Metabolic Activity Of Tumor Cells Research Articles

Validation of dual energy X-ray absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.

Noninvasive imaging is central to preclinical, in vivo models of pancreatic ductal adenocarcinoma (PDAC). While bioluminescent imaging (BLI) is a gold standard, its signal is dependent on the metabolic activity of tumor cells. In contrast, dual energy X-ray absorptiometry (DEXA) is a direct measure of body composition. Thus, we aimed to assess its potential for longitudinal quantification of tumor burden versus BLI. We utilized the KCKO murine model of PDAC and subjected tumor-bearing (n = 20) and non-tumor control (NTC) (n = 10) animals to weekly BLI and DEXA measurements for up to 10 weeks. While BLI detected tumors at 1-week, it failed to detect tumor growth, displayed a decreasing trend overtime (slope = -9.0x108; p = 0.0028), and terminal signal did not correlate with ex vivo tumor mass (r = 0.01853; p = 0.6286). In contrast, DEXA did not detect elevated changes in abdominal cavity lean mass until week 2 post inoculation and tumors were not visible until week 3, but successfully quantified a tumor growth trend (slope = 0.7322; p<0.0001), and strongly correlated with final tumor mass (r = 0.9351; p<0.0001). These findings support the use of BLI for initial tumor engraftment and persistence but demonstrate the superiority of DEXA for longitudinal tumor burden studies. As tumor detection by DEXA is not restricted to luciferase expressing models, future studies to assess its value in various cancer models and as an in vivo outcome measure of treatment efficacy are warranted.

Glucose metabolism reprogramming in gynecologic malignant tumors.

The incidence and mortality of gynecological tumors are progressively increasing due to factors such as obesity, viral infection, unhealthy habits, as well as social and economic pressures. Consequently, it has emerged as a significant threat to women's health. Numerous studies have revealed the remarkable metabolic activity of tumor cells in glycolysis and its ability to influence malignant biological behavior through specific mechanisms. Therefore, it is crucial for patients and gynecologists to comprehend the role of glycolytic proteins, regulatory molecules, and signaling pathways in tumorigenesis, progression, and treatment. This article aims to review the correlation between abnormal glucose metabolism and gynecologic tumors including cervical cancer (CC), endometrial carcinoma (EC), and ovarian cancer (OC). The findings from this research will provide valuable scientific insights for early screening, timely diagnosis and treatment interventions while also aiding in the prevention of recurrence among individuals with gynecological tumors.

Curbing Exosome Communications via Introducing Artificial Membrane Receptors for Metastatic Pancreatic Cancer Therapy.

Tumor-derived exosomes (TDEs) carry various biomolecular cargos and play crucial roles in metastasis. TDEs migrate to distal organs for intercellular communication and induce the formation of pre-metastatic niches (PMNs) to support tumor implantation and proliferation. Precise interference in the bioprocess of TDEs is expected to be efficacious for suppressing tumor metastasis. However, targeting both TDEs and the primary tumor is challenging. Here, based on metabolic glycoengineering and bio-orthogonal click chemistry, a two-step delivery strategy is designed to overcome this. During the first step, the tetraacetylatedN-azidoacetyl-d-mannosamine-loaded nanoparticle responds to the metabolic activity of tumor cells in the primary tumor, tagging both tumor cells and TDEs with azide groups; dibenzyl-cyclootyne-modified nanoparticles then can, as the second step, specifically react with tumor cells and TDEs through a bio-orthogonal click reaction. This strategy not only inhibits tumor growth in pancreatic cancer models but also curbs the communicative role of TDEs in inducing liver PMNs and metastasis by tracking and downregulating the exosomal macrophage migration inhibitory factor.

Immunometabolism in the Tumor Microenvironment

Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells are shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity.

RELATIONSHIP BETWEEN THE RESULTS OF IMMUNOHISTOCHEMICAL EXAMINATION (PHH3, KI-67) AND POSITRON EMISSION TOMOGRAPHY DATA (SUVMAX) OF OROPHARYNGEAL SQUAMOUS CELL CARCINOMA

The authors established the relationship between the indicators of immunohistochemical examination — proliferation markers (Ki67) and mitotic count (pHH3) with the indicators of positron emission tomography — SUVmax. The identified patterns of cancer cells differentiation and their metabolic activity are promising for the diagnosing and screening of tumours of varying degrees of progression and origin, which will allow forecasting the course of the disease at all stages of diagnostics. The study intends to assess the level of oropharyngeal squamous cell histopathological differentiation by immunohistochemical diagnostic methods, and their metabolic activity using positron emission tomography.1. Study of the activity of metabolic processes of transformed oropharyngeal cancer cells using positron emission tomography;2. Determination of tumour proliferative potential by the number of positive stains to Ki-67 (%) and pHH3 by immunohistochemical diagnostic methods;3. Identification of the relationship between morphological changes of oropharyngeal cancer cells and their metabolic activity.Materials and methods. We studied 130 samples of squamous cell carcinoma of the oropharyngeal area. We determined the level of metabolic activity — SUVmax — by positron emission tomography (PET) at the preoperative patient treatment stage. In the postoperative period, the proliferation index (Ki67) and the mitotic count (pHH3) were determined by histological and immunohistochemical methods. Upon assessment of the level of differentiation of tumour cells, patients were divided into three groups: Group I - patients having tumour cells in the G1 phase of mitosis (28 patients); Group II — tumour cells in the G2 phase of mitosis (48 patients); Group III — tumour cells in the G3 phase of mitosis (54 patients). We evaluated PET results according to the Maximum Standard Unit Value (SUVmax).We determined the relationship between morphological changes and metabolic activity of tumour cells by 2- fluoro-[18F]-2-deoxy-D-glucose accumulation and immunohistochemical examination.Results. We established a statistically significant difference between the groups (p&lt;0.001 according to the Kruskal- Wallis test for all indicators). Thus, with decreasing Me level, the differentiation of SUVmax of tumours significantly (p&lt;0.05) increases, which indicates an increase in the degree of malignancy of tumours. We evaluated the results of immunohistochemical examination by Ki67 and pH3 markers in the study groups. Comparing Ki67 and pHH3, a statistically significant difference was found between the groups (p&lt;0.001 according to the Kruskal- Wallis test for all indicators). Thus, with a decrease in the Me level, the differentiation of Ki67 increases significantly (p&lt;0.05), and an increase in pH3 indicates an increase in the degree of malignancy of tumours. Conclusions. We statistically proved the relationship between Ki67, pH3 and SUVmax in oropharyngeal squamous cell carcinoma. We established the possibility of preoperative forcasting of the level of tumour differentiation and the use of pHH3 immunohistochemical marker as a reliable criterion for assessing the level of tumour differentiation, including hardly diagnosable squamous cell carcinoma.

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment.

Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.

Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies.

Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid–lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.

Navigating metabolic pathways to enhance antitumour immunity and immunotherapy.

The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.

PO-232 Lewis glycans and their epigenetic regulation are associated with neuroblastoma aggressiveness

IntroductionThe mTOR (mammalian target of rapamycin) is a receptor tyrosine kinase which plays an important role in cell growth regulation, proliferation and tumour cell survival in cancer cells. Differences of mTOR activity were described in tumours. mTOR dependent and independent metabolic activity of tumour cells could be essential in survival and therapy resistance of breast cancer. Changes of mTOR and metabolic activity of breast cancer could correlate to the patients’ treatment outcome.Material and methodsIn our work, the correlations between the metabolic phenotype and mTOR activity of breast cancer cell lines were studied. Furthermore, the expressions of mTOR activity related proteins and several metabolic transporter, enzymes were studied by Western blot, ICC and IHC using breast cancer cell lines and human tissue samples. The metabolic phenotypes were also analysed using LC-MS. Moreover, the effect of mTOR, metabolic inhibitors and chemotherapeutics were also studied in vitro.Results and discussionsSubtypes independent differences in mTORC1/C2 complex and metabolic activities were detected in breast cancer cell lines. Certain cell lines were characterised with high glucose uptake, high mTORC1 complex activity and high lactate production, while other cell lines showed balanced mTORC1 and mTORC2 activity, well-functioning oxidative phosphorylation capacity and higher levels of TCA metabolites which were related to intact mitochondrial functions. The metabolic phenotype and mTORC1/C2 activity correlated to the detected mTOR inhibitors, metabolic inhibitors and chemotherapeutic sensitivity of breast cancer cell lines in vitro. The metabolic and mTOR activity differences can be observed in human tissue samples independently of breast carcinoma cell subtypes, as well.ConclusionDifferences of metabolic and mTOR related protein levels may explain the different therapeutic sensitivity. We suggest evaluating the metabolic phenotype and mTOR activity in breast cancer subtypes, which may help to introduce therapeutic drug combinations and predict therapy resistance.Supported by STIA-KF-17(SA), Bolyai-590/2015(SA), ÚNKP-17-3(HZ)−17-3(KI)−17-2(DT) and EFOP-3.6.3-VEKOP-16-2017-00009.

Modeling of the metabolic energy dissipation for restricted tumor growth.

Energy dissipation mostly represents unwanted outcome but in the biochemical processes it may alter the biochemical pathways. However, it is rarely considered in the literature although energy dissipation and its alteration due to the changes in cell microenvironment may improve methods for guiding chemical and biochemical processes in the desired directions. Deeper insight into the changes of metabolic activity of tumor cells exposed to osmotic stress or irradiation may offer the possibility of tumor growth reduction. In this work effects of the osmotic stress and irradiation on the thermodynamical affinity of tumor cells and their damping effects on metabolic energy dissipation were investigated and modeled. Although many various models were applied to consider the tumor restrictive growth they have not considered the metabolic energy dissipation. In this work a pseudo rheological model in the form of "the metabolic spring-pot element" is formulated to describe theoretically the metabolic susceptibility of tumor spheroid. This analog model relates the thermodynamical affinity of cell growth with the volume expansion of tumor spheroid under isotropic loading conditions. Spheroid relaxation induces anomalous nature of the metabolic energy dissipation which causes the damping effects on cell growth. The proposed model can be used for determining the metabolic energy "structure" in the context of restrictive cell growth as well as for predicting optimal doses for cancer curing in order to tailor the clinical treatment for each person and each type of cancer.

High-content, full genome siRNA screen for regulators of oncogenic HRAS-driven macropinocytosis.

Uptake of nutrients, such as glucose and amino acids, is critical to support cell growth and is typically mediated by cell surface transporters. An alternative mechanism for the bulk uptake of nutrients from the extracellular space is macropinocytosis, a nonclathrin, and nonreceptor-mediated endocytic process, in which extracellular fluid is taken up into large intracellular vesicles called macropinosomes. Oncogenic transformation leads to the increased metabolic activity of tumor cells, and in the Ras-driven tumor part of this enhanced activity is the stimulation of macropinocytosis. To measure oncogene-dependent macropinocytosis, we used HeLa cells expressing oncogenic HRAS(G12D) driven from a Tet-regulated promoter. Upon oncogenic HRAS expression, the cells undergo metabolic changes that include the elevation of macropinocytosis. We detected macropinocytosis through the uptake of lysine-fixable tetramethyl rhodamine (TMR)-Dextran (70 kDa) from the cell media into nascent intracellular macropinosomes. These macropinosomes were quantified by image-based high-content analysis, with the size, intensity, and position of macropinosomes measured. Using this model system, we ran a full genome-wide siRNA screen (siGenome™; GE) to identify genes involved in controlling oncogenic HRAS-dependent macropinocytosis. Hits from the primary screen were confirmed with siRNA reagents from a different library (GE, OTP), which allowed us to mitigate potential off-target effects. Candidate genes from this screen include known regulators of macropinocytosis as well as novel targets.

Immunometabolic editing: a new type of immunoediting in tumorigenesis (TUM7P.1027)

Abstract Immune evasion and deregulated metabolic transformation are hallmarks of cancer that contribute to tumor aggressiveness and metastasis through different mechanisms. However, it has not been examined whether there is a connection between these two hallmarks. In this study, we approach this question by both melanoma engraftment and a genetically modified melanoma mouse model. First we investigated whether the presence of CD4 or CD8 T cells during tumorigenesis has any effect on a tumors metabolic profile by depleting these cells post-tumor induction. We found that T cell depletion in the early phase of tumorigenesis led to down regulation of hexokinase 2 and pyruvate kinase isozyme M2. Then we investigated whether the effector functions of T cells, especially CD40L and interferon gamma (IFNγ), promote tumor cells to acquire deregulated metabolic activity. It appears the IFNγ may be a major player in the metabolic selection process. Finally, we aim to examine whether the metabolic activity of tumor cells has an effect on the immune activity. In the pilot test, we identified three different melanoma cell lines derived from genetically modified melanomas that have distinct glycolytic activity and oxidative phosphorylation. These tools lay a foundation for future analysis to investigate whether the metabolic features of melanoma cells can play a regulatory role in controlling anti-tumor immunity and the formation of an immunosuppressive microenvironment.

Prognostic Value of the Maximum Standardized Uptake Value on Positron Emission Tomography for Esophageal Squamous Cell Carcinoma.

Esophageal cancer is a malignant tumor with one of the worst prognosis. Positron emission tomography (PET) reveals the degree of metabolic activity of tumor cells. We hypothesized that a high maximum standardized uptake value (SUVmax) on PET would predict a poor clinical outcome. From November 2004 to August 2011, we reviewed 88 patients with esophageal squamous cell carcinoma who underwent preoperative PET followed by surgery. SUVmax values of primary sites were measured. The patients were divided into two groups with median SUVmax as a cutoff value and outcomes were compared. The median SUVmax was 6.35. Cervical and upper thoracic cancer, large tumor size, stage ≥ T2, and lymph node metastasis were significantly associated with the high SUVmax group. Cervical and upper thoracic cancer (p = 0.038), SUVmax (p = 0.038), number of lymph nodes dissected (p = 0.009), stage ≥ T2 (p = 0.003), lymph node metastasis (p < 0.001), and incomplete resection (p = 0.031) were significant predictors for the disease-free survival. A high SUVmax ( ≥ 6.35, p = 0.023) and stage ≥ T2 (p = 0.025) were significantly associated with overall survival by multivariate analysis. High preoperative SUVmax on PET predicts advanced T stage and worse prognosis. SUVmax on PET may provide useful information combined with current stage for determining optimal treatment in esophageal cancer.

163: Metabolic activity of tumor cells in a variable microenvironment: combinations of glucose, glutamine, lactate and pH

163: Metabolic activity of tumor cells in a variable microenvironment: combinations of glucose, glutamine, lactate and pH

In vivo visualization of GL261-luc2 mouse glioma cells by use of Alexa Fluor–labeled TRP-2 antibodies

For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies. GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope. Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes. Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors.

The role of PET-CT in the follow-up of patients with urothelial cancer diagnosis.

291 Background: Positron emission tomography (PET) is an imaging technique whose principle is the detection of metabolic activity of tumor cells but in urology its use had been restricted due to urinary excretion of the radiotracer and overlap with urological structures, the use of hybrid PET (PET-CT) would allow its use for monitoring patients with urothelial tumors. Methods: Between 2007 and 2010 we performed PET-TC images in consecutive patients with suspected recurrences in CT scan or MRI. All patients had renal, bladder and uretral cancer and were treated with urothelial cancer diagnosis. We evaluate the usefulness of FDG PET-CT and its impact on behavior therapy in suspected recurrence in patients with urothelial carcinoma, compared with conventional studies. Results: 17 patients were studied for suspected recurrence. All patients had positive images previously on CT scan and MRI; positive PET-TC was observed in 14 and 3 studies were negative. The positive PET-CT showed more number of lesions and change the medical and surgical strategy. Of the three studies negative on PET- CT none had recurrence and remain disease free. PET/CT is in a great benefit to the detection recurrence in the follow up of patients with urothelial cancer diagnosis. These results showed an increased sensitivity and specificity over previous work with conventional PET technology. In the series studied, the implementation of PET-CT (FDG) in the follow up of patients with urothelial tumors were an useful tool. Conclusions: PET/CT is in a great benefit to the detection recurrence in the follow up of patients with urothelial cancer diagnosis. These results showed an increased sensitivity and specificity over previous work with conventional PET technology. In the series studied, the implementation of PET-CT (FDG) in the follow up of patients with urothelial tumors were an useful tool. However, multicenter studies and more patients are required to define its role. No significant financial relationships to disclose.

Thyroid Status is a Key Modulator of Tumor Oxygenation: Implication for Radiation Therapy

In normal tissues, thyroid hormones play a major role in the metabolic activity and oxygen consumption of cells. Because the rate of oxygen consumption is a key factor in the response of tumors to radiation, we hypothesized that thyroid hormones may affect the metabolic activity of tumor cells and hence modulate the response to cytotoxic treatments. We measured the influence of thyroid status on the tumor microenvironment in experimental tumors. Hypothyroidism and hyperthyroidism were generated in mice by chronic treatment with propyl thiouracil and l-thyroxine. Thyroid status significantly modified tumor pO(2) as measured with EPR oximetry. Mechanistically, this was the result of the profound changes in oxygen consumption rates. Thyroid status was associated with a significant change in tumor radiosensitivity since the regrowth delay was increased in hypothyroid mice compared to euthyroid mice, an effect that was abolished when temporarily clamped tumors were irradiated. This study provides unique insights into the impact of modulating tumor oxygen consumption and could have implications in the management of cancer patients with thyroid disorders.

Differential subcellular distribution of glucose transporters GLUT1–6 and GLUT9 in human cancer: Ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues

It has been proposed that the enhanced metabolic activity of tumor cells is accompanied by an increased expression of facilitative hexose transporters (GLUTs). However, a previous immunohistochemical analysis of GLUT1 expression in 154 malignant human neoplasms failed to detect the GLUT1 isoform in 87 tumors. We used 146 normal human tissues and 215 tumor samples to reassess GLUT1 expression. A similar number of samples were used to compare the expression of GLUT2-6 and 9. The classical expression of GLUT1-5 in different normal human tissues was confirmed, however, we were unable to detect GLUT2 in human pancreatic islet cells. GLUT6 was principally detected in testis germinal cells and GLUT9 was localized in kidney, liver, heart, and adrenal. In tumor samples, GLUT1, 2, and 5 were the main transporters detected. GLUT1 was the most widely expressed transporter, however, 42% of the samples had very low-to-negative expression levels. GLUT2 was detected in 31% of the samples, being mainly expressed in breast, colon, and liver carcinoma. GLUT5 was detected in 27% of breast and colon adenocarcinoma, liver carcinoma, lymphomas, and testis seminoma samples. In situ RT-PCR and ultrastructural immunohistochemistry confirmed GLUT5 expression in breast cancer. GLUT6 and 9 are not clearly over-expressed in human cancer. The extensive expression of GLUT2 and 5 (glucose/fructose and fructose transporters, respectively) in malignant human tissues indicates that fructose may be a good energy substrate in tumor cells. Our functional data obtained in vitro in different tumor cells support this hypothesis. Additionally, these results suggest that fructose uptake could be used for positron emission tomography imaging and, may possibly represent a novel target for the development of therapeutic agents in different human cancers.

How to optimize staging in early non-small cell lung cancer

The topic was discussed by Dr Johan Vansteenkiste, Leuven Belgium. PET is an exciting new imaging modality that has rapidly acquired a prominent position in evaluation of solitary pulmonary nodules (SPN) and staging of lung cancer. It is based on the principle that cancer cells have a higher rate of glycolysis and an increased cellular uptake of glucose due to increased number of transport proteins than non-neoplastic cells. The PET tracer, 18 fluoro-deoxyglucose (18 FDG) is taken up into cells and metabolically trapped and accumulates. 18 FDG is a positron emitter, and therefore, can be measured. Thus, PET provides evidence of metabolic activity of tumor cells and has opened up the relative new field of ‘molecular imaging’. PET has a sensitivity of approximately 90% and a specificity of 85 /90% for evaluating SPN, but the data available is based on nodules ]/1 cm in size [1]. The resolution limit of PET is thought to be 7 /8 mm. For nodules smaller than 1 cm, the sensitivity and specificity is unknown. The sensitivity and specificity of the CT scan for evaluating mediastinal lymph nodes for metastasis is 60 /70% each [2,3]. This means that 30 /40% of lymph nodes one cm or smaller will have microscopic metastasis (sensitivity) and 30 /40% of lymph nodes /1 cm in size will not contain metastases, but will only be reactive (specificity). In contrast, data presented and a published meta-analysis documents a sensitivity of 89% and specificity of 92% for PET evaluation of mediastinal nodes in patients with NSCLC [4]. A limitation of PET is that it lacks precise anatomic details. Studies have shown that the sensitivity and accuracy of PET is significantly improved when it is correlated with the CT scan. New scanners are just coming on the market that fuse the CT and PET images, thus giving better anatomic detail. It is likely that these new CT/PET scanners may replace the current PET scanners. They decrease the PET scan time from 60 to 30 min. False positive PET scans can occur in patients with tuberculosis, other granulomatous disease, sarcoidosis, and anthrasilicosis. Care must be taken to distinguish a malignancy adjacent to mediastinum from adjacent mediastinal nodal metastasis with the current scanners. False negative PET scans may occur in patients with carcinoid tumors and bronchoalveolar cell carcinoma because of the low metabolic activity. PET will also miss microscopic lymph node metastases (resolution size limitation). Dr Vansteenkiste recommended that PET evaluation of mediastinum be used as follows:

Volume Fraction of Dense-Core Granules Correlates Strongly with Survival in Disseminated (Stage IV) Neuroendocrine Cell Carcinomas of the Lung of the Well Differentiated and Small Cell Subtypes

In order to verify whether ultrastructural quantitative morphological indices of neuroendocrine cell carcinoma of the lung may help to predict survival in disseminated disease (Stage IV), 21 biopsy specimens were studied. Volume density of mitochondria and dense-core granules was assessed by a conventional point-counting procedure. Survival in months after biopsy was considered the dependent variable of age and of the morphometric parameters, in a multivariate linear regression analysis. The significance level was set at 5%. Survival was positively correlated (p = 0.011, multiple r = 0.686) with volume fraction of dense-core granules (p = 0.0025) and negatively correlated with volume fraction of mitochondria (p = 0.035), and also with age (p = 0.034). Our data indicate that survival is strongly dependent on the degree of neuroendocrine differentiation and of metabolic activity of tumour cells and that improved prognostic accuracy is provided by the use of quantitative analyses as compared with the conventional subtyping of malignant pulmonary neuroendocrine neoplasms.