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Abstract: Objectives: Tumor infiltrating lymphocytes (TILs) and T regulatory cells (Tregs) have been associated with prognosis in ovarian cancer, but their prognostic significance in ascites has not been studied. We performed a prospective study of T lymphocytes isolated from ascites from patients with ovarian carcinoma and we compared them with the respective populations in blood and tumors. Methods: Mononuclear cells from ascites (n =71) and blood were isolated by Ficoll, while tumor lymphocytes (n =20) were obtained upon mechanical dissociation. Phenotypic analysis was performed with flow cytometry. Ascites from 10 patients with cirrhosis was used as control. Results: Tregs containing CD4+CD25+ cells, NK-T containing CD3+CD56+ cells and CD69 and HLADR expression of CD4 and CD8 lymphocytes were significantly increased in tumor ascites compared to blood and control ascites. A selective accumulation of these populations in the ascites of cancer patients, was suggested by the significantly higher ascites/blood (A/B) ratios in cancer patients but not controls. Cancer cell content in ascites was correlated with CD4+CD25+, CD4+CD69+, CD4+HLADR+ and CD8+CD69+ cells. There was no correlation of lymphocyte populations between ascites and samples from peritoneal metastases. Higher tumor grade was associated with increased A/B CD4+CD25+ ratio and reduced CD3+CD56+ cells, while platinum resistance was associated with reduced A/B CD3+CD56+ ratio. Conclusions: There are significant differences of CD3+CD56+ and CD25+CD4+ lymphocytes and increase in lymphocyte activation between blood, ascites and peritoneal metastases from patients with ovarian cancer. The selective accumulation of CD3+CD56+ population in ascites may be a predictive factor for platinum resistance. [Copyright &y& Elsevier]

Objective: The aim of this study is to evaluate the implementation of the elements of enhanced recovery (ERAS) protocols in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for metastatic ovarian cancer. ERAS protocols have shown improvement in the perioperative outcomes of patients who underwent cytoreductive surgery for metastatic ovarian cancer by reducing the length of stay as well as the postoperative complications and by improving patients' postoperative experience ., Methods: This is a feasibility study involving retrospective analysis from (31) patients who underwent cytoreductive surgery and HIPEC versus (35) a control group that underwent cytoreductive surgery only, prior to the introduction of the HIPEC programme for metastatic ovarian cancer. All patients had undergone neoadjuvant chemotherapy prior to surgery. We compared the compliance for each element of the ERAS protocol between the two study groups., Results: We analyzed data from 66 patients, 31 in HIPEC group and 35 in the control goup. We found no significant difference in the patients' characteristics between the two groups and there were no differences in the implementation of 8 elements of the ERAS protocols (100 % for both groups). The use of nasogastric tube was more frequently observed in patients undergoing surgery and HIPEC compared to those undergoing surgery alone (42 % vs 0 %, respectively; p < 0.001). The number of patients who were mobilized on the first postoperative day was higher in the group undergoing surgery and HIPEC (87.1 % vs 57.1 %, respectively; p = 0.007), however there was no significant difference in the percentage of patients that had early removal of the urinary catheter (p = 0.12), nor in the percentage of patients that received early feeding (p = 0.18). Finally, there were no statistically significant differences in the complication rates, the length of hospital stay and the re-admission rates between the two groups., Conclusion: Enhanced recovery protocols can be implemented safely in patients undergoing cytoreductive surgery and HIPEC for ovarian cancer., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The purpose of our systematic review was to examine the effects of any physical activity/exercise intervention combined with any diet/nutrition intervention on any biological/biochemical index, quality of life (QoL), and depression in breast, lung, colon and rectum, prostate, stomach, and liver cancer patients and/or cancer survivors., Methods: A systematic review and meta-analysis were undertaken, using PRISMA guidelines and the Cochrane Handbook. The systematic review protocol can be found in the PROSPERO database; registration number: CRD42023481429., Results: We found moderate-quality evidence that a combined intervention of physical activity/exercise and nutrition/diet reduced body mass index, body weight, fat mass, insulin, homeostatic model assessment for insulin resistance, C-reactive protein, triglycerides, and depression, while it increased high-density lipoprotein, the physical component of QoL, and general functional assessment of cancer therapy., Conclusions: We conclude that a combined intervention of physical activity/exercise and diet/nutrition may decrease body weight, fat mass, insulin levels, and inflammation, and improve lipidemic profile, the physical component of QoL, and depression in cancer patients and survivors. These outcomes indicate a lower risk for carcinogenesis; however, their applicability depends on the heterogeneity of the population and interventions, as well as the potential medical treatment of cancer patients and survivors.

Purpose: This study aimed to examine the recovery kinetics (i.e., time-dependent changes) of performance-related variables between two 120-min male football games performed 3 d apart with and without carbohydrate supplementation., Methods: Twenty male players (20 ± 1 yr; body fat, 14.9% ± 5.1%; maximal oxygen consumption, 59.4 ± 3.7 mL·kg -1 ·min -1 ) participated in two 120-min football games (G1, G2) according to a randomized, two-trial, repeated-measures, crossover, double-blind design. Participants received carbohydrate/placebo supplements during recovery between games. Field activity was monitored during the games. Performance testing and blood sampling were performed before and at 90 and 120 min of each game. Muscle biopsies were collected at baseline and at 90 and 120 min of G1 and pre-G2., Results: Compared with G1, G2 was associated with reduced total distance (10,870 vs 10,685 m during 90 min and 3327 vs 3089 m during extra 30 min; P = 0.007-0.038), average (6.7 vs 6.2 km/h during extra 30-min game-play; P = 0.007) and maximal speed (32.2 vs 30.2 km/h during 90 min and 29.0 vs 27.9 km/h during extra 30 min; P < 0.05), accelerations/decelerations ( P < 0.05), and mean heart rate ( P < 0.05). Repeated sprint ability ( P < 0.001), jumping ( P < 0.05), and strength ( P < 0.001) performance were compromised before and during G2. Muscle glycogen was not restored at G2 baseline ( P = 0.005). Extended game-play reduced lymphocyte, erythrocyte counts, hematocrit, hemoglobin, reduced glutathione ( P < 0.05) and increased delayed onset of muscle soreness, creatine kinase activity, blood glycerol, ammonia, and protein carbonyls ( P < 0.05) before and during G2. Pax7 + ( P = 0.004) and MyoD + cells ( P = 0.019) increased at baseline G2. Carbohydrate supplementation restored performance and glycogen, reduced glycerol and delayed onset of muscle soreness responses, and increased leukocyte counts and Pax7 + and MyoD + cells., Conclusions: Results suggest that extended football games induce a prolonged recovery of performance, which may be facilitated by carbohydrate supplementation during a congested game fixture., (Copyright © 2024 by the American College of Sports Medicine.)

Background/aim: Emerging data suggest that addition of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of interval cytoreduction for patients with metastatic ovarian cancer is associated with a survival benefit. However, the implementation of this treatment is affected by concerns related to its potential morbidity. We present data from the first centre in the UK implementing HIPEC as part of treatment for patients with advanced ovarian cancer undergoing interval cytoreductive surgery., Patients and Methods: This is a prospective study of patients planned to undergo cytoreductive surgery and HIPEC for advanced ovarian cancer over a 30-month period. All patients had undergone neoadjuvant chemotherapy prior to surgery. Patients with stage III/IV ovarian cancer who underwent complete or near complete cytoreduction (<2.5 mm residual disease) received HIPEC using a closed technique., Results: A total of 31 patients were included in the study, of which 30 had complete cytoreduction and 1 patient had residual disease <2.5 mm. The mean age of the patients was 63.7±2.8 years. Median peritoneal cancer index score was 9 (range=3-31). The mean operating time was 515.4±55.1 min. The mean length of hospital stay was 7.6±0.8 days. In total, 24 complications were observed in 18 patients (58.1%), while 6.5% of the patients experienced grade 3/4 complications. There were no deaths within 30-days from the surgery. Age was found to be an independent predictor of both postoperative complications of any grade and prolonged hospital stay., Conclusion: Interval cytoreductive surgery and HIPEC for patients with advanced ovarian cancer is associated with low perioperative morbidity., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: We conducted a systematic review to evaluate the outcomes and role of ultra-minimally invasive surgical approaches for treatment of women diagnosed with endometrial cancer. Although, there is no agreed definition of the term "ultraminimal," we considered the hysteroscopic surgery, single-port surgery, mini/microlaparoscopy and percutaneous laparoscopy as surgical approaches that would best fit this description., Evidence Acquisition: The current systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Guidelines. We performed a literature search using MEDLINE (PubMed), EMBASE and Cochrane Library databases for English-language studies published before August 1, 2020. We used the following keywords including "endometrial cancer," "endometrial malignancy," "fertility-sparing or preserving," "hysteroscopy," "hysteroscopic resection," "dilatation and curettage," "ultra-minimally invasive surgery," "progestin therapy," "hormone therapy," "single port," "single-site," "minilaparoscopy," "microlaparoscopy," "percutaneous" and "3 mm laparoscopy.", Evidence Synthesis: A total of 21 studies, reporting on 229 patients were included. 219 (95.6%) of the patients were premenopausal. Among premenopausal women, complete disease response was reported in 186 (84.9%) patients. The complete response rate was 77.1% in patients who underwent focal or extensive endometrial resection, 90.9% in patients who had the two-step approach and 88.9% in the group of patients treated with the three-step technique. Among 98 women who wished and attempted to conceive, 65 (66.3%) women became pregnant. Recurrent disease was diagnosed in 26 of 219 (11.9%) patients. No surgical complications were reported. In 10 postmenopausal patients that underwent hysteroscopic resection, no recurrences were detected after 5 years of follow-up. We identified 11 studies that reported on the use single-port laparoscopic surgery and included a total of 447 patients. The rate of intraoperative and postoperative complications was 2.6% and 5.2%, respectively. The majority of the studies did not report on the duration of follow-up or oncological outcomes. Ten studies, including 296 patients, investigated the role of single-port robotic-assisted laparoscopy. The overall rate of intraoperative and postoperative complications was 1.0% and 7.1%, respectively. Two studies, including 38 patients, reported on the role of minilaparoscopy. None of these cases required conversion to laparotomy. Data on overall survival in the cohort of patients that underwent minilaparoscopy were not reported. We found only one publication reporting on the use of percutaneous laparoscopy. This prospective study included 30 patients. No complication was reported, and with a median follow-up time of 14 months (range 12-36) no recurrences were diagnosed., Conclusions: Several ultra-minimally invasive surgical techniques have been developed and implemented in selected patients with endometrial cancer. The results of this review support the feasibility and perioperative safety of these approaches, while long-term outcomes are not adequately studied. However, further work is required in standardization of the techniques, in determining the learning curve of the operator and establishing their oncological safety.

Background: Global concern on seafarers' health and its potential cost is widely evident across the shipping industry. Seafarers are at increased cardiovascular risk since it is common to have risk factors associated with that risk such as hyperlipidaemia, obesity and smoking. The aim of this study is to assess the prevalence of the main risk factors for cardiovascular disease (CVD), i.e. hyperlipidaemia, smoking and obesity, in Greek seafarers., Materials and Methods: During pre-embarkation medical examination, seafarers undergo an interview with a physician, physical examination and laboratory tests. The parameters studied included hyperlipidaemia, identified as low density lipoprotein > 150 mg/dL, tobacco use or severe obesity, as defined by body mass index > 35 kg/m2., Results: A total of 3712 seafarers have been examined. Seafarers had overall rates of 3% hyperlipidaemia, 4% tobacco use and 0.2% severe obesity, with similar distributions in all age groups. Our study shows that Greek seafarers have lower risk for CVD, as low rates of obesity, tobacco use, and hyperlipidaemia are observed. The related literature is discussed. Unhealthy eating patterns are the rule and contribute to CVD. Shipping management could improve diet on board; however, smoking falls rather under individual control., Conclusions: We conclude that, despite the low rates of hyperlipidaemia, smoking and obesity among Greek seafarers compared to other nations, campaigns for promoting awareness of the phenomenon and on the potential health impact of these conditions should be promoted.

Aims/hypothesis: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome)., Methods: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center., Results: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation., Conclusions/interpretation: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity., Trial Registration: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Background: Mammalian target of rapamycin (mTOR) forms 2 active complexes in the cell: the rapamycin-sensitive mTOR-Raptor (mTORC1) and the rapamycin-insensitive mTOR-Rictor (mTORC2). The latter activates AKT kinase, which promotes tumor cell survival and proliferation by multiple downstream targets. Mammalian stress-activated protein kinase interacting protein 1 (SIN1), an essential subunit of the mTORC2 complex, maintains the integrity of the complex and substrate specificity and regulates Akt activation. The role of mTOR-Rictor complex activation in thyroid carcinogenesis remains unknown. Therefore, we investigated expression patterns of Sin1 in the cells lines of thyroid carcinoma and tumors and their association with AKT activation, histologic type, and tumor aggressiveness., Methods: Tissue specimens from 42 patients with thyroid cancer, including follicular (5), papillary (18), medullary (16), and poorly differentiated (3) carcinomas were analyzed via immunohistochemistry for SIN1 expression and AKT phosphorylation at Ser473 residue (Ser473-p-AKT). Eight of 18 papillary carcinomas were aggressive histologic variants. In addition, expression of Sin1 and activation of AKT kinase were analyzed in fresh-frozen tissue samples (normal/tumor), primary cell cultures (papillary thyroid carcinoma [PTC]), and an established thyroid cancer cell line (medullary thyroid carcinoma) by Western blotting., Results: With immunohistochemistry, we found that Sin1 was overexpressed in medullary thyroid carcinomas and aggressive variants of papillary thyroid carcinoma compared with conventional papillary and follicular carcinomas (P < .001). Sin1 expression correlated with AKT activation in the entire study group (P = .002). Using Western blot analysis, we found that Sin1 and p-AKT were detected at a greater level in cultured primary cells from aggressive PTC compared with conventional PTC as well as in cell lines of medullary and anaplastic thyroid carcinoma. High expression levels of SIN1 were detected in papillary thyroid carcinomas compared with benign nodules in immunoblots in which we used fresh-frozen patient samples. Two of the Sin1 protein isoforms, p76 and p55, were detected predominantly in PTC samples., Conclusion: Sin1, a critical factor of the mTORC2 complex is overexpressed in clinically aggressive thyroid cancer types and is associated strongly with activation of AKT kinase. Sin1-dependent AKT activation might represent a target for experimental therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL., (© 2014 John Wiley & Sons Ltd.)

Osteoarthritis (OA) is a major cause of suffering for millions of people. Investigating the disease directly on humans may be challenging. The aim of the present study is to investigate the advantages and limitations of the animal models currently used in OA research. The animal models are divided into induced and spontaneous. Induced models are further subdivided into surgical and chemical models, according to the procedure used to induce OA. Surgical induction of OA is the most commonly used procedure, which alters the exerted strain on the joint and/or alter load bearing leading to instability of the joint and induction of OA. Chemical models are generated by intra-articular injection of modifying factors or by systemically administering noxious agents, such as quinolones. Spontaneous models include naturally occurring and genetic models. Naturally occurring OA is described in certain species, while genetic models are developed by gene manipulation. Overall, there is no single animal model that is ideal for studying degenerative OA. However, in the present review, an attempt is made to clarify the most appropriate use of each model.

The objective of the study was to evaluate the effect of parathyroidectomy (PTX) versus 35 mg once-weekly (ow) risedronate administration on volumetric bone mineral density (vBMD) and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism (PHPT). Our open-label prospective observational study included 32 postmenopausal women with PHPT as the study group: 16 underwent PTX and 16 were treated with 35 mg ow risedronate for 2 years. We assessed areal BMD (aBMD) by DXA, and vBMD and bone mineral content (BMC) (cortical and trabecular area) by peripheral quantitative computed tomography (pQCT) at the tibia at baseline and at 2 years. Risedronate did not result in any significant change on vBMD and structural pQCT indices. PTX resulted in significant increase in trabecular (trab) BMC (6.44 %) and vBMD (4.64 %), with percent increase being significantly higher than risedronate (p < 0.05). At cortical sites, there was no significant change following PTX. However, the percent change in cortical (cort) vBMD was higher following PTX versus risedronate (0.39 % vs. -0.26 %, p < 0.05). In conclusion, in postmenopausal women with PHPT, PTX is superior to ow risedronate, in terms of improvement of trabecular mineralization and vBMD at the tibia, whereas the effect at cortical sites is less pronounced.

What Is Already Known About This Subject: Previous studies have indicated that the levels of DNA damage induced in peripheral blood mononuclear cells by the alkylating drugs melphalan, cisplatin and carboplatin can serve as useful biomarkers predictive of the therapeutic response of cancer patients to these drugs., What This Study Adds: In the present study we developed a quantitative PCR-based assay, for the measurement of DNA damage. The advantages of this methodology are based on: its far greater sensitivity (about 250 times) than the traditional Southern blot-based method (the detection limit is ~10-20 lesions/10(6) nucleotides from the equivalent DNA of ~8000 cells); its simplicity and speed (results obtained within ~8h); its excellent reproducibility, with a coefficient of variance of 10-15% for different DNA preparations from similarly treated cells; its requirement for only minute amounts of material, and; the avoidance of radioisotope labeling. Moreover, emphasis was given to translate basic research findings into clinical practice through the validation of this assay for prediction of clinical outcome in multiple myeloma patients., Aim: In order to develop and validate a simple, sensitive and rapid method for the quantitation of alkylating drug-induced DNA damage., Methods: HepG2 cells and blood samples were treated with alkylating drugs (melphalan, cisplatin, carboplatin). Gene-specific damage was examined using Southern blot and a multiplex long quantitative PCR (QPCR) carried out in a 7 kb fragment (part of the p53 gene) and a 0.5 kb fragment (part of the IFN-β1 sequence; internal standard)., Results: The extent of PCR amplification of a p53 fragment was inversely proportional to the treatment concentrations of all anticancer drugs examined, indicating a dose-related inhibition by the DNA adducts formed. Parallel analysis of the same samples using both Southern blot and QPCR showed that the DNA adducts measured by QPCR corresponded to the interstrand cross-links in the case of melphalan, and to total drug-induced lesions in the case of the platinum drugs. The detection limit was ~10-20 lesions/10(6) nucleotides using DNA from ~8000 cells. The method is about 250 times more sensitive than the Southern blot-based method and the reproducibility is excellent, with an intraday coefficient of variance (CV) of 5-9% and an interday CV of 4-12%. Application of the QPCR assay to ex vivo melphalan-treated peripheral blood mononuclear cells from multiple myeloma patients, showed that the positive predictive value of this assay for clinical response to melphalan therapy was 92.9%., Conclusion: The PCR-based assay developed in this study can be used for the selection of cancer patients more likely to benefit from therapeutic treatment with alkylating drugs., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Objective: To investigate the effect of rheumatoid arthritis (RA) on volumetric bone mineral density (vBMD) and bone geometry in postmenopausal women treated with bisphosphonates., Methods: Fifty-three postmenopausal women with RA and 87 control subjects, comparable in terms of age, body mass index, and years since menopause, underwent peripheral quantitative computed tomography (pQCT) of the nondominant tibia., Results: At 4% (trabecular site), trabecular bone mineral content (BMC) and vBMD (p < 0.001) were lower in the RA group, while trabecular area was comparable. At 38% (cortical site), cortical BMC (p < 0.01), area (p < 0.05), and thickness (p < 0.001) were lower in the RA group, whereas vBMD was comparable. Endosteal circumference was higher (p < 0.05), whereas periosteal circumference was comparable, indicating cancellization of cortical bone. In the RA group, muscle area was lower (p < 0.001), while at 14% polar stress strength index was significantly lower (p < 0.01) in patients with RA, indicating impairment of bone mechanical properties., Conclusion: RA is associated with negative effects on both cortical and cancellous bone in postmenopausal women treated with bisphosphonates. Cortical geometric properties are also adversely affected mainly by increased endosteal circumference, whereas trabecular geometric properties are generally preserved.

Background: Because mammalian target of rapamycin (mTOR) may be involved in thyroid carcinogenesis, we investigated the expression and activation patterns of mTOR signaling proteins in thyroid carcinoma cells and tumors and their association with tumor histology and aggressiveness., Methods: Tissue specimens from 50 patients with thyroid cancer were analyzed for eIF4E, a critical downstream target of the mTOR pathway, using immunohistochemistry. In addition, fresh-frozen samples from patients, and primary tumor cell cultures were analyzed for expression and activation of mTOR signaling proteins by Western blot. Moreover, pharmacologic studies with rapamycin were performed., Results: High expression of eIF4E was observed in medullary thyroid carcinomas (MTC) and in aggressive variants of papillary thyroid carcinomas (PTC) as compared with conventional PTC and follicular thyroid carcinomas (P < .0001). The level of eIF4E expression also correlated with tumor stage (P = .002). Using Western blot analysis, p-rpS6, p-4EBP1, 4EBP1, and eIF4E were detected at higher levels in aggressive PTC and MTC cells. Treatment of MTC cells with increasing concentrations of rapamycin resulted in significant cell death and in decreased cell growth associated with deactivation of the mTOR pathway., Conclusion: mTOR signaling, which controls protein synthesis through regulation of translation initiation, is activated in aggressive PTC and MTC and represents a promising target for investigational therapies in these patients., (Copyright © 2011 Mosby, Inc. All rights reserved.)