CyberKnife radiosurgery for inoperable stage IA non-small cell lung cancer: 18F-fluorodeoxyglucose positron emission tomography/computed tomography serial tumor response assessment

Abstract

Management of localized primary gastric B lymphoma (PGL) remains controversial. The aim of this study is to compare two treatments: chemotherapy alone and surgery plus chemotherapy.

Materials

Records of all patients with a diagnosis of gastric lymphoma and which were treated in the National Institute of Oncology, between 1999 and 2006, were reviewed and patients fulfilling the following criteria were included in this study: histologically proven large-cell B lymphoma of the stomach; complete clinical information stage I/II disease according to the Musshoff staging; patients who received surgery followed by chemotherapy (group I) or chemotherapy alone (group II).

Results

This study included 82 patients who were treated for cancer in our Institute. All clinical and pathological features were similar between the two groups, except that patients of group-I had significantly more stage II disease (P = 0.023) than that of group II. Among the 52 patients who could be evaluated for response to chemotherapy, there were 45 who had complete response to treatment, 3 had partial response to the treatment and 4 had progressive disease. The projected 5-year relapse-free survival (RFS) and overall survival (OS) of group I were 86.69% (95% CI, 57.9 - 97.7%) and 90.0% (95% CI, 58.0 - 97.8%), respectively. And the projected 5-year relapse-free survival RFS and OS of group II were 86.67% (95% CI, 57.0 - 88.2%) and 93.33% (95% CI, 73.3 - 98.7%) respectively. There were no statistically significant differences in RFS (P = 0.485) and OS (P = 0.551) between the two groups.

Conclusion

Our data suggest that chemotherapy alone may be a reasonable alternative treatment for stage I/II gastric large-cell lymphoma but this result must be confirmed by prospective randomized clinical trials.     

Genetic alterations associated with 18F-fluorodeoxyglucose positron emission tomography/computed tomography in head and neck squamous cell carcinoma

BackgroundWe investigated the relationship between genetic alterations and ¹⁸F-FDG PET/CT findings in head and neck squamous cell carcinoma (HNSC).MethodsUsing mRNA-sequences of HNSC samples (480 patients) from the Cancer Genome Atlas (TCGA) portal, gene coexpression networks were constructed via a weighted correlation network analysis (WGCNA) algorithm, and their association with the tumor-to-blood signal ratio on ¹⁸F-FDG PET/CT data (21 patients) was explored. An elastic-net regression model was developed to estimate the PET tumor-to-blood ratio from the gene networks and to derive an FDG signature score (FDG_SS). The FDG_SS was evaluated with regard to clinical variables and general mutational profiles, as well as alterations to oncogenic signaling pathways.FindingsThe FDG_SS values differed across clinical stages (p = 0.027), HPV-status (p< 0.001), and molecular subtypes of HNSC (p< 0.001). Multivariate Cox regression demonstrated that FDG_SS was an independent predictor for overall (p = 0.019) and progression-free survival (p = 0.024). FDG_SS positively correlated with total mutation rate (p = 0.016), aneuploidy (p < 0.001), and somatic copy number alteration scores (p < 0.001). CDKN2A in the cell cycle pathway (q = 0.014) and the TP53 gene in the TP53 pathway (q = 0.005) showed significant differences between high and low FDG_SS patients.ConclusionFDG_SS based on the gene coexpression network was associated with the mutational landscape of HNSC. ¹⁸F-FDG PET/CT is therefore a valuable tool for the in vivo imaging of these cancers, being able to visualize the glucose metabolism of the tumor and allow inferences to be made on the underlying genetic alterations in the tumor.     

Baseline blood volume identified by dynamic contrast-enhanced computed tomography as a new independent prognostic factor in metastatic renal cell carcinoma

BackgroundPreliminary data showed prognostic impact of contrast-enhanced computed tomography (DCE-CT) identified Blood Volume (BV) in patients with metastatic renal cell carcinoma (mRCC). BV as an independent prognostic factor remains to be assessed.Materials and MethodsDCE-CT identified BV was prospectively quantified in patients with mRCC receiving first line therapies, adjusted for International mRCC Database Consortium (IMDC) individual features and treatments, and associated with overall survival (OS), progression-free survival (PFS) and objective response (ORR), using Cox and logistic regression, respectively.Results105 patients with mRCC were included. Median baseline BV was 32.87 mL × 100 g⁻¹ (range 9.52 to 92.87 mL × 100 g⁻¹). BV above median was associated with IMDC favorable risk category (P = 0.004), metastasis free interval ≥ 1 year (P = 0.007), male gender (P = 0.032), normal hemoglobin (P = 0.040) and normal neutrophils (P = 0.007), whereas low BV was associated with poor risk IMDC features (P < 0.05). Patients with high vs. low baseline BV had longer PFS (12.5 vs. 5.6 months, P = 0.015) and longer OS (42.2 vs. 22.4 months, P = 0.001), respectively. In multivariate analysis high baseline BV remained independent favorable for OS (HR 0.49, 95% CI 0.30–0.78, P = 0.003) and PFS (HR 0.64; 95% CI 0.42–0.97, P = 0.036). BV as a continuous variable was also associated with OS in the multivariate analysis (HR 0.98, 95% CI 0.96–1.00, P = 0.017). The estimated concordance index (c-index) was 0.688 using IMDC score and 0.701 when BV was added.ConclusionsDCE-CT identified Blood Volume is a new, independent prognostic factor in mRCC, which may improve the prognostic accuracy of IMDC.     

Application of radiography of computed tomography in non-small cell lung cancer using prognosis model

ObjectiveStudying the diagnostic value of CT imaging in non-small cell lung cancer (NSCLC), and establishing a prognosis model combined with clinical characteristics is the objective, so as to provide a reference for the survival prediction of NSCLC patients.MethodCT scan data of NSCLC 200 patients were taken as the research object. Through image segmentation, the radiology features of CT images were extracted. The reliability and performance of the prognosis model based on the optimal feature number of specific algorithm and the prognosis model based on the global optimal feature number were compared.Results30-RELF-NB (30 optimal features, RELF feature selection algorithm and NB classifier) has the highest accuracy and AUC (area under the subject characteristic curve) in the prognosis model based on the optimal features of specific algorithm. Among the prognosis models based on global optimal features, 25-NB (25 global optimal features, naive Bayes classification algorithm classifier) has the highest accuracy and AUC. Compared with the prediction model based on feature training of specific feature selection algorithm, the overall performance and stability of the prediction model based on global optimal feature are higher.ConclusionThe prognosis model based on the global optimal feature established in this paper has good reliability and performance, and can be applied to the CT radiology of NSCLC.     

Small-animal imaging using clinical positron emission tomography/computed tomography and super-resolution

Considering the high cost of dedicated small-animal positron emission tomography/computed tomography (PET/CT), an acceptable alternative in many situations might be clinical PET/CT. However, spatial resolution and image quality are of concern. The utility of clinical PET/CT for small-animal research and image quality improvements from super-resolution (spatial subsampling) were investigated. National Electrical Manufacturers Association (NEMA) NU 4 phantom and mouse data were acquired with a clinical PET/CT scanner, as both conventional static and stepped scans. Static scans were reconstructed with and without point spread function (PSF) modeling. Stepped images were postprocessed with iterative deconvolution to produce super-resolution images. Image quality was markedly improved using the super-resolution technique, avoiding certain artifacts produced by PSF modeling. The 2 mm rod of the NU 4 phantom was visualized with high contrast, and the major structures of the mouse were well resolved. Although not a perfect substitute for a state-of-the-art small-animal PET/CT scanner, a clinical PET/CT scanner with super-resolution produces acceptable small-animal image quality for many preclinical research studies.     

Novel positron emission tomography/computed tomography of diffuse parenchymal lung disease combining a labeled somatostatin receptor analogue and 2-deoxy-2[18F]fluoro-D-glucose

We prospectively investigated the potential of positron emission tomography (PET) using the somatostatin receptor (SSTR) analogue ??Ga-DOTATATE and 2-deoxy-2[1?F]fluoro-D-glucose (1?F-FDG) in diffuse parenchymal lung disease (DPLD). Twenty-six patients (mean age 68.9 ± 11.0 years) with DPLD were recruited for ??Ga-DOTATATE and 1?F-FDG combined PET/high-resolution computed tomography (HRCT) studies. Ten patients had idiopathic pulmonary fibrosis (IPF), 12 patients had nonspecific interstitial pneumonia (NSIP), and 4 patients had other forms of DPLD. Using PET, the pulmonary tracer uptake (maximum standardized uptake value [SUV(max)]) was calculated. The distribution of PET tracer was compared to the distribution of lung parenchymal changes on HRCT. All patients demonstrated increased pulmonary PET signal with ??Ga-DOTATATE and 1?F-FDG. The distribution of parenchymal uptake was similar, with both tracers corresponding to the distribution of HRCT changes. The mean SUV(max) was 2.2 ± 0.7 for ??Ga-DOTATATE and 2.8 ± 1.0 (t-test, p = .018) for 1?F-FDG. The mean ??Ga-DOTATATE SUV(max) in IPF patients was 2.5 ± 0.9, whereas it was 2.0 ± 0.7 (p = .235) in NSIP patients. The correlation between ??Ga-DOTATATE SUV(max) and gas transfer (transfer factor of the lung for carbon monoxide [TLCO]) was r = -.34 (p = .127) and r = -.49 (p = .028) between 1?F-FDG SUV(max) and TLCO. We provide noninvasive in vivo evidence in humans showing that SSTRs may be detected in the lungs of patients with DPLD in a similar distribution to sites of increased uptake of 1?F-FDG on PET.     

Prognostic value of LIPC in non-small cell lung carcinoma

Non-small cell lung carcinoma (NSCLC) is the most common form of lung cancer and is associated with a high mortality rate worldwide. The majority of individuals bearing NSCLC are treated with surgery plus adjuvant cisplatin, an initially effective therapeutic regimen that, however, is unable to prevent relapse within 5 years after tumor resection in an elevated proportion of patients. The factors that predict the clinical course of NSCLC and its sensitivity to therapy remain largely obscure. One notable exception is provided by pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. PDXK has recently been shown to be required for optimal cisplatin responses in vitro and in vivo and to constitute a bona fide prognostic marker in the NSCLC setting. Together with PDXK, 84 additional factors were identified that influence the response of NSCLC cells to cisplatin, in vitro including the hepatic lipase LIPC. Here, we report that the intratumoral levels of LIPC, as assessed by immunohistochemistry in two independent cohorts of NSCLC patients, positively correlate with disease outcome. In one out of two cohorts studied, the overall survival of NSCLC patients bearing LIPC^high lesions was unaffected, if not slightly worsened, by cisplatin-based adjuvant therapy. Conversely, the overall survival of patients with LIPC^low lesions was prolonged by post-operative cisplatin. Pending validation in appropriate clinical series, these results suggest that LIPC^low NSCLC patients would be those who mainly benefit from adjuvant cisplatin therapy. Thus, the expression levels of LIPC appear to have an independent prognostic value (and perhaps a predictive potential) in the setting of NSCLC. If these findings were confirmed by additional studies, LIPC expression levels might allow not only for NSCLC patient stratification, but also for the implementation of personalized therapeutic approaches.     

Quantification of atherosclerotic plaque activity and vascular inflammation using [18-F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)

Conventional non-invasive imaging modalities of atherosclerosis such as coronary artery calcium (CAC) and carotid intimal medial thickness (C-IMT) provide information about the burden of disease. However, despite multiple validation studies of CAC, and C-IMT, these modalities do not accurately assess plaque characteristics, and the composition and inflammatory state of the plaque determine its stability and, therefore, the risk of clinical events. [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) has been extensively studied in oncologic metabolism. Studies using animal models and immunohistochemistry in humans show that FDG-PET/CT is exquisitely sensitive for detecting macrophage activity, an important source of cellular inflammation in vessel walls. More recently, we and others have shown that FDG-PET/CT enables highly precise, novel measurements of inflammatory activity of activity of atherosclerotic plaques in large and medium-sized arteries. FDG-PET/CT studies have many advantages over other imaging modalities: 1) high contrast resolution; 2) quantification of plaque volume and metabolic activity allowing for multi-modal atherosclerotic plaque quantification; 3) dynamic, real-time, in vivo imaging; 4) minimal operator dependence. Finally, vascular inflammation detected by FDG-PET/CT has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. Plaque activity by FDG-PET/CT is modulated by known beneficial CV interventions such as short term (12 week) statin therapy as well as longer term therapeutic lifestyle changes (16 months). The current methodology for quantification of FDG uptake in atherosclerotic plaque involves measurement of the standardized uptake value (SUV) of an artery of interest and of the venous blood pool in order to calculate a target to background ratio (TBR), which is calculated by dividing the arterial SUV by the venous blood pool SUV. This method has shown to represent a stable, reproducible phenotype over time, has a high sensitivity for detection of vascular inflammation, and also has high inter-and intra-reader reliability. Here we present our methodology for patient preparation, image acquisition, and quantification of atherosclerotic plaque activity and vascular inflammation using SUV, TBR, and a global parameter called the metabolic volumetric product (MVP). These approaches may be applied to assess vascular inflammation in various study samples of interest in a consistent fashion as we have shown in several prior publications.     

Dosimetric impact of contrast-enhanced 4d computed tomography for stereotactic body radiation therapy of hepatocelluar carcinoma

BackgroundA purpose of the study was to investigate the dosimetric impact of contrast media on dose calculation using average 4D contrast-enhanced computed tomography (4D-CECT) and delayed 4D-CT (d4D-CT) images caused by CT simulation contrast agents for stereotactic body radiation therapy (SBRT) of liver cases.Materials and methodsFifteen patients of liver SBRT treated using the volumetric modulated arc therapy (VMAT) technique were selected retrospectively. 4D-CECT, and d4D-CT were acquired with the Anzai gating system and GE CT. For all patients, gross target volume (GTV) was contoured on the ten phases after rigid registration of both the contrast and delayed scans and merged to generate internal target volume (ITV) on average CT images. Region of interest (ROI) was drawn on contrast images and then copied to the delayed images after rigid registration of two average CT datasets. The treatment plans were generated for contrast enhanced average CT, delayed average CT and contrast enhanced average CT with electron density of the heart overridden.ResultsNo significant dosimetric difference was observed in plans parameters (mean HU value of the liver, total monitor units, total control points, degree of modulation and average segment area) except mean HU value of the aorta amongst the three arms. All the OARs were evaluated and resulted in statistically insignificant variation (p > 0.05) using one way ANOVA analysis.ConclusionsContrast enhanced 4D-CT is advantageous in accurate delineation of tumors and assessing accurate ITV. The treatment plans generated on average 4D-CECT and average d4D-CT have a clinically insignificant effect on dosimetric parameters.     

Positron emission tomography with [18F]fluorodeoxyglucose to evaluate neutrophil kinetics during acute lung injury

We measured neutrophil glucose uptake with positron emission tomographic imaging and [18F]fluorodeoxyglucose ([18F]FDG-PET) in anesthetized dogs after intravenous oleic acid-induced acute lung injury (ALI; OA group, n = 6) or after low-dose intravenous endotoxin (known to activate neutrophils without causing lung injury) followed by OA (Etx + OA group, n = 7). The following two other groups were studied as controls: one that received no intervention (n = 5) and a group treated with Etx only (n = 6). PET imaging was performed 1.5 h after initiating experimental interventions. The rate of [3H]deoxyglucose ([3H]DG) uptake was also measured in vitro in cells recovered from bronchoalveolar lavage (BAL) performed after PET imaging. Circulating neutrophil counts fell significantly in animals treated with Etx but not in the other two groups. The rate of [18F]FDG uptake, measured by the influx constant Ki, was significantly elevated (P < 0.05) in both Etx-treated groups (7.9 +/- 2.6 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx group, 9.3 +/- 4.8 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx + OA group) but not in the group treated only with OA (3.4 +/- 0.8 x 10-3 ml blood x ml lung(-1) x min(-1)) when compared with the normal control (1.6 +/- 0.4 x 10(-3) ml blood x ml lung(-1) x min(-1)). [3H]DG uptake was increased (73 +/- 7%) in BAL neutrophils recovered from the Etx + OA group (P < 0.05) but not in the OA group. Ki and [3H]DG uptake rates were linearly correlated (R2 = 0.65). We conclude that the rate of [18F]FDG uptake in the lungs during ALI reflects the state of neutrophil activation. [18F]FDG-PET imaging can detect pulmonary sequestration of activated neutrophils, despite the absence of alveolar neutrophilia. Thus [18F]FDG-PET imaging may be a useful tool to study neutrophil kinetics during ALI.     

Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma

Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.     

The big dilemma: the chemotherapy of non-small cell lung carcinoma

The most problematic area in pulmonary oncology is the chemotherapy of non-small cell lung carcinoma and its place in the therapeutic strategy. Chemotherapy based on the earlier alkylating agents worsened survival of NSCLC patients. That was the reason for the nihilistic approach by many colleagues toward chemotherapy in NSCLC. Today this question has been resolved. Platinum based combined chemotherapy significantly prolongs survival and improves quality of life. Other possibilities are to incorporate the new chemotherapeutic agents (taxanes, Gemcitabine, Vinorelbine, Irinotecan) into the chemotherapeutic regimens. These agents improve the response rate and the quality of life and can be safely administered in outpatient bases, although in comparison to the earlier agents the survival gain is moderate. In early stages the role of adjuvant chemotherapy is questionable. Chemotherapy, surgery and postoperative irradiation may all have a role in the case of N2 disease.In locally advanced disease the use of radiochemotherapy is recommended. In advanced NSCLC chemotherapy is suggested in good performance status. The author summarises the role of chemotherapy in NSCLC, based on literature and on his own experience.     

Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography

A noninvasive method to determine postprandial fatty acid tissue partition may elucidate the link between excess dietary fat and type 2 diabetes. We hypothesized that the positron-emitting fatty acid analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered (18)FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant (18)FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of (18)FTHA in the distal thoracic duct, reaching a peak at time 240 min. (18)FTHA mean standard uptake value increased progressively in the liver, heart, quadriceps, and subcutaneous and visceral adipose tissues between time 60 and 240 min. Most circulating (18)F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received (18)FTHA by gavage, we confirmed that >90% of this tracer reached the circulation as triglycerides. This novel noninvasive method to determine tissue dietary fatty acid distribution in humans should prove useful in the study of the mechanisms leading to lipotoxicity.     

Positron emission tomography imaging of cell death with [18F]FPDuramycin

The noninvasive imaging of cell death, including apoptosis and necrosis, is an important tool for the assessment of degenerative diseases and in the monitoring of tumor treatments. Duramycin is a peptide of 19-amino acids. It binds specifically to phosphatidylethanolamine a novel molecular target for cell death. N-(2-¹⁸F-Fluoropropionyl)duramycin ([¹⁸F]FPDuramycin) was prepared as a novel positron emission tomography (PET) tracer from the reaction of duramycin with 4-nitrophenyl 2-[¹⁸F]fluoropropionate ([¹⁸F]NFP). Compared with control cells (viable tumor cells), the in vitro binding of [¹⁸F]FPDuramycin with apoptotic cells induced by anti-Fas antibody resulted in a doubling increase, while the binding of [¹⁸F]FPDuramycin with necrotic cells induced by three freeze and thaw cycles resulted in a threefold increase. Biodistribution study in mice exhibited its rapid blood and renal clearance and predominant accumulation in liver and spleen over 120 min postinjection. Small-animal PET/CT imaging with [¹⁸F]FPDuramycin proved to be a successful way to visualize in vivo therapeutic-induced tumor cell death. In summary, [¹⁸F]FPDuramycin seems to be a potential PET probe candidate for noninvasive visualization of in vivo cell death sites induced by chemotherapy in tumors.     

Differences in expression of pro-caspases in small cell and non-small cell lung carcinoma.

Expression of several molecular determinants of apoptosis was analyzed in 10 untreated small cell (SCLC) and 6 untreated non-small cell (NSCLC) lung carcinoma cell lines. Although SCLC lines were more prone to spontaneous apoptosis compared with NSCLC lines, the former showed higher Bcl-2 expression and a higher Bcl-2/Bax ratio. In order to understand this apparent contradiction, the expression of pro-caspases as well as calpain was analyzed in these cell lines at the protein and mRNA levels. No differences in protein level of pro-caspases-2, -3, -7, and -9 and of calpain were detected between the SCLC and the NSCLC lines, but a striking difference in pro-caspase-8 expression was noted. All 6 NSCLC, but only 2 of the 10 SCLC lines, expressed pro-caspase-8 protein. Further experiments using the RNase protection assay indicated that the lack of pro-caspase-8 expression at the mRNA level was characteristic for SCLC. Using the same experimental approach, we found that SCLC cell lines in addition to pro-caspase-8 were deficient in mRNA expression of pro-caspases-1, -4, and -10, suggesting a different caspase-activating cascade in SCLC compared with NSCLC. This first systematic characterization of pro-caspase expression in lung cancer surprisingly showed that SCLC, which are more prone to undergo spontaneous apoptosis, are deficient in several pro-caspases and have a high Bcl-2/Bax ratio. Thus, the propensity of SCLC cells to undergo apoptosis cannot be explained only by the expression of factors involved in regulation or execution of apoptosis.     

Arginase and ornithine, as markers in human non-small cell lung carcinoma

The arginase activity and ornithine level were determined in tissue obtained from patients with non-small cell lung carcinoma (NSLC). The arginase activity and ornithine level in tumor tissues were 1.89 +/- 1.28 U/mg protein and 42.32 +/- 25.82 nmol/mg protein, respectively versus 0.67 +/- 0.19 U/mg protein and 10.12 +/- 3.69 nmol/mg protein for normal tissues (p < 0.01).     

Positron emission tomography (18FDG-PET) in the detection of medullary thyroid carcinoma metastases

INTRODUCTION: Medullary thyroid carcinoma (MTC) is usually more advanced at presentation than differentiated thyroid cancers and often has distant metastases. The primary treatment of MTC is total thyroidectomy and regional lymph node dissection. The efficacy of these procedures has been limited by the aggressiveness of the disease and metastatic spread at the time of surgery. Persistently elevated levels of calcitonin (CT) and carcinoembryonic antigen (CEA) or their increase postoperatively are indicative for residual or recurrent disease. Conventional imaging methods such as ultrasonography, computed tomography, magnetic resonance imaging and MIBI scintigraphy usually fail to find the source of calcitonin. Better imaging properties have been shown by DMSA scintigraphy, somatostatin receptor scintigraphy or by positron emission tomography (PET). The aim of the study was to evaluate the diagnostic accuracy of PET for the localisation of occult MTC in patients after surgery with increased concentrations of CT, in whom conventional imaging procedures have not been successful. MATERIAL AND METHODS: The PET investigation using (18)F-fluoro- 2-deoxy-D-glucose combined with computed tomography ((18)FDG-PET/CT) was performed at the Department of Nuclear Medicine (Oncology Centre in Bydgoszcz) between January and October 2004. In five patients with postoperative calcitonin ranging from 164 to > 2000 ng/l (normal < 10 ng/l) no tumour lesions were found using other imaging methods. RESULTS: In four of five cases, responsible lesions with a higher metabolism of FDG, indicating MTC tissue (remnants or metastases), were localised. In one patient no focus of FDG accumulation was found despite high CT concentration. PET detected tumour manifestations in the neck and the mediastinum in two patients, in the lung and the left adrenal gland in one case and in the neck and the liver in another patient. As a result of surgery for the removal of a residual tumour or metastases the accuracy of diagnosis was confirmed by histopathology in all four cases and a decrease in CT and CEA levels was observed in 3/4 cases. The metabolic imaging findings by PET/CT ensured that the surgery on these patients was successful. CONCLUSIONS: For the detection of occult residual or metastatic MTC lesions, (18)FDG-PET is a valuable procedure in imaging diagnostics.     

Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma

Background

Valosin-containing protein (VCP)/p97 is an AAA ATPase molecular chaperone that regulates vital cellular functions and protein-processing. A recent study indicated that VCP expression levels are correlated with prognosis and progression of non-small cell lung carcinoma (NSCLC). We not only verified these findings but also identified the specific role of VCP in NSCLC pathogenesis and progression.

Methodology/Principal Findings

Our results show that VCP is significantly overexpressed in non-small cell lung carcinoma (NSCLC) as compared to normal tissues and cell lines (p<0.001). Moreover, we observed the corresponding accumulation of ubiquitinated-proteins in NSCLC cell lines and tissues as compared to the normal controls. VCP inhibition by si/shRNA or small-molecule (Eeyarestatin I, EerI) significantly (p<0.05, p<0.00007) suppressed H1299 proliferation and migration but induced (p<0.00001) apoptosis. Cell cycle analysis by flow cytometry verified this data and shows that VCP inhibition significantly (p<0.001, p<0.003) induced cell cycle arrest in the G0/G1 phases. We also found that VCP directly regulates p53 and NFκB protein levels as a potential mechanism to control tumor cell proliferation and progression. Finally, we evaluated the therapeutic potential of VCP inhibition and observed significantly reduced NSCLC tumor growth in both in vitro and xenograft murine (athymic-nude) models after EerI treatment (p<0.05).

Conclusions/Significance

Thus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFκB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.