling. We found that upon MYC inactivation, tumors exhibited a slight reduction in uptake of (18)FDG and a significant increase in the uptake of (18)F along with associated histological changes. Thus, these cells have apparently lost their neoplastic properties based upon both examination of their histology and biologic activity. However, these tumors continue to accumulate (18)FDG at levels significantly elevated compared to normal bone. Therefore, PET can be used to distinguish normal bone cells from tumors that have undergone differentiation upon oncogene inactivation. In addition, we found that (18)F is a highly sensitive tracer for detection of pulmonary metastasis. Collectively, we conclude that combined modality PET/CT imaging incorporating both (18)FDG and (18)F is a highly sensitive means to non-invasively measure osteosarcoma growth and the therapeutic response, as well as to detect tumor cells that have undergone differentiation upon oncogene inactivation.     

The role of FDG PET in the clinical management of head and neck cancer

Positron emission tomography (PET) with fluorodeoxyglucose (FDG) allows the visualization of metabolic tissue activity. Use of FDG in in-vivo cancer imaging is based on enhanced glycolysis in tumor cells. In vivo experiments have demonstrated the potential use of FDG PET in squamous-cell head and neck tumors and the detection of tumor involvement in lymph nodes. Since its introduction in this area, several papers have appeared on the use of this imaging modality. Indications for the use of FDG PET in patients with head and neck cancer are discussed.     

Imaging bone and soft tissue tumors with the proliferation marker [18F]fluorodeoxythymidine.

PURPOSE: We have determined the ability of positron emission tomography (PET) with the thymidine analogue 3'-deoxy-3'[18F]fluorothymidine (FLT) to detect manifestation sites of bone and soft tissue tumors, to assess tumor grading, and to differentiate malignant from benign tumors. MATERIALS AND METHODS: In this prospective bicenter trial, FLT-PET was done in 22 patients with established or suspected soft or bone tissue lesions. Routine diagnostic procedures included incisional biopsy, magnetic resonance imaging, and/or contrast-enhanced spiral computed tomography in all patients and [18F]fluorodeoxyglucose (FDG)-PET in 15 patients. Forty-five to 60 minutes after i.v. injection of 350 to 425 MBq FLT, emission and transmission scanning was done. Tracer uptake in the tumor was evaluated semiquantitatively by calculation of mean and maximum standardized uptake values (FLT-SUV) and compared with respective values of FDG. Results were correlated to histopathology and tumor grading. RESULTS: FLT-PET detected all malignant bone or soft tissue tumors (17 of 17). Mean FLT-SUV in benign lesions was 0.7 (range, 0.3-1.3), and 1.3 in low-grade sarcoma (grade 1; range, 1.0-1.6), 4.1 (range, 2.2-6.0; P = 0.002) and 6.1 (range, 2.5-8.3; P = 0.001) in grade 2 and grade 3 tumors, respectively. FLT but not FDG uptake correlated significantly with tumor grading (r = 0.71 versus r = 0.01), and a cutoff value of 2.0 for FLT-SUV discriminated between low- and high-grade tumors. CONCLUSION: In this clinical study, the proliferation marker FLT was suitable for imaging malignant bone or soft tissue tumors. FLT but not FDG uptake correlated significantly with the tumor grade, suggesting FLT as superior PET tracer for noninvasive grading of sarcomas.     

Initial experience in small animal tumor imaging with a clinical positron emission tomography/computed tomography scanner using 2-[F-18]fluoro-2-deoxy-D-glucose

The feasibility of small animal imaging using a clinical positron emission tomography/computed tomography (PET/CT) scanner with [F-18]-fluoro-2-deoxy-D-glucose (FDG) was evaluated. As tumor-bearing small animal models, rabbits with VX-2 liver tumors, rats with mammary tumors on the back, and mice with LS174T human colon tumor xenografts were prepared. Two-dimensional PET, CT, and fused PET/CT images were obtained and reconstructed with a combined PET/CT system using a conventional protocol for humans and dedicated high-resolution mode protocols specialized for each species. Estimated radioactivity concentrations in tumors and normal organs determined noninvasively on FDG-PET/CT were compared with the actual tissue radioactivity levels determined from gamma-counting after vivisection in rats. In addition, recovery-corrected radioactivity concentrations were calculated and evaluated using the tumor/normal organ sizes measured on CT. Tumors in rabbits and rats were clearly visualized by FDG-PET/CT in the dedicated protocols, and images were considered suitable for research purposes. With the aid of thin-slice CT-mapping images, FDG uptake was correctly localized in the viable tumor regions. In mice, increased FDG uptake in tumors with varying activity levels was observed, but detailed anatomical information was not optimally provided from the images, even using specialized protocols. The estimated radioactivity concentrations of tumors and normal organs were close to the actual radioactivity concentrations obtained by gamma-counting (r = 0.97, P < 0.001, the estimated/actual slope: 1) when recovery correction was applied using the sample sizes measured on CT. FDG-PET/CT imaging with a modern clinical scanner was demonstrated to be feasible, of excellent quality, and quite quantitatively accurate for research in rabbits or rats with tumors of appropriate size (>2 cm without recovery correction and >1 cm with recovery correction). Evaluation of FDG uptake within a tumor was possible with the aid of CT images. Dedicated small animal PET/CT scanner would be better suited for evaluating tumor-bearing mice and likely could enhance imaging smaller tumors in rabbits or rats. Although it has limitations, small animal imaging with a clinical PET/CT scanner may be quite adequate for sequential noninvasive imaging in oncology research because the CT is of high resolution, allowing for localization of PET findings and for more precise noninvasive estimation of radioactivity concentration through partial volume corrections.     

Taxotere chemosensitivity evaluation in mice prostate tumor: validation and diagnostic accuracy of quantitative measurement of tumor characteristics by MRI, PET, and histology of mice tumor

Increased PET and MRI image intensities of mouse prostate tumors were correlated with histostaining tumor characteristics. The hypothesis was that increased intracellular sodium microMRI signal intensities and flouro-2-deoxy-glucose utilization by microPET in apoptosis rich regions in tumors were positively correlated as chemosensitivity assay of Taxotere. The PC-3 cancer cell line induced prostate tumor MRI and PET images and histology slices were digitally captured and compared in pre- and post-Taxotere treated tumors. The optimization of inversion recovery MRI parameters was done to generate sodium images of phantom. The (18)FDG biotransformation was optimized to measure PET image intensities. A criterion was developed to evaluate malignancy by histology. For correlation, regression analysis was done using imaging, histology, and immunostaining data from PC3 tumor after 24 and 48 hours post-Taxotere treatment. Apoptosis indices were calculated by histostaining and ss-DNA antibody assay. Sodium MRI and PET signal intensity distributions were comparable at specific locations relatively and measured in tumor tissue regions. In tumors, Taxotere induced an increase in intracellular sodium MRI signal 30% (p<0.001) with decreased tumor size (20%; p<0.001) and micro-PET showed FDG uptake increase 15% (p<0.001) with decreased tumor size (10%; p<0.001) than that of control tumors after 24 hours. Histological features indicated tumor risk (high 'intracellular/extracellular ratio', high mitotic index, and apoptotic index), decreased tumor viability (reduced mitotic figures, reduced diploidy or aneuploidy, and proliferation index) after Taxotere treatment. These features in co-registered intracellular sodium, microPET hypermetabolic, and monoclonal antibody (ss-DNA) sensitive regions showed (% difference > 6%). Apoptosis rich regions showed characteristic nuclei with S phase DNA histogram, appearing brighter on IC-Na images and mild active on PET images (sensitivity=65%; specificity=70%). In conclusion, MRI and PET multimodal imaging may be rapid non-invasive chemosensitivity assay to monitor the drug anticancer effect.     

Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging.

PURPOSE: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.     

应用流式细胞术研究肿瘤细胞在不同细胞周期中癌胚抗原的含量变化

应用流式细胞术,分析了4株肿瘤细胞(BCAP-37,BCG823,KATO,LOVO)在不同细胞周期中癌胚抗原(CEA)的含量变化。结果显示。不同细胞周期CEA含量有极显著差异(P<0,001),S和G2M期CEA含量比GOGI期显著增高。说明,在能够产生CEA的恶性肿瘤,肿瘤生长越快,恶性程度越高,CEA含量也越高。因而推想在能够产生CEA的组织中,CEA含量与细胞的增殖状态有关。处于S和G2M期的细胞比例越高,组织中CEA含量也越高。     

Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report

PURPOSE: Tumor hypoxia is associated with poor response to therapy. We have investigated whether pretreatment tumor hypoxia assessed by positron emission tomography (PET) with Cu-60 diacetyl-bis(N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) predicts responsiveness to subsequent therapy in cervical cancer. METHODS AND MATERIALS: Fourteen patients with biopsy-proved cervical cancer were studied by PET with (60)Cu-ATSM before initiation of radiotherapy and chemotherapy. (60)Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M) and peak slope index of tumor tracer uptake. All patients also underwent clinical PET with F-18 fluorodeoxyglucose (FDG) before institution of therapy. The PET results were correlated with follow-up evaluation (14-24 months). RESULTS: Tumor uptake of (60)Cu-ATSM was inversely related to progression-free survival and overall survival (log-rank p = 0.0005 and p = 0.015, respectively). An arbitrarily selected T/M threshold of 3.5 discriminated those likely to develop recurrence; 6 of 9 patients with normoxic tumors (T/M < 3.5) are free of disease at last follow-up, whereas all of 5 patients with hypoxic tumors (T/M > 3.5) have already developed recurrence. Similar discrimination was achieved with the peak slope index. The frequency of locoregional nodal metastasis was greater in hypoxic tumors (p = 0.03). Tumor FDG uptake did not correlate with (60)Cu-ATSM uptake (r = 0.04; p = 0.80), and there was no significant difference in tumor FDG uptake between patients with hypoxic tumors and those with normoxic tumors. CONCLUSION: (60)Cu-ATSM-PET in patients with cervical cancer revealed clinically relevant information about tumor oxygenation that was predictive of tumor behavior and response to therapy in this small study.     

PET evaluation of glucose metabolism in cancer]

Accelerated glycolysis is one of the biochemical characteristics of cancer cells. Based on this fact, positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been used in the diagnosis of various cancers. After intravenous injection of FDG and PET scans, most cancers are identified by high FDG accumulation. This metabolic tumor imaging method has been used successfully in the differentiation of benign and malignant tumors, in the diagnosis of metastasis or recurrence, in the detection of primary unknown cancers, and in cancer screening. Because the degree of FDG accumulation reflects tumor glucose consumption, quantification of FDG uptake by PET can be used in predicting biological malignancy and in monitoring treatment in both radiation and chemotherapy. The potential utility of Glut-1 and hexokinase, reported to be responsible for increased glucose metabolism, as biological markers of cancers is yet to be determined.