Clinical Presentation, Diagnosis, and Radiological Findings of Neoplastic Meningitis.

BACKGROUND: Neoplastic meningitis is a complication of solid and hematological malignancies. It consists of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. METHODS: A literature review was conducted to summarize the clinical presentation, differential diagnosis, laboratory values, and imaging findings of neoplastic meningitis. RESULTS: Neoplastic meningitis is an event in the course of cancer with a variable clinical presentation and a wide differential diagnosis. In general, characteristic findings on gadolinium-enhanced magnetic resonance imaging and the presence of malignant cells in the cerebrospinal fluid remain the cornerstones of diagnosis. However, both modalities do not always confirm the diagnosis of neoplastic meningitis despite a typical clinical picture. CONCLUSIONS: Clinicians treating patients with cancer should be aware of the possibility of neoplastic meningitis, especially when multilevel neurological symptoms are present. Neoplastic meningitis can be an elusive diagnosis, so clinician awareness is important so that this malignant manifestation is recognized in a timely manner.

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

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.

Volumetric bone mineral density and bone geometry assessed by peripheral quantitative computed tomography in women with differentiated thyroid cancer under TSH suppression.

OBJECTIVE: TSH suppression therapy in patients with differentiated thyroid cancer (DTC) has been associated with adverse effects on areal bone mineral density (aBMD) only in postmenopausal women. The purpose of study was to examine the effect of TSH suppression therapy on skeletal integrity using peripheral quantitative computed tomography (pQCT) at the radius and tibia in pre- and postmenopausal women with DTC and controls. STUDY DESIGN AND PATIENTS: Subjects included 80 women with DTC (40 pre- and 40 postmenopausal) and 89 (29 and 60, respectively) controls. pQCT was performed at the radius and tibia, Dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine, while samples were taken for calciotropic hormones and bone markers. RESULTS: No differences were observed concerning aBMD by DXA. In premenopausal women, there were no significant differences concerning vBMD, while cortical thickness was higher at the radius in patients with DTC (P < 0·01) compared with controls. In postmenopausal women with DTC trabecular bone mineral content (BMC), area and vBMD were lower at the radius (all P < 0·05), while at the tibia trabecular BMC and vBMD were lower at the mixed transition zone (14% from the distal end, P < 0·05) compared with controls. Cortical thickness was lower at the radius (P < 0·01) in postmenopausal patients compared with controls. Serum CTX was higher in postmenopausal women with DCT (P < 0·01), while in premenopausal patients, parathyroid hormone (PTH) was lower (P = 0·01) compared with controls. CONCLUSIONS: TSH suppression therapy is associated with higher bone resorption only in postmenopausal women; this adversely affects trabecular and cortical bone properties especially at nonweight-bearing sites such as the radius.

Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism.

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.

Useful animal models for the research of osteoarthritis.

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.

Interval Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Ovarian Cancer: Report of a Single-center Experience.

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.

Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues.

Cytotoxic lymphocyte antigen-4 (CTLA-4) blockade is an active immunotherapeutic strategy that is currently in clinical trials in cancer. There are several ongoing trials of anti-CTLA-4 in the metastatic setting of prostate cancer patients with reported clinical responses consisting of decreases in the prostate specific antigen (PSA) tumor marker for some patients. Immunologic markers that correlate with these clinical responses are necessary to guide further development of anti-CTLA-4 therapy in the treatment of cancer patients. We recently reported that CD4(+) inducible co-stimulator (ICOS)(hi) T cells that produce interferon-gamma (IFN-gamma) are increased in the peripheral blood and tumor tissues of bladder cancer patients treated with anti-CTLA-4 antibody. Here we present data from the same clinical trial in bladder cancer patients demonstrating a higher frequency of CD4(+)ICOS(hi) T cells and IFN-gamma mRNA levels in nonmalignant prostate tissues and incidental prostate tumor tissues removed at the time of radical cystoprostatectomy. Our data suggest immunologic markers that can be used to monitor prostate cancer patients who receive anti-CTLA-4 therapy and indicate that the immunologic impact of anti-CTLA-4 antibody can occur in both tumor and nonmalignant tissues. These data should be taken into consideration for evaluation of efficacy as well as immune-related adverse events associated with anti-CTLA-4 therapy.

CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.

Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody. All clinical trials to date, comprising over 3,000 patients, have been conducted in the metastatic disease setting, which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment. We conducted a pre-surgical clinical trial in six patients with localized bladder cancer, which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome. We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS). These CD4(+)ICOS(hi) T cells produced IFN-gamma (IFNgamma) and could recognize the tumor antigen NY-ESO-1. Increase in CD4(+)ICOS(hi) cells led to an increase in the ratio of effector to regulatory T cells. To our knowledge, these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of this agent to improve clinical responses.

Ultra-minimally invasive approaches for endometrial cancer treatment: review of the literature.

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.

Cardiovascular risk factors among 3712 Greek seafarers.

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.

Learning curve for gynecological oncologists in performing upper abdominal surgery.

BACKGROUND: To assess the learning curve for gynecological oncologists in performing upper abdominal surgery for management of patients with advanced epithelial ovarian cancer (EOC). METHODS: Patients undergoing cytoreductive surgery for stage IIIC and IV EOC that required at least one surgical procedure in the upper abdomen were divided in three numerically equal groups: group 1, 2 and 3 that underwent surgery between December 2012 and July 2014, August 2014 to March 2016 and April 2016 to March 2018 respectively. RESULTS: One hundred and twenty-six patients were included. The percentage of patients undergoing primary surgery for group 1, 2 and 3 was 47.6%, 50.0% and 73.8%, respectively (P=0.02). There was significant increase in the percentage of patients undergoing cholecystectomy (P=0.02), resection of disease from porta hepatis (P=0.008), liver capsulectomy (P<0.001), lesser omentectomy (P<0.001) and celiac trunk lymphadenectomy (P<0.001) in the group 3. There was no difference in the percentage of patients undergoing splenectomy, diaphragmatic peritonectomy/resection and gastrectomy. Complete cytoreduction was achieved in 54.8%, 35.7% and 64.3% of patients in group 1, 2 and 3 respectively (P=0.028). There was no significant difference in the occurrence of grade 3-5 complications. Presence of a liver surgeon was required in 9.1%, 5.6% and 0% of cases in group 1, 2 and 3 respectively. CONCLUSIONS: The results reflect the evolution of surgical skills in the upper abdomen through the increase in the percentage of patients undergoing primary surgery, with the surgical team undertaking more complex procedures, less involvement of other specialties and simultaneously achieving higher rates of complete cytoreduction.

Cholecystectomy as Part of Cytoreductive Surgery for Advanced Ovarian Cancer: Perioperative Outcomes.

BACKGROUND/AIM: To assess the perioperative outcomes of cholecystectomy in cytoreductive procedures for epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Prospectively collected perioperative data of patients that underwent cytoreduction for advanced EOC, between 2014 and 2018, were analysed. Patients were divided in two groups on the basis of whether cholecystectomy was performed. RESULTS: A total of 144 patients with stage IIIC/IV EOC were included. Cholecystectomy was performed in 22 (15.3%) patients. Those who underwent cholecystectomy more likely required diaphragmatic peritonectomy, splenectomy, lesser omentectomy, excision of disease from the porta hepatis and liver's capsule (p<0.001). There was no difference in the cytoreductive outcomes (complete or optimal) and the rate of grade 3-5 complications between the two groups (p=0.10 & p=0.06, respectively). No direct complications related to cholecystectomy were observed. CONCLUSION: A significant percentage of patients with advanced EOC require cholecystectomy. Gynecologic oncologists should embrace the opportunity to develop advanced surgical skills including cholecystectomy.

The Role of Magnetic Resonance Imaging in the Pre-operative Evaluation of Women Diagnosed With Atypical Endometrial Hyperplasia.

BACKGROUND/AIM: To evaluate the role of MRI in patients with atypical endometrial hyperplasia (AEH) and incorporate MRI findings in predictive models estimating the risk of co-existent endometrial cancer (EC). PATIENTS AND METHODS: Data from 189 women diagnosed with AEH and had MRI scan prior to operation, over nine years, were retrospectively collected. RESULTS: Histology showed EC in 51 (27%) cases. Presence of myometrial invasion on MRI was more commonly detected in patients with EC compared to those with benign pathology (37.3% versus 10.9%, p<0.001). The sensitivity and specificity of MRI in identifying cancer were 37% and 89%, respectively. Age, menopausal status and presence of invasion on MRI were the best predictors for the presence of malignancy. CONCLUSION: Myometrial invasion on MRI is associated with increased risk of EC in women with AEH. Its accuracy in detecting malignancy improves when combined with clinical parameters. This could be of value for conservative-management candidates.

Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human bladder cancer.

The idea of generating cytotoxic T-lymphocytes that have anti-tumor activity has been the focus of many clinical trials aimed at delivering effective immunotherapy to cancer patients. We have gained insight into the human immune system in cancer patients as a result of these numerous clinical investigations. It is now clear that although various vaccination methods are capable of inducing tumor antigen-specific T-cells in the circulating blood, these immunological responses are infrequently correlated with clinical responses. Therefore, it appears that priming of a T-cell response is not sufficient for tumor regression and other avenues, downstream of the priming phase, need to be investigated. Mechanisms of immune evasion at the effector phase of the anti-tumor phase are currently under investigation, with an increasing focus on the tumor microenvironment. There is evidence indicating that multiple variables may contribute to immune escape, including: regulatory cells; inhibitory ligands on tumor cells, such as PD-L1 and B7x; soluble factors such as TGF-beta and IL-10; and nutrient-catabolizing enzymes, such as indoleamine-2,3-dioxygenase (IDO). In addition, there are ongoing efforts to assess the presence and function of effector cells within the tumor microenvironment. Tumor infiltrating lymphocytes (TILs) have been observed in patients with melanoma, colon cancer, and ovarian cancer. TILs in these patients have been associated with favorable clinical outcomes. In the clinical setting of bladder cancer, as compared to melanoma, there is limited data regarding TILs. This review will focus on immunological responses to bladder cancer and ongoing studies to identify factors that are amenable to therapeutic manipulation.

A Tongue Lesion as a Sign of a Systemic Disease.

Amyloidosis is the extracellular fibril deposition of a variety of proteins, many of which circulate as plasma ingredients. It is a disease difficult to identify due to its nonspecific symptoms and manifestations. Amyloidosis of the tongue, either isolated or part of the systemic disease, is rare and its features resemble those of a tumor. We report the case of a patient with amyloidosis who presented with a tongue lesion, weakness, nonspecific arthritis, and dyspnea on exertion that resulted in multiorgan system failure.

Changes of serum sclerostin and Dickkopf-1 levels during the menstrual cycle. A pilot study.

Studies in postmenopausal women have identified sclerostin as a strong candidate for mediating estrogen effects on the skeleton. The effects of estradiol on sclerostin and Dickkopf-1 in younger women remain unclear. The main purpose of this study is to investigate the impact of estradiol and gonadotrophins fluctuations during the menstrual cycle on circulating sclerostin and Dickkopf-1 levels and the possible relationship of sclerostin and Dickkopf-1 with changes in N-terminal propeptide of type 1 collagen and C-telopeptide of collagen cross-links. Fourteen healthy premenopausal Caucasian women, with regular menses, aged 33.6 ± 4.5 years participated. After the first day of menstruation and every-other-day up to the next menses, fasting serum estradiol, luteinizing hormone, follicle-stimulating hormone, sclerostin, Dickkopf-1, N-terminal propeptide of type 1 collagen, and C-telopeptide of collagen cross-links levels were measured in peripheral blood. Participants completed dietary questionnaires and the International physical activity questionnaire during the cycle. Neither sclerostin nor Dickkopf-1 levels changed significantly across the menstrual cycle (p = 0.18 and p = 0.39, respectively), while N-terminal propeptide of type 1 collagen and C-telopeptide of collagen cross-links levels presented cyclic variation (p < 0.001 and p = 0.004, respectively). Baseline sclerostin (29.23 ± 10.62 pmol/L) positively correlated with N-terminal propeptide of type 1 collagen (r = 0.71, p < 0.01) and C-telopeptide of collagen cross-links (r = 0.63, p < 0.05), while Dickkopf-1 (4.82 ± 2.23 pmol/L) correlated positively with N-terminal propeptide of type 1 collagen (r = 0.56, p < 0.05). Mid-cycle E2 levels presented significant negative association with the percent decrease of C-telopeptide of collagen cross-links at all-time points during the luteal period (r = -0.60 to -0.68, p < 0.05-0.01). Circulating sclerostin and Dickkopf-1 levels do not change across the menstrual cycle and do not demonstrate any relationship with estradiol in premenopausal women. Further investigation is needed concerning the role of sclerostin and Dickkopf-1 on bone turnover in young estrogen-sufficient women.

CD3(-)CD16(-)CD56(bright) immunoregulatory NK cells are increased in the tumor microenvironment and inversely correlate with advanced stages in patients with papillary thyroid cancer.

BACKGROUND: The innate immune system is the first line of defense and plays a key role in thyroid cancer development. The role of the tumor-infiltrating natural killer (NK) cells is becoming increasingly important in research and potential cancer therapies. NK cell subpopulations, CD3(-)CD16(+)CD56(dim) and CD3(-)CD16(-)CD56(bright), demonstrate a significant role in the tumor immuno-surveillance process. METHODS: We investigated the distribution of CD3(-)CD16(+)CD56(dim) and CD3(-)CD16(-)CD56(bright) NK subpopulations in tissue and blood samples from patients with papillary thyroid cancer (PTC) and nodular goiter (NG). Twenty-eight patients with PTC, 13 patients with NG, and 50 healthy donors were included in the study. Tissue and blood samples from all patients and blood samples from healthy donors were analyzed for CD3(-)CD16(+)CD56(dim) and CD3(-)CD16(-)CD56(bright) NK cells by flow cytometry. RESULTS: A significant predominance of CD3(-)CD16(+)CD56(dim) cells compared to CD3(-)CD16(-)CD56(bright) NK cells was found in blood samples in all groups (p<0.0001 in PTC, NG, and healthy donors). Increased infiltration by CD3(-)CD16(-)CD56(bright) NK cells was observed in thyroid tissue of patients with PTC, as compared to CD3(-)CD16(+)CD56(dim) NK cells (p=0.046), while CD3(-)CD16(+)CD56(dim) NK cells demonstrated a higher infiltration of NG tissues. CD3(-)CD16(+)CD56(dim) NK cell tissue infiltration positively correlated with advanced stages of PTC. In contrast, the CD3(-)CD16(-)CD56(bright) NK cell population was negatively associated with tumor stage in patients with PTC. CONCLUSION: CD3(-)CD16(-)CD56(bright) NK cell infiltration seems to be associated with PTC progression. These findings contribute to a better understanding of the immune response in PTC and may lead to novel immunotherapeutic approaches in these patients.

Phenotypical analysis of lymphocytes with suppressive and regulatory properties (Tregs) and NK cells in the papillary carcinoma of thyroid.

CONTEXT: The immune system seems to play a key role in preventing metastasis and recurrence of thyroid cancer. T regulatory lymphocytes (Tregs) and natural killer (NK) cells play an important role in the dysfunction of the host immune system in cancer patients. OBJECTIVE: We investigated thyroid gland infiltration by Tregs and NK cells in patients with papillary thyroid cancer (PTC) and thyroid nodular goiter (TNG). The correlation between the extent of the disease and the lymphocytic infiltration of Tregs and NK cells was examined. DESIGN, SETTING, AND PARTICIPANTS: A total of 65 patients with PTC, 25 with TNG, and 50 healthy controls were studied. Blood and tissue samples from 28 patients with PTC and 13 with TNG and blood samples from the healthy controls were analyzed for T4 (CD3(+)CD4(+)), T8 (CD3(+)CD8(+)), NK (CD3(-)CD16(+)CD56(+)), and CD4(+)CD25(+)CD127(-/low) Tregs by flow cytometry (FC). Tissue samples were also analyzed for Foxp3(+) Tregs by immunohistochemistry. RESULTS: Tregs showed greater infiltration in thyroid tissue of PTC patients compared with patients with TNG (P < 0.0009 for FC and P < 0.0001 for immunohistochemistry); FC analysis of blood samples showed no difference between the groups. Flow cytometry analysis showed significantly increased NK cells in PTC tissue compared with TNG tissue (P = 0.037), whereas blood samples showed no difference. CD4(+) and CD8(+) T cells did not differ in blood and tissue samples. Increased Tregs tissue infiltration was positively correlated with advanced disease stage (P < 0.0026), whereas NK infiltration was negatively correlated (P < 0.0041). CONCLUSION: Tregs and NK cells may be important regulators of thyroid cancer progression.

Activation of mTOR signaling in medullary and aggressive papillary thyroid carcinomas.

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.

The use of bisphosphonates in women prior to or during pregnancy and lactation.

OBJECTIVE: The unique pharmacokinetics of bisphosphonates (BPs) in conjunction with their use by an increasing number of women at reproductive age has raised serious concerns about their safety during pregnancy and lactation. Bisphosphonates cross the placenta. Animal studies have shown adverse effects on both the fetus and the mother, mostly at doses much higher than those commonly used in humans. Protracted parturition, maternal mortality, embryolethality, severe general underdevelopment and marked skeletal retardation of the fetuses (increased amount of diaphyseal bone trabeculae, decreased diaphyseal length), small fetal weight and abnormal tooth growth have been observed. DESIGN: We conducted a thorough research of the literature in order to identify human studies concerning this issue. RESULTS: We identified a total of 78 cases involving fetuses whose mothers had been exposed to BPs before conception or during pregnancy, along with 7 cases of BPs exposure prior to or during lactation. The vast majority of mothers and infants did not demonstrate serious adverse effects. However, there were cases of shortened gestational age, low neonatal birth weight and transient hypocalcaemia of the newborns, while the very few reported cases of spontaneous abortions and congenital anomalies probably resulted from maternal underlying diseases and concomitant medication. CONCLUSION: The administration of bisphosphonates in pregnancy should be assessed in view of their potential hazardous effects on both mother and fetus. In cases of absolute or relative indications of BPs prior to pregnancy, close observation of the mother and the infant, especially during the first two weeks of life, is imperative for the successful outcome of pregnancy.