Labeling male anorectal malformations: objective evaluation of radiologic imaging before surgery.

Purpose: Prone cross-table lateral x-ray (CTLxR) and colostogram aid surgical planning for anorectal malformations (ARMs) without perineal fistulas. We suggest objective imaging tools to classify ARMs. Methods: Three observers prospectively evaluated CTLxR and colostograms of male ARM patients (2012-2022) without perineal fistulas. The level of the rectal pouch was estimated with pubococcygeal (PC) and ischiatic (I) lines. On CTLxR, we described the "pigeon sign", defined as the rectal pouch ending with a beak-like image, suspicious for a rectourinary fistula. ARM was defined as rectobulbar when the rectal pouch was below the I line, rectoprostatic when between PC and I lines, and rectovesical when above the PC line. Concordance was assessed with Fleiss' kappa. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the "pigeon sign" were calculated. Results: Thirteen patients were included in this study. The interobserver agreement on CTLxR was 69.2% (k = 0.54) on pouch ending, 84.6% (k = 0.69) on the "pigeon sign", and 76.9% (k = 0.69) on diagnosis; concordance between observers and intraoperative diagnosis was 66.6% (k = 0.56). The "pigeon sign" had 75% sensitivity, 100% specificity, 100% PPV, and 50% NPV. The interobserver agreement on colostograms was 84.6% (k = 0.77) on pouch ending and 89.7% (k = 0.86) on diagnosis; concordance between observers and intraoperative diagnosis was 92.3% (k = 0.90). Conclusion: PC and I lines and the "pigeon sign" are useful tools in examining CTLxR and colostograms. Adequate CTLxR interpretation may modify surgical strategy.

Talking about sexuality with your own child. The perspective of the parents of children born with arm.

PURPOSE: Evaluate whether parents have ever discussed sexuality with their children with anorectal malformations (ARM), which sexuality issues they think should be addressed and who, in their opinion, should address these issues. METHODS: Parents from the Italian Parents' and Patients' Association for Anorectal Malformation participated in meetings organized by the Association together with local Pediatric Surgical Units and were asked to fill in a questionnaire. RESULTS: 103 parents participated. Overall, 66% of parents had never talked about sex with their children. Children's age was marginally correlated with occasions to talk about sexuality (r = .202, p = 0.53) indicating that the older were the children, the more the parents talked about sexuality. The majority of parents reported that their children should have the possibility to talk about sex with them (72%), psychologists (57%), gynecologists/andrologists (47%), pediatric surgeons (33.5%), surgeons specialized in ARM (39.8%), friends (28%), nurses (24.7%) and teachers (20.4%), respectively. The most important topic they thought their children should address was handling serene sexuality, although the most common topic effectively discussed with them was the conception. CONCLUSION: Psychologists, gynecologists/andrologists, and pediatric surgeons are seen as key resources for talking about sexuality. A great number of parents express the wish that their children had more opportunities to discuss sexual topics with pediatric surgeons.

Association between MBOAT7 rs641738 polymorphism and non-alcoholic fatty liver in overweight or obese children.

BACKGROUND AND AIM: The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children. METHODS AND RESULTS: We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98-1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD. CONCLUSIONS: The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children.

High uric acid, reduced glomerular filtration rate and non-alcoholic fatty liver in young people with obesity.

OBJECTIVE: To evaluate the association between high uric acid (UA), reduced estimated glomerular filtration rate (eGFR), and non-alcoholic fatty liver disease (NAFLD) in outpatient children and adolescents with overweight (OW) or obesity (OB). METHODS: Anthropometric, biochemical, hepatic ultrasound and eGFR data were available from 2565 young people with OW/OB (age 5-18 years). eGFR was calculated using the Schwartz's bedside formula and reduced eGFR (ReGFR+) was defined by a value < 90 mL/min/1.73 m2. High UA was defined as ≥ 75th percentile by sex in children and adolescents. RESULTS: The population was stratified in four categories: (1) normal eGFR and absence of NAFLD (ReGFR-/NAFLD-) (n = 1,236); (2) ReGFR+ and absence of NAFLD (ReGFR+/NAFLD- (n = 155); (3) normal eGFR and presence of NAFLD (ReGFR-/NAFLD+) (n = 1019); (4) presence of both conditions (ReGFR+/NAFLD+) (n = 155). Proportions of youth with high UA across the four categories were 17%, 30%, 33% and 46%, respectively (P < 0.0001). Young people with high levels of UA had odds ratio (95% CI) of 2.11 (1.43-3.11) for ReGFR+; 2.82 (2.26-3.45) for NAFLD+; and 5.04 (3.45-7.39) for both conditions (P < 0.0001 for all), independently of major confounders. CONCLUSIONS: High levels of UA were independently associated with ReGFR, NAFLD and the combination of both conditions in young people with OW/OB. The strength of this association was the highest in cases presenting both reduced eGFR and NAFLD. UA may serve as marker to identify patients at risk for these conditions.

Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis.

Leukocyte infiltration plays an active role in controlling tumor development. In the early stages of carcinogenesis, T cells counteract tumor growth. However, in advanced stages, cancer cells and infiltrating stromal components interfere with the immune control and instruct immune cells to support, rather than counteract, tumor malignancy, via cell-cell contact or soluble mediators. In particular, metabolites are emerging as active players in driving immunosuppression. Here we demonstrate that in a prostate cancer model lactate released by glycolytic cancer-associated fibroblasts (CAFs) acts on CD4+ T cells, shaping T-cell polarization. In particular, CAFs exposure (i) reduces the percentage of the antitumoral Th1 subset, inducing a lactate-dependent, SIRT1-mediated deacetylation/degradation of T-bet transcription factor; (ii) increases Treg cells, driving naive T cells polarization, through a lactate-based NF-kB activation and FoxP3 expression. In turn, this metabolic-based CAF-immunomodulated environment exerts a pro-invasive effect on prostate cancer cells, by activating a previously unexplored miR21/TLR8 axis that sustains cancer malignancy.

25(OH) vitamin D and functional outcomes in older adults admitted to rehabilitation units: the safari study.

Vitamin D (25(OH)D) deficiency is associated with poor physical performance; little is known about its impact on geriatric rehabilitation. We found a positive non-linear relationship between 25(OH)D and functional gain, stronger in levels < 16 ng/ml (below the cutoff for "deficiency"). An early 25(OH)D dosage may be advisable for this population. INTRODUCTION: Vitamin D (25(OH)D) deficiency is highly prevalent in older people, and it is associated with poor muscular strength and physical performance. Its impact on functional outcomes during geriatric rehabilitation has been poorly studied. We aim to analyze the association between 25(OH)D and functional recovery in geriatric rehabilitation units. METHODS: We conducted a prospective multi-center cohort study including patients ≥ 65 years old admitted to 3 geriatric rehabilitation units in Italy and Spain, after orthopedic events or stroke. Outcomes were absolute functional gain (AFG, discharge-admission Barthel index) and ability to walk (AW) at 3 months after admission. The association between 25(OH)D quartiles (Q1-Q2-Q3-Q4) and outcomes was explored using linear or logistic regression models. RESULTS: We included 420 patients (mean age = 81.2 years [SD = 7.7], 66.4% females, mean 25(OH)D concentration = 13.5 ng/ml [SD = 8.7]) (to convert to nmol/l multiply by 2.496). A non-linear relationship between 25(OH)D and AFG was found, with a stronger association for 25(OH)D levels < 16 ng/ml. Compared to Q1 (25(OH)D ≤ 6 ng/ml), participants in Q3 (25(OH)D 11.5-18.2 ng/ml) had the best AFG and AW (mean AFG [SD], Q1 = 28.9 [27.8], Q2 = 32.5 [23.5], Q3 = 43.1 [21.9], Q4 = 34.5 [29.3], R2 = 7.3%; AW, Q1-Q2 = 80%, Q3 = 91%, Q4 = 86%). Regression models adjusted for potential confounders confirmed these results (AGF Q2, ß = 2.614, p = 0.49; Q3, ß = 9.723, p < 0.01; Q4, ß = 4.406, p = 0.22; AW Q2, OR [95% CI] = 1.84 [0.67-5.33]; Q3, OR [95% CI] = 4.01 [1.35-13.48]; Q4, OR [95% CI] = 2.18 [0.81-6.21]). CONCLUSIONS: In our study, 25(OH)D concentration showed a positive association with functional outcomes at 3 months. The association is stronger below the usual cutoff for "deficiency." Dosage of 25(OH)D concentration may help identify geriatric rehabilitation patients at risk for a worse functional recovery.

Frailty Related Factors as Predictors of Functional Recovery in Geriatric Rehabilitation: The Sarcopenia And Function in Aging Rehabilitation (SAFARI) Multi-Centric study.

BACKGROUND: Frailty-related characteristics, such as sarcopenia, malnutrition and cognitive impairment, are often overlooked, both in clinical practice and research, as potential contributors to functional recovery during geriatric rehabilitation. OBJECTIVE: The aim of the study was to identify frailty-related characteristics associated with functional recovery in a cohort of post-orthopedic surgery and post-stroke older adults. DESIGN: Multi-centric cohort study. Participanst and Settings: Patients over 65 years, admitted to three geriatric rehabilitation units, in Spain and Italy, after an orthopedic event or a stroke, from December 2014 to May 2016. MEASUREMENTS: The Absolute Functional Gain (AFG) defined as the difference between Barthel Index score at discharge and at admission, and the Relative Functional Gain (RFG) that represents the percentage of recovery of the function lost due to the event, were selected as outcomes. Both outcomes were analyzed as continuous and dichotomous variables. Analyses were also stratified as diagnostic at admission. RESULTS: We enrolled 459 patients (mean age±SD=80.75±8.21 years), 66.2% women, 69.5% with orthopedic conditions and with a length of stay of 28.8±9.1 days. Admission after a stroke (Odds Ratio=0.36, 95% Confidence Interval=0.22-0.59]) and a better functional status at admission (OR=0.96, 95% CI=0.94-0.97), were associated with a lower likelihood of AFG, while a better pre-event Barthel index (OR=1.03 for each point in score, 95% CI=1.01-1.04), being able to walk (OR=2.07, 95% CI=1.16-3.70), and a better cognitive status at admission (OR=1.05, 95% CI=1.01-1.09), were associated with a higher chance of AFG. Post-stroke patients with delirium at admission had a re-duced chance of AFG (OR=0.25, 95% CI=0.07-0.91]). Patients admitted after an ortho-pedic event with better pre-event functional status (OR=1.04, 95% CI=1.02-1.06) and able to walk at admission (OR=2.79, 95% CI=1.29-6.03]) had an increased chance of AFG. Additionally, in both diagnostics groups, a better handgrip strength increased the chance of RFG. CONCLUSIONS: Among frailty-related variables, physical, cognitive and muscular function at admission could be relevant for functional improvement during geriatric reha-bilitation. If confirmed, this data might orient targeted interventions.

Development of dementia in patients with femoral neck fracture who experience postoperative delirium-A three-year follow-up study.

OBJECTIVES: It remains unclear to what extent postoperative delirium (POD) affects the incidence of dementia in hip fracture patients, and the methods used to detect delirium and dementia require validation. The aim of this study was to investigate the development of dementia within 3 years of femoral neck fracture repair surgery, with a focus on POD as a potential predictive factor. METHODS: Patients were assessed for cognition, delirium, depression, psychological well-being, and nutritional status during their hospitalization as well as 4, 12, and 36 months after the operation. Logistic regression models were used to analyse factors associated with POD and factors associated with the development of dementia. RESULTS: The study sample consisted of 135 patients without a history of dementia, of whom 20 (14.8%) were delirious preoperatively and 75 (55.5%) postoperatively. Three years after their operations, 43/135 patients (31.8%) were diagnosed with dementia. A greater portion of patients diagnosed with dementia (39/43, 90.6%) than patients with no dementia (36/92, 39.1%) were included among the 75 patients who had experienced POD (P < 0.001). In a logistic regression model, after adjustment for covariates (age, sex, diabetes, delirium pre-and postoperatively, hyperactive delirium, days with delirium, urinary tract infection, and Mini Nutritional Assessment score), POD emerged an independent predictor for the development of new dementia (odds ratio, 15.6; 95% confidence interval, 2.6-91.6) within 3 years after the operation. CONCLUSION: Geriatric hip fracture patients who exhibit POD should be monitored closely for the development of dementia.

A new index to simplify the screening of hypertension in overweight or obese youth.

BACKGROUND AND AIMS: Hypertension (HTH) is a frequent complication in pediatric obesity. To simplify the screening of HTH in overweight/obese (Ow/Ob) youth, we compared the performance of a new index (High Blood Pressure index, HBPi) with respect to the standard criteria of the IV Report [systolic BP (SBP) and/or diastolic BP (DBP) ≥95th percentile for age, gender and height]. We also compared the performance of HBPi with other simplified indices such as the BP/height ratio and the absolute height-specific BP thresholds. Ten pediatrics' outpatient centers participating in the "CARdiometabolic risk factors in ITALY study" provided medical records of 4225 Ow/Ob children and adolescents (age 6-16 years). METHODS AND RESULTS: Centers were divided into two groups: training set (TS) (n = 2204 participants) and validation set (VS) (n = 2021 participants). The simplified HBPi (mmHg) was: (SBP/2 + DBP/10) - age + (1 × female gender). In the TS, a HBPi value ≥57 mmHg in both children and adolescents had high sensitivity (0.89), specificity (0.97), positive (0.89) and negative (0.97) predictive values in classifying youth at high risk of HTN compared with the IV Report. In the VS, the HBPi showed a better performance than high levels of BP/height ratio and height-specific BP thresholds in classifying individuals at risk of HTN: area under curves 0.95 (0.93-0.96), 0.80 (0.78-0.82), 0.76 (0.74-0.79), respectively; specificities 0.95 (0.94-0.96), 0.69 (0.67-0.72), 0.60 (0.57-0.62), respectively. CONCLUSIONS: HBPi, combining SBP and DBP, gender and age, may help pediatricians to implement HTN screening in Ow/Ob youth.

High-fat meal, systemic inflammation and glucose homeostasis in obese children and adolescents.

We aimed to assess in obese youths the relationships between interleukin-6 (IL-6), fat meal-induced endotoxemia and glucose homeostasis. Twenty obese children/adolescents (9-17 years old, 11 boys) underwent a standard oral glucose tolerance test and, 7-14 days later, a 5-h fat meal test (fat=69% of energy, saturated/monounsaturated/polyunsaturated fatty acids=31.5%/35%/33.5%), with serial measures of IL-6 and two markers of lipopolysaccharide (LPS) exposure and translocation, LPS-binding protein (LBP) and soluble CD14 (sCD14). IL-6 correlated not only with basal (homeostatic model assessment-insulin resistance) but also with post-prandial (Matsuda index) insulin sensitivity (r=0.61 (0.24-0.82), P=0.005, r=-0.53 (0.12-0.78), P=0.03, respectively). IL-6 did not change after the meal whereas LBP and sCD14 decreased significantly, indicating LPS translocation. Neither basal sCD14 and LBP nor their incremental concentrations correlated with IL-6 or glucose homeostasis. In our sample, IL-6 was associated with insulin sensitivity but not with LPS exposure, suggesting that meals with a balanced content of saturated/monounsaturated/polyunsaturated fatty acids may not be associated with LPS-induced inflammation and metabolic impairment.

Green tea polyphenol extract in vivo attenuates inflammatory features of neutrophils from obese rats.

PURPOSE: Our study aimed to evaluate whether obesity induced by cafeteria diet changes the neutrophil effector/inflammatory function and whether treatment with green tea extract (GT) can improve neutrophil function. METHODS: Male Wistar rats were treated with GT by gavage (12 weeks/5 days/week; 500 mg/kg of body weight), and obesity was induced by cafeteria diet (8 weeks). Neutrophils were obtained from the peritoneal cavity (injection of oyster glycogen). The following analyses were performed: phagocytic capacity, chemotaxis, myeloperoxidase activity (MPO), hypochlorous acid (HOCl), superoxide anion (O 2 (·-) ), hydrogen peroxide (H2O2), IL-1ß, IL-6 and TNFα, mRNA levels of inflammatory genes, calcium mobilisation, activities of antioxidant enzymes, hexokinase and G6PDH. RESULTS: Neutrophils from obese rats showed a significant decrease in migration capacity, H2O2 and HOCl production, MPO activity and O 2 (·-) production. Phagocytosis and CD11b mRNA levels were increased, while inflammatory cytokines release remained unmodified. mRNA levels of TLR4 and IκK were enhanced. Treatment of obese rats with GT increased neutrophil migration, MPO activity, H2O2, HOCl and O 2 (·-) production, whereas TNF-α and IL-6 were decreased (versus obese). Similar reductions in TLR4, IκK and CD11b mRNA were observed. Catalase and hexokinase were increased by obesity, while SOD and G6PDH were decreased. Treatment with GT reduced catalase and increased the GSH/GSSG ratio. CONCLUSION: In response to a cafeteria diet, we found a decreased chemotaxis, H2O2 release, MPO activity and HOCl production. We also showed a significant immunomodulatory effect of GT on the obese condition recovering some of these factors such H2O2 and HOCl production, also reducing the levels of inflammatory cytokines.

Green tea catechins alone or in combination alter functional parameters of human neutrophils via suppressing the activation of TLR-4/NFκB p65 signal pathway.

The purpose of this study was to evaluate the potential of a mixture containing the four main catechins found in green tea, as well it separately, as modulators of the functional parameters of human neutrophils. The cells were obtained from peripheral blood of healthy individuals isolated and cultured with a mix: 30 µM of EGCG, 3 µM of EGC, 2 µM of ECG and 1.4 µM of EC, as well as each one alone. We evaluated the cytotoxicity of catechins, production of several reactive oxygen species (ROS), antioxidant enzymes (SOD, CAT, GPx and GR), Nrf2, TLR4/IKK/NFκB, CD11b mRNA levels, intracellular calcium release, chemotactic and phagocytic capacity, myeloperoxidase (MPO), and G6PDH activities, hypochlorous acid (HOCl) and pro-inflammatory cytokines release, protein levels of TLR4, p38 MAPK, iNOS and p-65 NFκB. The actions of the catechins were evidenced by the reduction in inflammatory parameters, including the suppression of TLR4, NFκB and iNOS protein expression, decreased release of TNF-α, IL-1ß and IL-6, migration capacity, MPO activity and HOCl production and the suppression of ROS, nitric oxide and peroxynitrite production, while inducing antioxidant enzyme activities and Nrf2 mRNA levels, phagocytic capacity and calcium release. Our results demonstrate that catechins present marked immunomodulatory actions, either alone or in combination.

Fucoxanthin in association with vitamin C acts as modulators of human neutrophil function.

INTRODUCTION: Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing and digesting bacteria and fungi. During this process, neutrophils produce reactive oxygen species (ROS), which in excess, can damage the cells themselves and surrounding tissues. The carotenoid fucoxanthin (Fc) has been studied concerning its antioxidant and anti-inflammatory actions. Vitamin c (Vc) also demonstrates potent antioxidant action. This study aimed to evaluate the effect of Fc (2 µM) in association with Vc (100 µM) on functional parameters of human neutrophils in vitro. MATERIALS AND METHODS: We evaluated the migration and phagocytic capacity, intracellular calcium mobilization, ROS production (O2(·)⁻, H2O2, HOCl), myeloperoxidase activity, profile of antioxidant enzymes, phosphorylation of p38 MAPK and p65 NFκB subunit, GSH/GSSG ratio and release of pro-inflammatory cytokines (TNF-α and IL-6) in neutrophils under different stimuli. RESULTS: We verified an increase in phagocytic capacity for all treatments, together with an increase in intracellular calcium only in cells treated with Fc and Fc + Vc. ROS production was reduced by all treatments, although Vc was a better antioxidant than Fc. Phosphorylation of the p-65 subunit of NFκB was reduced in cells treated with Fc + Vc and release of TNF-α and IL-6 was reduced by all treatments. These findings indicate that the regulation of inflammatory cytokines by neutrophils is not exclusively under the control of the NFκB pathway. Fc reduced the activity of some antioxidant enzymes, whereas Vc increased GR activity and the GSH/GSSG ratio. CONCLUSION: In conclusion, the results presented in this study clearly show an immunomodulatory effect of the carotenoid fc alone or in combination with Vc on the function of human neutrophils.

Screening for impaired glucose tolerance in obese children and adolescents: a validation and implementation study.

UNLABELLED: What is already known about this subject Fasting triglycerides above 1.17 mmol/L have been shown to be useful to select obese children and adolescents who may present impaired glucose tolerance in a Canadian cohort. Fasting plasma glucose is associated with the risk to present impaired glucose tolerance in several cohorts of obese children and adolescents. What this study adds When applied to Italian cohorts of obese children and adolescents, the triglycerides cut-off of 1.17 mmol/L has similar validity as in the Canadian cohort to select patients who may present impaired glucose tolerance. Fasting plasma glucose and fasting triglycerides can be combined to obtain an accurate criterion to select obese children and adolescents who may present impaired glucose tolerance. OBJECTIVES: We aimed to validate fasting triglycerides > 1.17 mmol L(-1) , a criterion recently proposed for selecting obese children at risk of impaired glucose tolerance (IGT), and to assess whether the accuracy of triglycerides (TG) can be improved by the use of other variables. METHODS: We studied an Italian cohort of 817 obese children and adolescents (8-18.4 years) who underwent clinical examination, fasting blood analysis and the oral glucose tolerance test (OGTT). The discriminative properties of TG > 1.17 mmol L(-1) were assessed and compared with those observed in a Canadian cohort from which this criterion was derived: 71.4 [57.8-85.1]% sensitivity and 64.1 [57.7-70.4]% specificity. The possible contribution of other variables was evaluated by assessing the net reclassification improvement (NRI), i.e., the net increase in the percentage of subjects correctly classified. RESULTS: Thirty-nine children (4.7%) had IGT. The 1.17 mmol L(-1) TG threshold showed 66.6 [51.8-81.4]% sensitivity and 68.2 [64.9-71.5]% specificity, thus successfully validated. Fasting plasma glucose (FPG) was independently associated with IGT (odds ratio = 3.86 [2.09-7.14], P < 0.001), besides TG. The bivariate criterion of TG ≥ 1.13 mmol L(-1) plus FPG ≥ 4.44 mmol L(-1) had a 69.2 [54.7-83.7]% sensitivity and a 78.2 [76.8-79.6]% specificity, thus displaying a 12.6% NRI (P < 0.001) compared with TG>1.17 mmol L(-1) . CONCLUSIONS: TG > 1.17 mmol L(-1) is a useful criterion to detect roughly 66% of obese children with IGT through OGTT performed in about 33% of all obese children. However, the 'TG≥1.13 mmol L(-1) plus FPG≥4.44 mmol L(-1) ' criterion improved discrimination accuracy, leading to the possibility of detecting even more than 66% of obese children with IGT though limiting OGTT to just 25% of all obese children.

Chromatin-associated CSF-1R binds to the promoter of proliferation-related genes in breast cancer cells.

The colony-stimulating factor-1 (CSF-1) and its receptor CSF-1R physiologically regulate the monocyte/macrophage system, trophoblast implantation and breast development. An abnormal CSF-1R expression has been documented in several human epithelial tumors, including breast carcinomas. We recently demonstrated that CSF-1/CSF-1R signaling drives proliferation of breast cancer cells via 'classical' receptor tyrosine kinase signaling, including activation of the extracellular signal-regulated kinase 1/2. In this paper, we show that CSF-1R can also localize within the nucleus of breast cancer cells, either cell lines or tissue specimens, irrespectively of their intrinsic molecular subtype. We found that the majority of nuclear CSF-1R is located in the chromatin-bound subcellular compartment. Chromatin immunoprecipitation revealed that CSF-1R, once in the nucleus, binds to the promoters of the proliferation-related genes CCND1, c-JUN and c-MYC. CSF-1R also binds the promoter of its ligand CSF-1 and positively regulates CSF-1 expression. The existence of such a receptor/ligand regulatory loop is a novel aspect of CSF-1R signaling. Moreover, our results provided the first evidence of a novel localization site of CSF-1R in breast cancer cells, suggesting that CSF-1R could act as a transcriptional regulator on proliferation-related genes.

Extrarenal testicular Wilms' tumor in a 3-year-old child.

We report an extremely rare case of extrarenal testicular Wilms' tumor in a 3-year-old boy with intrabdominal undescended left testis. The patient was admitted because of pain and vomiting, with evidence of a huge abdominal mass. At surgery a large tumor arising from the intrabdominal testis was found. Histology showed the classical triphasic Wilms' tumor elements: epithelial, mesenchymal and blastemal areas. Extrarenal Wilms' tumors account for only 3% of all Wilms' tumors and just -100 cases have been reported in literature. Testicular origin is anecdotic. We present histomorphological, histogenetic, clinical, diagnostic, prognostic and therapeutic features of this rare tumor.

[Cryptorchidism: medium- and long-term follow-up].

AIM: Cryptorchidism represents the most frequent male genital anomaly in paediatric population and may potentially interfere with fertility and determine neoplastic testicular diseases. We wanted to evaluate the correlation between age at orchiopexy and follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels in adulthood, determining the long-term complications of surgical treatment. METHODS: Fifty-seven patients (mean age 19 years, range 18-27) surgically treated for cryptorchidism in pediatric age were included in a medium and long-term follow-up (10-19 years). We divided this population into four groups: A) monolateral cryptorchidism operated on before 36 months of age (15); B) monolateral cryptorchidism operated on over 36 months (32); C) bilateral cryptorchidism operated on before 36 months (5); and D) bilateral cryptorchidism operated on over 36 months (5). All patients underwent andrological examination, testosterone, FSH and LH dosage, measurement of testicular volume and spermiogram. RESULTS: Significant different FSH levels were found between group A and C and between A and D (P<0.01), while groups A and D presented also different mean testicular volume (P<0.01). In addition group D showed an abnormal morphology of spermiogram. The main complications found in follow-up were hydrocele (17,5%), varicocele (8,7%) and epididymal cysts (3.6%). CONCLUSION: Monolateral cryptorchidism is associated with normal fertility when treated early (group A). Subjects in Group D, on the contrary, have a rise of FSH, a reduction of testicular volume and semen abnormalities. The long-term follow-up of these patients can also detect associated.

Surgical treatment of toraco-abdominal teratoma diagnosed in utero, approached with mini-invasive technique: a case report.

Thoracic tumours of childhood arise either in the mediastinum, or from the chest wall and rarely from the lung parenchyma. Mediastinal teratoma occur in the anterior mediastinum and are usually very large at presentation; initial treatment is under discussion, but it appears that surgical excision and histological examination are the treatments of choice and it will determine whether the lesion is benign or malignant. The authors report a case of thoracic-abdominal teratoma, diagnosed in utero, and treated successfully with thoracoscopy and laparoscopy. No complication was described in short follow up, and the child was discharged in day 8th postoperative day. Histology showed mature teratoma. Follow-up at one year: no evidence of recurrence. Due to the rarity of multifocal teratoma in newborns, author believe that mini-invasive technique was useful to stage histological the mass, giving the opportunity to plans a second stage in treatment of the patient. Day of hospitalization resulted shorter in both surgical approaches, and discomfort less for the thoracic approach. This staging must be anyway planned, in the way of prenatal counselling and in the perinatal period, with the team involved in the procedure, that include anaesthetists, oncology staff, obstetricians, neonatologists and pediatric surgeons. It is mandatory in cases like the one reported that a multisciplinary team manage the patients and expert surgeons, especially in minimal invasive surgery, make the adequate plans.

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERalpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERalpha. In this study, we show that in ERalpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERalpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERalpha transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM(R)-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERalpha-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors.