RESUMEN
PURPOSE: Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population. METHODS: In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC. RESULTS: Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone. CONCLUSION: Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/patología , Estudios Retrospectivos , Marcadores Genéticos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/genética , Pronóstico , Medición de RiesgoRESUMEN
Posttreatment evaluation of gastric mucosa-associated lymphoid tissue (MALT) lymphoma currently relies on esophagogastroduodenoscopy with histological assessment of biopsies. Overexpression of the G protein-coupled C-X-C chemokine receptor type 4 (CXCR4) has been previously observed in MALT lymphoma. The aim of this prospective study was to evaluate positron emission tomography (PET) with the novel CXCR4 tracer [68Ga]Pentixafor as a potential alternative to follow up biopsies for assessment of residual disease (noncomplete remission [CR]) after first-line Helicobacter pylori eradication. Forty-six post-H pylori eradication [68Ga]Pentixafor-PET/magnetic resonance imaging (MRI) examinations of 26 gastric MALT lymphoma patients, and 20 [68Ga]Pentixafor-PET/MRI examinations of 20 control group patients without lymphoma, were analyzed. In the MALT lymphoma group, time-matched gastric biopsies were used as reference standard and showed CR in 6 cases. Pooled examination-based accuracy, sensitivity, specificity, and positive and negative predictive values of [68Ga]Pentixafor-PET for detection of residual gastric MALT lymphoma at follow-up were 97.0%, 95.0%, 100.0%, 100.0%, and 92.9%, respectively. Maximum and mean PET standardized uptake values showed moderate correlation with immunohistochemistry-based CXCR4+ cell counts, with correlation coefficients of r = 0.51 and r = 0.52 (P = .008 and P = .006). In summary, CXCR4 imaging with [68Ga]Pentixafor-PET may represent a promising test for assessment of residual gastric MALT lymphomas after H pylori eradication.
Asunto(s)
Complejos de Coordinación/análisis , Radioisótopos de Galio/análisis , Linfoma de Células B de la Zona Marginal/diagnóstico por imagen , Péptidos Cíclicos/análisis , Receptores CXCR4/análisis , Neoplasias Gástricas/diagnóstico por imagen , Anciano , Antibacterianos/uso terapéutico , Estudios de Seguimiento , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Humanos , Linfoma de Células B de la Zona Marginal/microbiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Estudios Prospectivos , Neoplasias Gástricas/microbiologíaRESUMEN
INTRODUCTION: the diagnostic performance of [64Cu]-DOTAGA-PSMA PET-CT imaging was compared retrospectively to [18F]-PSMA PET-CT in prostate cancer patients with recurrent disease and in the primary staging of selected patients with advanced local and possible metastatic disease. METHODS: We retrospectively selected a total of 100 patients, who were consecutively examined in our department, with biochemical recurrence after radical prostatectomy or who had progressive local and possible metastatic disease in the last 3 months prior to this investigation. All patients were examined with a dedicated PET-CT scanner (Biograph; Siemens Healthineers). A total of 250 MBq (3.5 MBq per kg bodyweight, range 230-290 MBq) of [64Cu]-DOTAGA-PSMA or [18-F]-PSMA was applied intravenously. PET images were performed 1 h post-injection (skull base to mid-thigh). The maximum standardized uptake values (SUVmax) of PSMA-positive lesions and the mean standardized uptake value (SUVmean) of the right liver lobe were measured. RESULTS: All but 9/50 of the patients (18%; PSA range: 0.01-0.7 µg/L) studied with [64Cu]-DOTAGA-PSMA and 6/50 of the ones (12%; PSA range: 0.01-4.2) studied with [18F]-PSMA had at least one positive PSMA lesion shown by PET-CT. The total number of lesions was higher with [64Cu]-DOTAGA-PSMA (209 vs. 191); however, the median number of lesions was one for [64Cu]-DOTAGA-PSMA and two for [18F]-PSMA. Interestingly, the median SUVmean of the right liver lobe was slightly higher for [18F]-PSMA (11.8 vs. 8.9). CONCLUSIONS: [64Cu]-DOTAGA-PSMA and [18F]-PSMA have comparable detection rates for the assessment of residual disease in patients with recurrent or primary progressive prostate cancer. The uptake in the liver is moderately different, and therefore at least the SUVs of the lesions in both studies would not be comparable.
Asunto(s)
Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Diagnóstico por Imagen , Humanos , Masculino , Prostatectomía , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/cirugía , Estudios RetrospectivosRESUMEN
PURPOSE: [177Lu]Lu-PSMA-617 radio-ligand therapy (PSMA-RLT) is emerging in patients with an advanced metastatic castration-resistant prostate cancer (mCRPC). Here, we aimed to estimate the results of PSMA-RLT in terms of response, progression-free survival (PFS), and overall survival (OS) in patients receiving a highly standardized treatment regimen due to mCRPC. The toxicity of PSMA-RLT has also been evaluated. PATIENTS AND METHODS: Fifty-four patients (mean age 72 ± 7 years, median PSA at time of initial therapy 66 [range 1.0-4890 µg/L]), receiving three PSMA-RLT cycles (mean 7315 ± 573 MBq) at four weekly intervals, were included in this retrospective analysis. Hematological and biochemical parameters were regularly determined in every patient. Kaplan-Meier estimates were used to assess PFS and OS and a Cox proportional hazard model was used to analyze significant associations. Treatment response was based on PSA measurements 4 weeks after the 3rd treatment. RESULTS: The majority of patients were previously treated with abiraterone/enzalutamide (69%) and docetaxel/cabazitaxel (67%). In total, 79% of the patients showed a decrease in PSA (median PSA decrease from 66 to 19.8, range 0.7-4563 µg/L, P < 0.001) 1 month after the 3rd therapy cycle. Among them, 58% and 35% demonstrated a PSA-decline of > 50% and > 80%, respectively. Median OS was 119 weeks; median PFS was 25 weeks. Patients presenting with a PSA decline had significantly longer PFS (27 vs. 15 weeks, P < 0.0001) and OS (median survival not reached vs. 52 weeks, P < 0.001) than patients with no PSA reduction. Moreover, patients with reduction in PSA levels ≥ 50% (median survival not reached vs. 52 weeks, P < 0.0001) and ≥ 80% (median survival not reached vs. 87 weeks, P = 0.008) lived significantly longer. While hemoglobin did not change during treatment, levels of platelets (236 ± 71 g/L vs. 193 ± 67 g/L) and leucocytes (6.5, range 2.9-13.7 g/L vs. 4.8, range 1.5-12.3 g/L) decreased significantly, both P < 0.001. Two grade 3 leukocytopenia and one grade 3 anemia were observed. CONCLUSION: Intense PSMA-RLT regime with four weekly intervals between the cycles is well-tolerated and offers favorable response rates, PFS, and survival rates for patients with mCRPC.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Anciano , Dipéptidos , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Humanos , Masculino , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
MALT lymphomas express the chemokine receptor CXCR4 on a regular basis, and [68Ga]Ga-Pentixafor-PET has been shown to quantify CXCR4 expression non-invasively. We, therefore, aimed to evaluate [68Ga]Ga-Pentixafor-PET/MRI for the non-invasive assessment of MALT lymphomas. METHODS: We included 36 MALT lymphoma patients, who had not undergone previous systemic or radiation therapy, in our prospective, IRB-approved, proof-of-concept study. Involved anatomic regions were the orbit (n=14), stomach (n=10), lungs (n=5), and other sites (soft-tissues n=3; adrenal gland, tonsils, parotid gland, and urinary bladder n=1, respectively). MRI sequences included an axial 2-point Dixon T1 VIBE SPAIR 3D sequence for PET attenuation correction; a coronal T2 HASTE sequence; and an axial echo-planar imaging SPAIR-based diffusion-weighted sequence (DWI) obtained during free-breathing (b-values, 50 and 800), with corresponding ADC (apparent diffusion coefficient) maps. RESULTS: In 33/36 patients, there were MALT lymphomas with an increased uptake of [68Ga]Ga-Pentixafor; all current lymphoma manifestations showed an increased uptake and, accordingly, were positive on the PET/MRI. The remaining three patients had undergone surgery for their orbital MALT lymphomas prior to PET/MRI. Mean SUVmax was 8.6 ± 4.7, mean SUVmean was 4.7 ± 1.8, and mean SUVpeak was 8.0 ± 4.2. The mean SUVmax of the liver was 1.8, and the mean tumor-to-liver ratio was 2.9 ± 2.0. There were no significant differences in SUVmax (P=0.22), SUVmean (P=0.53), SUVpeak (P=0.29), or SUVt/l (P=0.92) between the four anatomic regions (orbit, stomach, lungs, other). The mean tumor volume was 146 ± 499. CONCLUSIONS: Our results thus indicate that [68Ga]Ga-Pentixafor-PET is feasible for the assessment of MALT lymphomas, with a good tumor-to-background ratio in terms of radiotracer uptake.
Asunto(s)
Complejos de Coordinación , Linfoma de Células B de la Zona Marginal/diagnóstico , Péptidos Cíclicos , Receptores CXCR4/metabolismo , Adulto , Anciano , Femenino , Radioisótopos de Galio , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios ProspectivosRESUMEN
PURPOSE: Accurate photon attenuation assessment from MR data remains an unmet challenge in the thorax due to tissue heterogeneity and the difficulty of MR lung imaging. As thoracic tissues encompass the whole physiologic range of photon absorption, large errors can occur when using, for example, a uniform, water-equivalent or a soft-tissue-only approximation. The purpose of this study was to introduce a method for voxel-wise thoracic synthetic CT (sCT) generation from MR data attenuation correction (AC) for PET/MR or for MR-only radiation treatment planning (RTP). METHODS: Acquisition: A radial stack-of-stars combining ultra-short-echo time (UTE) and modified Dixon (mDixon) sequence was optimized for thoracic imaging. The UTE-mDixon pulse sequence collects MR signals at three TE times denoted as UTE, Echo1, and Echo2. Three-point mDixon processing was used to reconstruct water and fat images. Bias field correction was applied in order to avoid artifacts caused by inhomogeneity of the MR magnetic field. ANALYSIS: Water fraction and R2* maps were estimated using the UTE-mDixon data to produce a total of seven MR features, that is UTE, Echo1, Echo2, Dixon water, Dixon fat, Water fraction, and R2*. A feature selection process was performed to determine the optimal feature combination for the proposed automatic, 6-tissue classification for sCT generation. Fuzzy c-means was used for the automatic classification which was followed by voxel-wise attenuation coefficient assignment as a weighted sum of those of the component tissues. Performance evaluation: MR data collected using the proposed pulse sequence were compared to those using a traditional two-point Dixon approach. Image quality measures, including image resolution and uniformity, were evaluated using an MR ACR phantom. Data collected from 25 normal volunteers were used to evaluate the accuracy of the proposed method compared to the template-based approach. Notably, the template approach is applicable here, that is normal volunteers, but may not be robust enough for patients with pathologies. RESULTS: The free breathing UTE-mDixon pulse sequence yielded images with quality comparable to those using the traditional breath holding mDixon sequence. Furthermore, by capturing the signal before T2* decay, the UTE-mDixon image provided lung and bone information which the mDixon image did not. The combination of Dixon water, Dixon fat, and the Water fraction was the most robust for tissue clustering and supported the classification of six tissues, that is, air, lung, fat, soft tissue, low-density bone, and dense bone, used to generate the sCT. The thoracic sCT had a mean absolute difference from the template-based (reference) CT of less than 50 HU and which was better agreement with the reference CT than the results produced using the traditional Dixon-based data. CONCLUSION: MR thoracic acquisition and analyses have been established to automatically provide six distinguishable tissue types to generate sCT for MR-based AC of PET/MR and for MR-only RTP.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Tórax/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Análisis por Conglomerados , HumanosRESUMEN
BACKGROUND: Graves' disease (GD) is characterized by thyrotoxicosis and goiter and arises through circulating autoantibodies that bind to, and stimulate, the thyroid hormone receptor (TSHR). A temporal relation between the onset of hyperthyroidism and the onset of ophthalmopathy, a common extrathyroidal manifestation, has been demonstrated. Graves' ophthalmopathy (GO) is typically characterized by an inflammation and expansion of the extraocular muscles and an increase in retroorbital fat. There are currently three forms of therapies offered for hyperthyroidism caused by Graves' disease: antithyroid drugs (ATD) (thionamides), radioiodine ablation (RAI) and thyroidectomy (Tx). To date, there is no clear recommendation on the treatment of Graves' disease and GO, mainly due to the individuality of the disease in each patient. The aim of the study is to examine the difference in the outcome of GO in patients with moderate-to-severe GO who receive Tx versus further ATD after suffering their first relapse of GO, or in which GO stays the same following the initial decrease in ATD therapy after 6 months. METHODS/DESIGN: This prospective randomized clinical trial with observer-blinded analysis will analyze 60 patients with moderate-to-severe GO who receive Tx versus ATD without surgery. Main outcome variables include: muscle index measurements via ultrasound and thyroid antibody levels. Additional outcome variables include: Clinical Activity Score (CAScore), NOSPECS score, superonasal index measurements via ultrasound, and quality of life score. DISCUSSION: This study should allow for better therapeutic choices in patients with moderate-to-severe GO. In addition, it should demonstrate whether the outcome of GO in patients with moderate-to-severe GO is better in those who receive early Tx versus further ATD. Furthermore, this study will aim to establish a standard glucocorticoid scheme before and after Tx in patients with moderate-to-severe EO. TRIAL REGISTRATION: Eudra-CT: 2015-003515-38; Medical University of Vienna Protocol Record 1839/2015. Date of Ethics Committee approval: 19 January 2017. Registered on 27 January 2017.
Asunto(s)
Antitiroideos/uso terapéutico , Oftalmopatía de Graves/terapia , Tiroidectomía , Antitiroideos/efectos adversos , Austria , Ensayos Clínicos Fase III como Asunto , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/etiología , Humanos , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Índice de Severidad de la Enfermedad , Tiroidectomía/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Manual contouring remains the most laborious task in radiation therapy planning and is a major barrier to implementing routine Magnetic Resonance Imaging (MRI) Guided Adaptive Radiation Therapy (MR-ART). To address this, we propose a new artificial intelligence-based, auto-contouring method for abdominal MR-ART modeled after human brain cognition for manual contouring. METHODS/MATERIALS: Our algorithm is based on two types of information flow, i.e. top-down and bottom-up. Top-down information is derived from simulation MR images. It grossly delineates the object based on its high-level information class by transferring the initial planning contours onto daily images. Bottom-up information is derived from pixel data by a supervised, self-adaptive, active learning based support vector machine. It uses low-level pixel features, such as intensity and location, to distinguish each target boundary from the background. The final result is obtained by fusing top-down and bottom-up outputs in a unified framework through artificial intelligence fusion. For evaluation, we used a dataset of four patients with locally advanced pancreatic cancer treated with MR-ART using a clinical system (MRIdian, Viewray, Oakwood Village, OH, USA). Each set included the simulation MRI and onboard T1 MRI corresponding to a randomly selected treatment session. Each MRI had 144 axial slices of 266 × 266 pixels. Using the Dice Similarity Index (DSI) and the Hausdorff Distance Index (HDI), we compared the manual and automated contours for the liver, left and right kidneys, and the spinal cord. RESULTS: The average auto-segmentation time was two minutes per set. Visually, the automatic and manual contours were similar. Fused results achieved better accuracy than either the bottom-up or top-down method alone. The DSI values were above 0.86. The spinal canal contours yielded a low HDI value. CONCLUSION: With a DSI significantly higher than the usually reported 0.7, our novel algorithm yields a high segmentation accuracy. To our knowledge, this is the first fully automated contouring approach using T1 MRI images for adaptive radiotherapy.
Asunto(s)
Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias Pancreáticas/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Guiada por Imagen/métodos , Máquina de Vectores de Soporte , Humanos , Imagen Multimodal , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Tomografía Computarizada por Rayos X , Flujo de TrabajoRESUMEN
223Radium (223Ra) has emerged as treatment prolonging survival in patients with metastatic castration-resistant prostate cancer (CRPC). As 223Ra can cause hematotoxicity (HT), pre-existing hematopoiesis might influence the efficacy of 223Ra and the rate of hematotoxicity, but as to our knowledge such data has not been published yet, we retrospectively conducted an analysis on patients receiving 223Ra. 54 patients treated with 223Ra had a median survival of 67 weeks, which was significantly reduced in patients with pre-existing Hb toxicity (Tox) grade 2 (48 weeks P = 0.008) as compared to grade 1 (67 weeks) and normal levels of Hb (not reached); survival in patients with Plt Tox grade 1 was significantly reduced (44 weeks) as compared to normal Plt counts (71 weeks, P = 0.033). Patients with impaired hematopoiesis regarding Hb and Plts developed significantly more grade 3 and 4 HT (Hb < 10 g/dl: 42.9% [3/7] vs 10.6% [5/47], P < 0.001; Plt < 150 G/L: 28.6% [2/7] vs 6.4% [3/47], P = 0.002) and received significantly fewer treatment cycles (Hb <10 g/dl: 5.1 vs 5.8, P = 0.04; Plt < 150 G/L: 3.4 vs 5.6, P < 0.001). These results imply that pre-existing impaired hematopoiesis, in particular thrombocytopenia and anemia, before 223Ra therapy, is an important risk factor for worse outcome of treatment with 223Ra.
RESUMEN
PURPOSE: To investigate [11C]acetate PET-surrogate parameter of fatty acid synthase activity-as suitable tool for diagnosis and monitoring of liver steatosis. METHODS: In this retrospective study, data were obtained from 83 prostatic carcinoma patients from 1/2008 to 1/2014. Mean HU was calculated from unenhanced CT of all patients from liver with liver HU less than 40 as threshold for liver steatosis. SUVmax of the liver and of the blood pool in thoracic aorta (as background for calculation of a liver/background ratio [SUVl/b]) was measured. t test was used with a P < 0.05 considered as statistically significant difference and ROC analysis was used for calculating specificity and sensitivity. RESULTS: 19/83 patients (20%) had diagnosis of hepatic steatosis according to CT. Uptake of [11C]acetate was significantly higher in patients with hepatic steatosis as compared to control group (SUVmax 7.96 ± 2.0 vs. 5.48 ± 2.3 [P < 0.001]). There was also a significant correlation between both SUVmax (r = - 0.52, P < 0.001) and SUVl/b (r = - 0.59, P < 0.001) with the density (HU) of the liver. In ROC analysis for detection of liver steatosis SUVmax (threshold: 5.86) had a sensitivity of 94% and specificity of 69% with an AUC of 0.81. Increasing body mass index is correlated with the severity of steatosis. CONCLUSION: We showed for the first time that hepatic steatosis associates with increased [11C]acetate uptake. Also, severity of steatosis correlates with [11C]acetate uptake. [11C]acetate uptake PET seems promising for the assessment of liver steatosis.
Asunto(s)
Hígado Graso/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Acetatos , Anciano , Anciano de 80 o más Años , Carbono , Humanos , Masculino , Persona de Mediana Edad , Interpretación de Imagen Radiográfica Asistida por Computador , Radiofármacos , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
AIM: High levels of fatty acid synthase have shown to correlate with the aggressiveness of prostate cancer. As [(11) C]acetate exhibits a close correlation with the level of fatty acid synthase, we aimed to assess whether the SUV in [(11) C]acetate PET serves as a suitable prognostic marker in patients with recurrent prostate cancer. MATERIALS AND METHODS: In 123 consecutive patients, examined between 2010 and 2014, the maximum standardized uptake value (SUVmax) of local recurrences as well as lymph node and bone metastases was measured. Choosing the spleen as a standard for relatively high physiological uptake, a ratio of tumor to spleen uptake (SUVts) was calculated for standardizing the uptake, too. The corresponding initial Gleason scores (GS) and serum-PSA levels around the time of the performed PET/CT for each patient were retrospectively collected and PSA doubling together with PSA velocity were determined. For further analysis patients were divided with regard to their initial Gleason score (≤3 + 4 and ≥ 4 + 3). The median of PSA velocity was calculated to separate patients with a high and low PSA velocity and Mann-Whitney U or Student's t-test were used, testing for significant differences. For correlation Spearmen-Rho test was used. RESULTS: PET was positive for recurrence in 82/123 patients. PSA was significantly higher in PET-positive than in negative patients (5.9 vs. 3.2 ng/ml; P = 0.006). Initial Gleason score did not differ in PET negative and positive patients (P = 0.3), whereas PSA velocity was markedly higher in PET positive patients (0.4 vs. 0.1 ng/ml/month; P = 0.01). Median SUVmax of PET positive patients was 5.23 (mean 5.78; range 0.9-16.8) and meadian SUVts was 0.78 (mean 0.84, range 0.14-2.50). SUVts was significantly higher in patients with high PSA velocity (SUVts 0.76 vs. 0.92; P = 0.009), whereas SUVmax failed statistical significance (5.4 vs. 6.3 ng/ml/month; P = 0.08). Patients with a high SUVmax proved to have a significantly higher median Gleason score compared to low uptake 8.0 vs. 7.0; P = 0.004). Vice versa both SUVmax (GS 6: 5.0; GS 7: 5.6; GS 8: 5.7; GS 9: 6.5; r = 0.30, P = 0.008) and SUVts (GS 6: 0.63; GS 7: 0.68; GS 8: 0.85; GS 9: 0.89; r = 0.30, P = 0.006) significantly correlated with Gleason score. Patients with a Gleason score ≤ 3 + 4 had a significantly lower SUVmax (4.8 vs. 5.7; P = 0.02) and SUVts (0.67 vs. 0.85; P = 0.02) as compared to a Gleason score ≥ 4 + 3. CONCLUSION: [(11) C]acetate uptake demonstrated to correlate with initial Gleason score. Furthermore, patients with a high PSA velocity proved to have higher [(11) C]acetate uptake in tumor lesions.
Asunto(s)
Adenocarcinoma/metabolismo , Ácido Graso Sintasas/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Neoplasias de la Próstata/metabolismo , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patología , Pronóstico , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Cintigrafía , Radiofármacos , Estudios RetrospectivosRESUMEN
Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant cancer metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) and are inhibited by FASN blockers, whereas normal cells are FASN-negative and FASN-inhibitor-resistant. Here, we demonstrate that this holds true when ovarian/oviductal cells reside in their autochthonous tissues, whereas in culture they express FASN and are FASN-inhibitor-sensitive. Upon subculture, nonmalignant cells cease growth, express senescence-associated ß-galactosidase, lose FASN and become FASN-inhibitor-resistant. Immortalized ovarian/oviductal epithelial cell linesalthough resisting senescencereveal distinct growth activities, which correlate with FASN levels and FASN drug sensitivities. Accordingly, ectopic FASN stimulates growth in these cells. Moreover, FASN levels and lipogenic activities affect cellular lipid composition as demonstrated by thin-layer chromatography. Correlation between proliferation and FASN levels was finally evaluated in cancer cells such as HOC-7, which contain subclones with variable differentiation/senescence and corresponding FASN expression/FASN drug sensitivity. Interestingly, senescent phenotypes can be induced in parental HOC-7 by differentiating agents. In OC cells, FASN drugs induce cell cycle blockade in S and/or G2/M and stimulate apoptosis, whereas in normal cells they only cause cell cycle deceleration without apoptosis. Thus, normal cells, although growth-inhibited, may survive and recover from FASN blockade, whereas malignant cells get extinguished. FASN expression and FASN drug sensitivity are directly linked to cell growth and correlate with transformation/differentiation/senescence only indirectly. FASN is therefore a metabolic marker of cell proliferation rather than a marker of malignancy and is a useful target for future drug development.
Asunto(s)
Biomarcadores de Tumor/genética , Proliferación Celular/genética , Acido Graso Sintasa Tipo I/genética , Neoplasias Ováricas/genética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ciclo Celular , Línea Celular , Línea Celular Tumoral , Células Epiteliales/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
BACKGROUND: Sirtuin (SIRT) proteins are class I histone deacetylases displaying gene regulatory functions in inflammatory, cancer, and metabolic diseases. These SIRT actions involve the nuclear factor κ B and its inhibitor I κ B pathway. However, the regulation of SIRT in vivo is still unclear. MATERIAL AND METHODS: In a human endotoxemia model, 20 healthy male subjects received an intravenous bolus of 2 ng/kg body weight Escherichia coli endotoxin (LPS). SIRT expression was investigated in peripheral blood mononuclear cells (PBMC) with qPCR and Western blot before and 3 hours, 6 hours, and 24 hours after LPS challenge. Additionally, SIRT regulation was studied in vitro in cultivated PBMC after incubation with 20 ng/mL LPS. RESULTS: A downregulation by >40% of SIRT1 mRNA was detectable 3 hours after LPS and of SIRT3 mRNA 6 hours after LPS. SIRT3, IκBα, and IκB-ß protein expressions were decreased 3 and 6 hours after LPS. SIRT2 mRNA or protein expression did not change following LPS. These findings were consistent in vitro and associated with augmented phosphorylation of IκB-ß. DISCUSSION: In this E. coli endotoxemia model, SIRT1 and SIRT3 mRNA expressions in PBMC in humans were reduced after LPS challenge. This suggests that SIRT may represent an inflammatory target protein in vivo.