De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study.

BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.

Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time.

Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

Approaches to modelling radioactive contaminations in forests - Overview and guidance.

Modelling the radionuclide cycle in forests is important in case of contamination due to acute or chronic releases to the atmosphere and from underground waste repositories. This article describes the most important aspects to consider in forest model development. It intends to give an overview of the modelling approaches available and to provide guidance on how to address the quantification of radionuclide transport in forests. Furthermore, the most important gaps in modelling the radionuclide cycle in forests are discussed and suggestions are presented to address the variability of forest sites.

Vortexes tune the chirality of graphene oxide and its non-covalent hosts.

Graphene oxide (GO) is one of the most appealing bidimensional materials able to interact non-covalently with achiral molecules and to act as chiral inducers. Vortexes can tune chirality and, consequently transfer a specific handedness to non-covalent host molecules, either when dispersed in water or when deposited on a solid surface.

[Psychosocial vulnerability and substance use screening during pregnancy: Evaluation of a composite auto-questionnaire versus usual medical questioning]. / Dépistage des situations de vulnérabilité psychosociale et toxicologique pendant la grossesse : évaluation d'un auto-questionnaire par comparaison aux données du dossier médical.

AIM: To evaluate auto-questionnaire use for psychosocial vulnerability and substance use (smoking, alcohol consumption, depression, intimate violence) screening during pregnancy versus usual medical report. MATERIAL AND METHODS: An auto-questionnaire based on validated tests (Fagerström/HSI, T-ACE, EPDS, SSQ6) was proposed to 1977 pregnant patients at their first obstetrical consultation. We compared results of auto-questionnaire and usual medical questioning. RESULTS: The auto-questionnaire was filled by 1676 pregnant patients (89.4 %). The two Fagerström/HIS questions showed that 20.7 % smoked during pregnancy. T-ACE score was better than usual medical questioning to detect excessive alcohol consumption (4.0 % vs 0.1 %, P<0.05). Drug use before pregnancy was reported by 9.8 % patients in auto-questionnaire, but was only found in 4.9 % of medical files (P<0.001). Seven percent patients reported at least 3 depressive symptoms on 4 purposed in auto-questionnaire. Intimate violence, physical or psychological, was reported in 9.4 %. All of these vulnerability factors were linked together, in auto-questionnaire or in usual medical reports. CONCLUSION: Using auto-questionnaire based on standardized screening tests could help medical practioneers to detect psychosocial vulnerability and/or substance use during pregnancy.

Benefits and shortcomings of superselective transarterial embolization of renal tumors before zero ischemia laparoscopic partial nephrectomy.

AIMS: To report feasibility, safety and effectiveness of "zero-ischemia" laparoscopic partial nephrectomy (LPN) following preoperative superselective transarterial embolization (STE) for clinical T1 renal tumors. METHODS: We retrospectively reviewed perioperative data of 23 consecutive patients, who underwent STE prior LPN between March 2010 and November 2012 for incidental clinical T1 renal mass. STE was performed by two experienced radiologists the day before surgery. Surgical procedures were performed in extended flank position, transperitoneally, by a single surgeon. RESULTS: Mean patients age was 68 years (range 56-74), mean tumor size was 3.5 cm (range 2.2-6.3 cm). STE was successfully completed in 16 patients 12-15 h before surgery. In 4 cases STE failed to provide a complete occlusion of all feeding arteries, while in 3 cases the ischemic area was larger than expected. LPN was successfully completed in all patients but one where open conversion was necessary; a "zero-ischemia" approach was performed in 19/23 patients (82.6%) while hilar clamp was necessary in 4 cases, with a mean warm-ischemia time of 14.8 min (range 5-22). Mean operative time was 123 min (range 115-130) and mean intraoperative blood loss was 250 mL (range 20-450). No patient experienced postoperative acute renal failure and no patient developed new onset IV stage chronic kidney disease at 1-yr follow-up. CONCLUSIONS: STE is a viable option to perform "zero-ischemia" LPN at beginning of learning curve; however, hilar clamp was necessary to achieve a relatively blood-less field in 17.4% of cases.

A fast and simple approach for the estimation of a radiological source from localised measurements after the explosion of a radiological dispersal device.

After an explosion of a radiological dispersal device, decision-makers need to implement countermeasures as soon as possible to minimise the radiation-induced risks to the population. In this work, the authors present a tool, which can help providing information about the approximate size of source term and radioactive contamination based on a Gaussian Plume model with the use of available measurements for liquid or aerosolised radioactivity. For two-field tests, the source term and spatial distribution of deposited radioactivity are estimated. A sensitivity analysis of the dependence on deposition velocity is carried out. In case of weak winds, a diffusive process along the wind direction is retained in the model.

Modeling of the fate of radionuclides in urban sewer systems after contamination due to nuclear or radiological incidents.

After an accidental radioactive contamination by aerosols in inhabited areas, the radiation exposure to man is determined by complex interactions between different factors such as dry or wet deposition, different types of ground surfaces, chemical properties of the radionuclides involved and building development as well as dependence on bomb construction e.g. design and geometry. At short-term, the first rainfall is an important way of natural decontamination: deposited radionuclides are washed off from surfaces and in urban areas the resulting contaminated runoff enters the sewer system and is collected in a sewage plant. Up to now the potential exposure caused by this process has received little attention and is estimated here with simulation models. The commercial rainfall-runoff model for urban sewer systems KANAL++ has been extended to include transport of radionuclides from surfaces through the drainage to various discharge facilities. The flow from surfaces is modeled by unit hydrographs, which produce boundary conditions for a system of 1d coupled flow and transport equations in a tube system. Initial conditions are provided by a map of surface contamination which is produced by geo-statistical interpolation of γ-dose rate measurements taking into account the detector environment. The corresponding methodology is implemented in the Inhabited Area Monitoring Module (IAMM) software module as part of the European decision system JRODOS. A hypothetical scenario is considered where a Radiation Dispersal Device (RDD) with Cs-137 is detonated in a small inhabited area whose drainage system is realistically modeled. The transition of deposited radionuclides due to rainfall into the surface runoff is accounted for by different nuclide-specific entrainment coefficients for paved and unpaved surfaces. The concentration of Cs-137 in water is calculated at the nodes of the drainage system and at the sewage treatment plant. The external exposure to staff of the treatment plant is estimated. For Cs-137 radiation levels in the plant are low since wash-off of cesium from surfaces is an ineffective process.

Laser assisted green synthesis of free standing reduced graphene oxides at the water-air interface.

A single step, scalable and green strategy has been developed to obtain reduced graphene oxide layers in water dispersion through nanosecond laser pulse irradiation of carbon targets. The layers spontaneously migrate at the water-air interface, forming sheets of several tens of micrometers and show intense ultraviolet photoluminescence. This unique condition offers an intriguing environment where opposing dielectric media meet and can be used in all those processes where molecular interactions such as hydrogen bonding and electrostatic interactions are greatly enhanced.

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer.

The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.

Serum osteoprotegerin correlates with age and bone mass in postmenopausal, but not in fertile age women.

PURPOSE OF INVESTIGATION: Osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) are bone turnover modulators expressed by osteoblasts. The aim of this study was to assess the relationship between the circulating OPG/RANKL system, age and bone mass, in fertile age and postmenopausal women. METHODS: In this cross-sectional observational study on 48 patients (fertile age, n = 22; postmenopause, n = 26), we investigated the correlation between serum OPG and RANKL, age and bone mineral density (BMD). Serum concentrations of OPG and RANKL were determined by enzyme-linked immunosorbent assay (ELISA); estimate BMD evaluation was performed with heel quantitative ultrasonometry (QUS). RESULTS: Serum OPG significantly increased (p = 0.003) and serum RANKL significantly decreased (p = 0.002), in the postmenopausal group compared to fertile age women. A significant correlation of serum OPG with age (r(s) = 0.39, p = 0.047) and BMD (r(s) = 0.45, p = 0.023) in postmenopausal women, and between RANKL and BMD (r(s) = 0.48, p = 0.024) in fertile age was found. CONCLUSION: These data demonstrate in vivo that the OPG/RANKL system is significantly associated with menopausal status and could play a role in postmenopausal osteoporosis.

Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells.

We investigated the effects of cisplatin (cisPt) on matrix metalloproteinase-2 (MMP-2) gelatinolitic activity in transformed PC E1Araf rat thyroid cells. Cells incubated with increasing cisPt concentrations showed dose- and time-dependent decrease of the MMP-2 protein and activity. CisPt provoked the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-zeta) and the activation of PKB/AKT. The effect of cisPt on MMP-2 was dependent on PKC-zeta activation since it was potentiated by a myristoylated PKC-zeta pseudo substrate peptide or by PKC-zeta down-regulation by siRNA. Moreover, MMP-2 activity modulation by cisPt was also dependent on PKB/AKT activation since it was decreased by PKB/AKT down-regulation by siRNA or by pharmacological inhibition of PI3K, thus indicating the importance of the balance of PKB/AKT and PKC-zeta in regulating the cisPt effect on MMP-2 activity. The PC E1Araf cells displayed a migratory capacity that was blocked by MMP-2 down-regulation using siRNA or pharmacological inhibition. The inhibition of cell migration was also obtained with cisPt; in cisPt-treated cells the administration of MMP-2 active protein was able to restore cell migration capacity. In conclusion, the decrease of MMP-2 secretion after cisPt was allowed by PKB/AKT and counteracted by PKC-zeta; the cisPt-provoked inhibition of MMP-2 secretion ended in reduction of cell migration.

PKC-epsilon-dependent cytosol-to-membrane translocation of pendrin in rat thyroid PC Cl3 cells.

We studied the expression and the hormonal regulation of the PDS gene product, pendrin, which is, in thyrocytes, responsible for the iodide transport out of the cell. We show that PC Cl3 cells, a fully differentiated thyroid cell line, grown without TSH and insulin, express very low level of PDS mRNA; such expression is greatly increased after stimulation with insulin or TSH. (125)I pre-loaded cells showed an (125)I efflux accelerated in chloride-containing buffer with respect to chloride-free buffer, suggesting that this efflux is chloride dependent. By immunoblotting, pendrin was found in agonists-stimulated cells, whereas it was barely detectable in un-stimulated cells. An increase in both PDS mRNA and protein was also obtained using phorbol ester PMA, or using 8-Br-cAMP and forskolin. Stimulation with insulin (1 microg/ml; 0-40 min) provoked the cytosol-to-membrane translocation of pendrin and a decrease of intracellular I(-) content in (125)I pre-loaded cells. Insulin- or PMA-treated cells also showed a cytosol-to-membrane translocation of PKC-delta and -epsilon. Inhibition of both PKC-delta and -epsilon activities by GF109203X blocked pendrin translocation, whilst the inhibition of PKA did not. The selective inhibition of PKC-delta by rottlerin did not affect the insulin-provoked translocation of pendrin whilst it was inhibited by a PKC-epsilon translocation inhibitor peptide and also by PKC-epsilon downregulation using the small interfering RNA, thus indicating that such translocation was due to PKC-epsilon activity. In conclusion, our study demonstrates that, in PC Cl3 cells, pendrin expression and localisation are regulated by insulin and influenced by a PKC-epsilon-dependent intracellular pathway.

[Pt(O,O'-acac)(gamma-acac)(DMS)], a new Pt compound exerting fast cytotoxicity in MCF-7 breast cancer cells via the mitochondrial apoptotic pathway.

BACKGROUND AND PURPOSE: We showed previously that a new Pt complex containing an O,O'-chelated acetylacetonate ligand (acac) and a dimethylsulphide in the Pt coordination sphere, [Pt(O,O'-acac)(gamma-acac)(DMS)], induces apoptosis in HeLa cells. The objective of this study was to investigate the hypothesis that [Pt(O,O'-acac)(gamma-acac)(DMS)] is also cytotoxic in a MCF-7 breast cancer cell line relatively insensitive to cisplatin, and to gain a more detailed analysis of the cell death pathways. EXPERIMENTAL APPROACH: Cells were treated with Pt compounds and cytotoxicity tests were performed, together with Western blotting of various proteins involved in apoptosis. The mitochondrial membrane potential was assessed by fluorescence microscopy and spectrofluorometry and the Pt bound to cell fractions was measured by atomic absorption spectrometry. KEY RESULTS: In contrast to cisplatin, the cytotoxicity of [Pt(O,O'-acac)(gamma-acac)(DMS)] correlated with cellular accumulation but not with DNA binding. Also, the Pt content in DNA bases was considerably higher for cisplatin than for [Pt(O,O'-acac)(gamma-acac)(DMS)], thus excluding DNA as a target of [Pt(O,O'-acac)(gamma-acac)(DMS)]. [Pt(O,O'-acac)(gamma-acac)(DMS)] exerted high and fast apoptotic processes in MCF-7 cells since it provoked: (a) mitochondria depolarization; (b) cytochrome c accumulation in the cytosol; (c) translocation of Bax and truncated-Bid from cytosol to mitochondria and decreased expression of Bcl-2; (d) cleavage of caspases -7 and -9, and PARP degradation; (e) chromatin condensation and DNA fragmentation. CONCLUSIONS AND IMPLICATIONS: [Pt(O,O'-acac)(gamma-acac)(DMS)] is highly cytotoxic for MCF-7 cells, cells relatively resistant to many chemotherapeutic agents, as it activates the mitochondrial apoptotic pathway. Hence, [Pt(O,O'-acac)(gamma-acac)(DMS)] has the potential to provide us with new opportunities for therapeutic intervention.

Differential functions of PKC-delta and PKC-zeta in cisplatin response of normal and transformed thyroid cells.

We investigated the effects of cisplatin (cisPt) in normal PC Cl3 and in transformed and tumourigenic PC E1Araf cells. cisPt cytotoxicity was higher in PC Cl3 than in PC E1Araf cells. In both cell lines, cisPt provoked the ERK1/2 phosphorylation; this was unaltered by Gö6976, a conventional PKC inhibitor, whilst it was blocked by low doses (0.1 microM) or high doses (10 microM) of GF109203X, an inhibitor of all PKC isozymes, in PC Cl3 and in PC E1Araf cells, respectively. In PC E1Araf, the cisPt-provoked ERK phosphorylation was also blocked by the use of a myristoylated PKC-zeta pseudosubstrate peptide. Conversely, in PC Cl3 the cisPt-provoked ERK phosphorylation was blocked by the use of rottlerin, a PKC-delta inhibitor. Results show that cisPt activates both PKC (the -delta and the -zeta isozymes in PC Cl3 and in PC E1Araf cells, respectively) and ERK in association with prolonged survival of thyroid cell lines.

Seminal sparing cystectomy and ileocapsuloplasty: long-term followup results.

PURPOSE: The efficacy of nerve sparing techniques to save potency in cystoprostatectomy is about 50%. This radical surgery may be proposed to young men with normal sexual function. We report the results of a 13-year experience with our innovative seminal sparing cystectomy and bladder replacement to maintain sexual function in such patients. MATERIALS AND METHODS: Seminal sparing cystectomy is a modification of standard radical cystectomy in which the posterior bladder dissection is anterior to the seminal vesicle plane to preserve the vasa deferens, seminal vesicles, prostatic capsule and neurovascular bundles. Ablation of the whole bladder and the prostatic urothelium with surrounding hypertrophic tissue is guaranteed, and injury to the pelvic nerve plexus that provides autonomic innervation to the corpora cavernosa is avoided. From April 1990 to December 2002 we performed 68 procedures in 63 patients (7 of whom were lost to followup) with superficial bladder cancer resistant to conservative therapies (18 patients with stage T1G2 disease, 13 TaG2, 11 T1G3 and 14 TaG3) and in 5 patients with invasive bladder cancer (T2G3) which was monofocal and away from the bladder neck. All patients had normal sexual function. A complete clinical evaluation (with prostate specific antigen [PSA], digital rectal examination and transrectal ultrasound) to exclude concomitant prostate cancer was performed. Average patient age was 49 years and mean followup was 68 months. RESULTS: Normal erectile function was preserved in 58 patients (95%). Complete daytime continence was reached in 58 patients (95%) and nighttime continence was reached in 19 patients (31%). The early postoperative complication rate was 18% and the delayed complication rate was 26.2%. A total of 55 patients (90.2%) are alive and 6 patients (9.8%) died, 5 of cancer progression. High grade prostatic intraepithelial neoplasia was noticed in prostatic specimens in 3 patients and prostatic cancer was noted in 1 patient. These patients had a normal PSA before operation and a serum PSA less than 0.2 ng/ml at a mean followup of 19 months. No positive margins were identified on permanent histological analysis of the specimens, nor were local pelvic recurrences observed. CONCLUSIONS: Our innovative technique is safe, effective and easy to perform. The oncological and functional results obtained with a long followup justify seminal sparing cystectomy as an excellent surgical procedure which can be proposed to some oncological and nononcological cases.

Characterization of early presentation idiopathic ovarian failure in girls and adolescents.

This study focused retrospectively on a selected cohort of 20 adolescents with early onset premature ovarian failure (POF) and no apparent underlying cause, in order to characterize the idiopathic ovarian failure at pediatric age. This characterization was based on medical history, pedigree analysis, phenotypical and audiological evaluation, final and target heights, pelvic ultrasonography, endocrine assessment, routine hematochemical analyses and complete autoimmune screening. We found that: a) idiopathic POF presented either before or after puberty onset and also with secondary amenorrhea; b) final height prognosis was impaired only in patients with prepubertal presentation of POF; c) ovarian pattern at ultrasonography and endocrine picture were similar those previously reported in patients with adult onset POF; d) clinical history and pedigree analysis, phenotypical and audiological examination and complete autoimmune screening failed to highlight the existence of any possible cause for POF in 15/20 patients; e) no alterations of total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol serum levels were detected in any patient. On the basis of these results we concluded that: a) final height of the adolescents with POF may be impaired only in patients in whom POF presents as a pubertal delay; b) other parameters do not generally differ from those described by previous reports on young adults with POF, except for serum lipid levels which were normal in the present cohort.

Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity.

BACKGROUND: Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity. OBJECTIVES: To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity. SUBJECTS AND METHODS: Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5+/-2.6 y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and/or DHPLC pattern was performed. RESULTS: One novel missense mutation and one previously described polymorphism (Vall03Ile) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI)=35 kg/m(2)) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population. CONCLUSIONS: Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood.

[Pica and iron-deficiency anemia in a 2-year old Indian child]. / Pica e anemia ferropriva in una bambina indiana di due anni.

Pica is the compulsive ingestion of nonnutritive substances. The causes are not known, but the symptom is often associated either with iron-deficiency or with pregnancy. The authors report on a case of pica in a 2-year old Indian child, affected by a serious ferropenic anaemia.

Conservative treatment of iatrogenic urinary fistulas: the value of cyanoacrylic glue.

Once previously attempted conservative maneuvers have failed, iatrogenic persistent urinary fistulas usually require difficult repeated operations. We describe 3 patients in whom cyanoacrylic glue was used to repair endoscopically persistent urinary fistulas occurring after major pelvic surgery. At a mean follow-up of 21 months, all patients were free of urinary leakage and had no evidence of recurrent urinary fistulas. This approach may represent a safe and effective way to repair postoperative urinary fistulas.