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Background Choledochal cysts are divided into 5 types. Physicians believe that Caroli disease (which refers to type V biliary cysts) is a special type of biliary cyst caused by a mutation in the PKHD1 gene and is associated with autosomal recessive polycystic kidney disease (ARPKD). There is currently no clear association between other types of choledochal cysts and polycystic kidney disease. Case presentation We report a 65-year-old male patient with jaundice, decreased appetite, and itchy skin. His biochemistry test results indicated obstructive jaundice disease. Cross-sectional imaging showed a type IVA choledochal cyst accompanied by autosomal dominant polycystic kidney disease (ADPKD). Due to economic difficulties, the patient achieved percutaneous transhepatic cholangial drainage (PTCD) instead of surgery. Conclusion To our knowledge, this is the second case report of the coexistence of type IVA choledochal cysts and ADPKD. We conclude that it is vital to be aware that the above condition is a possibility. This case report will aid earlier diagnosis and management and possibly prevent further damage to liver and kidney function.

Plasma tumour DNA (ptDNA) is a potential early noninvasive biomarker of treatment outcome in metastatic castration‐resistant prostate cancer (mCRPC). Herein, we investigated whether pretreatment ptDNA levels reflect metabolic tumour burden in mCRPC and better predict treatment outcome in combination with functional imaging. Targeted next‐generation sequencing was performed to estimate the ptDNA fraction from 102 mCRPC patients receiving abiraterone or enzalutamide. The maximum standardized uptake value (SUVmax), total lesion activity (TLA) and metabolic tumour volume (MTV) were evaluated on 18F‐fluorocholine positron emission tomography/computed tomography. We assessed a Weibull multiple regression model to determine the combined impact of clinical, molecular and imaging characteristics on overall survival (OS) and progression‐free survival (PFS), and to obtain prognostic scores. A significant association was seen between ptDNA and SUVmax, MTV and TLA. For survival analysis, patients were randomly allocated into a training (n = 68) and a validation (n = 34) set. In the training set, multivariable analyses showed that ptDNA, MTV and serum lactate dehydrogenase together with visceral metastasis were independent predictors of both OS and PFS. Prognostic scores were generated, with the identification of three groups of patients with significantly different median OS (29.2, 15.9 and 8.7 months) and PFS (13.3, 7.7 and 3.2 months) probabilities. The differences in median survival between risk groups were confirmed in the validation cohort for both OS and PFS. In our study, we showed that integrating plasma DNA analysis with functional imaging may improve prognostic risk stratification and treatment selection in mCRPC., Plasma tumour DNA (ptDNA) has been recently demonstrated as a potential early noninvasive biomarker in patients affected with metastatic castration‐resistant prostate cancer receiving androgen receptor signalling inhibitors. In our study, we initially showed that ptDNA reflected tumour metabolic activity. Additionally, integrating ptDNA analysis with functional imaging and clinical features showed potential for an improved outcome prediction as well as for a better treatment selection in these patients.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD. Methods and findings We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15–40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [−0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size. Conclusions In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4. Trial registration ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12., In this double-blind, placebo-controlled, phase 3 randomised trial, Piero Ruggenenti and co-workers assessed the renoprotective effects of Octreotide-LAR in adults with ADPKD at high risk of ESRD, Author summary Why was this study done? Autosomal dominant polycystic kidney disease is the most frequent genetically determined renal disease and affects approximately 10% of patients on chronic dialysis therapy because of end-stage kidney disease. The disease is characterized by relentless growth of renal cysts, with consequent disruption of normal parenchyma and progressive reduction of kidney function up to terminal kidney failure. Previous studies found that octreotide long-acting release (octreotide-LAR), an analog of somatostatin, slowed cyst growth and progressive renal function loss in patients with normal or slightly impaired kidney function. What did the researchers do and find? In this randomized and placebo-controlled trial, we evaluated whether the renoprotective effect of octreotide-LAR could be extended to patients with severe renal disease, that is, with chronic kidney disease stage 3b or 4. One-hundred patients with estimated glomerular filtration rate 15–40 ml/min/1.73 m2 were randomized to receive two 20-mg intramuscular injections of octreotide-LAR (n = 51) or sodium chloride (placebo; n = 49) every 28 days for 3 years. We found that 3-year treatment with octreotide-LAR did not appreciably affect glomerular filtration rate decline compared to placebo, but significantly slowed cyst growth and progression to end-stage kidney failure, in particular in patients with more severe renal insufficiency (stage 4) to start with, and was safe and tolerated well. What do these findings mean? Our present data—combined with previous evidence of a protective effect against kidney and liver volume growth and renal function loss in patients with normal or moderately reduced kidney function—indicate that octreotide-LAR could be a novel disease-modifying therapy that benefits patients with autosomal dominant polycystic kidney disease, including those with later-stage disease. Octreotide-LAR is an expensive medication. The identification of a subgroup of patients with CKD stage 4, accounting for approximately 10% to 15% of patients with autosomal dominant polycystic kidney disease, who are at high risk of kidney failure and at the same time may benefit the most from treatment may help increase the cost-effectiveness of octreotide-LAR for the prevention of end-stage renal disease (and related costs of renal replacement therapy and its complications) in this population.

alpha 1-Antitrypsin (alpha 1-protease inhibitor), an essential plasma protein, is synthesized predominantly in the liver of all mammals. We have previously shown that Mus caroli, a Southeast Asian mouse species is exceptional in that it expresses abundantly alpha 1-antitrypsin mRNA and polypeptide, in the kidney as well as the liver (Berger, F.G., and Baumann, H. (1985) J. Biol. Chem. 260, 1160-1165) providing a unique model for examination of the evolution of genetic determinants of tissue-specific gene expression. In the present paper, we have further characterized alpha 1-antitrypsin expression in M. caroli. The extrahepatic expression of alpha 1-antitrypsin is limited to the kidney, specifically within a subset of the proximal tubule cells. The developmental pattern of alpha 1-antitrypsin mRNA expression in the kidney differs from that in the liver. In the kidney, alpha 1-antitrypsin mRNA is present at only 2-4% adult level at birth and increases very rapidly to adult level during puberty between 26 and 36 days of age. There are no significant changes in liver alpha 1-antitrypsin mRNA levels during this period. Testosterone, while having only modest affects on alpha 1-antitrypsin mRNA accumulation in the adult kidney, causes a 20-fold induction of the mRNA in the pre-pubertal kidney. This suggests that the increase in alpha 1-antitrypsin mRNA expression during puberty is testosterone mediated. Southern blot analyses of Mus domesticus and M. caroli genomic DNA and a cloned M. caroli alpha 1-antitrypsin genomic sequence, indicate that a single alpha 1-antitrypsin gene exists in M. caroli, whereas multiple copies exist in M. domesticus. These data show that the alteration in tissue specificity of alpha 1-antitrypsin mRNA accumulation that has occurred during Mus evolution is associated with distinctive developmental and hormonally regulated expression patterns.

Background: A growing literature has revealed a relationship between shift-work, including night-shift, and the disturbance of sleep-wake cycle, leading to insomnia and/or increased daytime sleepiness in shift nurses; recent findings showed an association between shift work sleep disorders and distress, work accidents, decreased job performance and, consequently, lower quality of health service provision and lower standards of care. Objectives: To analyze across the gender how shift nurses experience shift work sleep disorders and job stress. Methods: A cross-sectional study was performed following the STROBE Statement. The Italian version of the Job Content Questionnaire, the Bergen Insomnia Scale and the Epworth Sleepiness Scale were administered to the registered nurses employed in three Departments of General Practice and Elderly Care Medicine. Results: No significant association was found between high job strain and insomnia and daytime sleepiness. Significantly more women than men experienced high job strain, insomnia and daytime sleepiness; among women the level of social support was significantly and negatively associated with insomnia and daytime sleepiness. Conclusions: The findings of this study suggest that interventions aimed to prevent shift work sleep disorder and job stress in shift-nurses should incorporate the assessment of social support across the gender. Moreover, longitudinal studies are required to evaluate the effectiveness of interventions targeted on social support to minimize the occurrence of insomnia and daytime sleepiness in shift nurses.

We investigate the gender gap in hypertension misreporting using the French Constances cohort. We show that false negative reporting of hypertension is more frequent among men than among women, even after conditioning on a series of individual characteristics. As a second step, we investigate the causes of the gender gap in hypertension misreporting. We show that women go to the doctor more often than men do and that they have better knowledge of their family medical history. Once these differences are taken into account, the gender gap in false negative reporting of hypertension is reversed. This suggests that information acquisition and healthcare utilisation are crucial ingredients in fighting undiagnosed male hypertension.

Malignant mesothelioma (MM) has a wide range of clinical, radiologic, and pathologic presentations, mimicking lung cancer or interstitial lung diseases when predominantly involving the lung parenchyma. The case herein refers to a 79-year-old man, active smoker without asbestos exposure, incidentally discovered to have a pulmonary nodule in the right upper lobe (1.5 cm). The lesion was misinterpreted as primary lung adenocarcinoma at the frozen section in light of the predominant lepidic growth pattern. Definitive examination confirmed neoplastic proliferation along alveolar structures. However, the unusual globous shape of tumor cells along the alveoli abruptly merging with normal pneumocytes prompted us to perform some immunostains that surprisingly revealed a mesothelial differentiation (positive staining with calretinin, cytokeratins (CK5/6), D2-40, and negativity with BRCA-associated protein 1 (BAP1), Thyroid Transcription Factor 1 [TTF-1], claudin-4, carcinoembryonic antigen [CEA], and napsin). MM represents the pathologic counterpart of so-called pseudomesotheliomatous carcinoma, since it appears as a localized pulmonary neoplastic nodule displaying a predominant lepidic growth pattern (pseudocarcinomatous mesothelioma). The challenging diagnostic features of this unique case and a review of similar cases in the literature are discussed.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Suboptimal nutrient quality/quantity during complementary feeding (CF) can impact negatively on infants’ healthy growth, even with adequate energy intake. CF must supplement at best human milk (HM) or formulas, which show nutritional differences. Considering this, a differentiated CF is probably advisable to correctly satisfy the different nutritional needs. To assess whether current needs at 6–24 months of age can still be met by one single CF scheme or different schemes are needed for breastfed vs. formula/cow’s milk (CM) fed infants, protein, iron and calcium intakes were assessed from daily menus using the same type and amount of solid food, leaving same amounts of HM and follow-up formula at 9 and again 18 months of age, when unmodified CM was added. Depending on the child’s age, calcium- and iron-fortified cereals or common retail foods were used. The single feeding scheme keeps protein intake low but higher than recommended, in HM-fed children while in formula/CM-fed ones, it achieves much higher protein intakes. Iron Population Recommended Intake (PRI) and calcium Adequate Intakes (AI) are met at the two ages only when a formula is used, otherwise, calcium-fortified cereals are needed. ESPGHAN statements on the futility of proposing different CF schemes according to the milk type fed do not allow to fully meet the nutritional recommendations issued by major Agencies/Organizations/Societies for all children of these age groups.

Regular medical supervision represents a fundamental component of the clinical management of obesity. In fact, when frequently supplied it reduces the risk of failure associated with any body weight reduction program (BWRP), resulting in body weight gain. The aim of the present study was to establish the potential beneficial effects of increasing medical supervision on weight loss and other auxometric and cardiometabolic parameters in a population of children and adolescents with obesity (n = 158, F/M = 94/64, age range 9.7–17.3 years, body mass index, BMI = 37.8 ± 6.9 kg/m2), followed up for one year in a real-world setting, after and before a 3-week in-hospital BWRP. Weight loss was significantly associated with medical supervision and changes in several auxometric and cardiometabolic parameters such as fat mass, fat-free mass, waist and hip circumferences, total and LDL cholesterols, triglycerides, glucose, insulin, HOMA-IR, systolic blood pressure and IDF criteria for the diagnosis of metabolic syndrome. As expected, weight loss and, congruently, medical supervision, were significantly higher in responsive and stable subjects than in those belonging to the non-responsive group and in responsive subjects than those belonging to the stable group. While weight loss was significantly higher in subjects having class 2 and 3 obesity than those belonging to class 1 obesity group, medical supervision was significantly higher in subjects having class 3 than those having class 1 obesity. Weight loss was significantly higher in subjects suffering from metabolic syndrome than those without, nevertheless, no significant difference was found in medical supervision between these groups. Finally, sex was associated with no differences in weight loss and medical supervision. In conclusion, based on the results of a real-world experience, frequent medical supervision increases the weight loss associated with a longitudinal multidisciplinary BWRP, with a parallel improvement of a set of auxometric and cardiometabolic parameters. Prospectively, incentivising regular medical supervision should reduce the risk of BWRP failure and body weight gain, thus contributing to counteract the detrimental transition from simple obesity to metabolic syndrome in pediatric patients.

Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.

Background: The Prognostic Nutritional Index (PNI) is a parameter of nutritional and inflammation status related to toxicity in cancer treatment. Since data for head and neck cancer are scanty, this study aims to investigate the association between PNI and acute and late toxicity for this malignancy. Methods: A retrospective cohort of 179 head and neck cancer patients treated with definitive radiotherapy with induction/concurrent chemotherapy was followed-up (median follow-up: 38 months) for toxicity and vital status between 2010 and 2017. PNI was calculated according to Onodera formula and low/high PNI levels were defined according to median value. Odds ratio (OR) for acute toxicity were calculated through logistic regression model, hazard ratios (HR) for late toxicity and survival were calculated through the Cox proportional hazards model. Results: median PNI was 50.0 (interquartile range: 45.5–53.5). Low PNI was associated with higher risk of weight loss &gt, 10% during treatment (OR = 4.84, 95% CI: 1.73–13.53 for PNI &lt, 50 versus PNI ≥ 50), which was in turn significantly associated with worse overall survival, and higher risk of late mucositis (HR = 1.84, 95% CI:1.09–3.12). PNI predicts acute weight loss &gt, 10% and late mucositis. Conclusions: PNI could help clinicians to identify patients undergoing radiotherapy who are at high risk of acute and late toxicity.

Background FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line. Patients and Methods Patients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H0: 55% and H1= 75%. Data were analyzed in intention to treat. Results Forty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification. Conclusion Although the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.

National audience; Money is a cultural artefact with a central role in human society. Here, we investigated whether some features of money may be traced back to the exchange habits of nonhuman animals, capitalizing on their ability to flexibly use tokens in dif-ferent domains. In Experiment 1, we evaluated whether capuchins can recognize token validity. Six subjects were required to exchange with the experimenter valid/familiar tokens, valid/unfamiliar tokens, invalid tokens, and no-value items. They first exchanged a similar number of valid/familiar and valid/unfamiliar tokens, followed by exchanges of invalid tokens and no-value items. Thus, as humans, capuchins readily recognized token validity, regardless of familiarity. In Experiment 2, we further evaluated the flexibility of the token–food association by assessing whether capuchins could engage in reverse food–token exchanges. Subjects spontaneously performed chains of exchanges, in which a food item was exchanged for a token, and then the token was exchanged for another food. However, performance was better as the advantage gained from the exchange increased. Overall, capuchins recognized token validity and successfully engaged in chains of reverse and direct exchanges. This suggests that—although nonhuman animals are far from having fully-fledged monetary systems—for capuchins tokens share at least some features with human money.

To evaluate the impact of faecal immunochemical test (FIT) screening on stage distribution at diagnosis, and to estimate relative incidence rates by stage in screened at first and subsequent rounds vs. unscreened. We included all incident cases occurring in 2000-2008 in 50- to 71-year-olds residing in areas with an FIT-screening programme. Multinomial logistic models were computed to estimate the relative risk ratio (RRR) of stages I and IV, compared to stage II + III, adjusting for age, sex, geographical area, and incidence year. Proportions were then used to estimate incidence rate ratios (IRR) by stage for screened subjects at the first and at subsequent rounds vs. unscreened subjects, applying the expected changes in overall incidence during screening phases. 11,663 cancers were included: 5965 in not-invited and 5,698 in invited subjects, 3,425 of whom attendees. Compared to not-invited, invited subjects had RRR 2.04 (95% CI: 1.84; 2.46) of stage I and RRR 0.77 (95% CI: 0.69; 0.87) of stage IV. Differences were stronger comparing attendees vs. nonattendees. Interval cancers were more frequently stage I compared to non-invited (RRR 1.54; 95% CI: 1.15; 2.04), but there was no difference for stage IV. IRRs in screened at first round vs. unscreened were 4.6 (95% CI: 4.2; 5.1), 1.4 (95% CI: 1.3; 1.5) and 0.7 (95% CI: 0.6; 0.9) for stages I, II + III and IV, respectively; in the following rounds the IRRs of screened vs. unscreened were 1.4 (95% CI: 1.2; 1.6), 0.8 (95% CI: 0.7; 0.9) and 0.3 (95% CI: 0.1; 0.4) for stages I, II + III and IV, respectively. FIT screening reduces the incidence of metastatic cancers by about 70% after the first round.

Background. In clinical practice, there is the diffuse conviction that obese subjects with metabolic syndrome may be more difficult to treat. Objectives and Methods. The aim of the present study was that to investigate the effectiveness of a 3-week in-hospital body weight reduction program (BWRP) in a large population of obese subjects with and without metabolic syndrome (n = 1922, 222 men and 1700 women, age range 18&ndash, 83 yr). Outcomes such as body mass index (BMI), total (TOT) and HDL cholesterol, systolic and diastolic blood pressures (SBP and DBP, respectively), coronary heart disease (CHD) score, fatigue severity score (FSS), and stair climbing test (SCT) time were evaluated before and after the intervention (&Delta, ). A sex-, BMI-, and age-related stratification of the obese population with or without metabolic syndrome was applied. Results. When compared to obese subjects without metabolic syndrome, at the basal conditions, obese subjects had a poorer cardiometabolic profile, as demonstrated by higher triglycerides, TOT-cholesterol, DBP, SBP, and CHD score, and a more compromised muscle performance (evaluated by SCT), associated with more perception of fatigue (measured by FSS). Nevertheless, obese subjects with metabolic syndrome obtained more benefits from BWRP than those without metabolic syndrome for some outcomes (i.e., &Delta, TOT-cholesterol, &Delta, SBP, and &Delta, CHD score). Despite these differences, the BWRP-induced weight loss was similar between the two groups (i.e., &Delta, BMI) as well as the gain of muscle performance (i.e., &Delta, SCT) and the reduction of fatigue (i.e., &Delta, FSS). Interestingly, the potentially deleterious fall in HDL-cholesterol levels after BWRP was less evident in obese subjects with metabolic syndrome than those without metabolic syndrome. When pooling all data, the &Delta, CHD score was associated with age, sex, and metabolic syndrome. The remaining outcomes, such as &Delta, BMI, &Delta, FSS, and &Delta, SCT time, were associated with sex and age but not with metabolic syndrome. Finally, &Delta, BMI was positively correlated with &Delta, CHD score, &Delta, SCT time in both obese subjects without metabolic syndrome and obese subjects with metabolic syndrome. Conclusions. When comparing obese subjects undergoing a BWRP, metabolic syndrome is not a negative predictive factor affecting the effectiveness of this intervention in terms of weight loss, muscle performance, and psychological well-being.

Cortical sources of resting state electroencephalographic (EEG) delta (2-4Hz) and low-frequency alpha (8-10.5Hz) rhythms show abnormal activity (i.e., current density) in patients with dementia due to Alzheimer's disease (AD). Here, we hypothesized that abnormality of this activity is related to relevant disease processes as revealed by cortical hypometabolism typically observed in AD patients by fluorodeoxyglucose positron emission tomography. Resting state eyes-closed EEG data were recorded in 19 AD patients with dementia and 40 healthy elderly (Nold) subjects. EEG frequency bands of interest were delta and low-frequency alpha. EEG sources were estimated in these bands by low-resolution brain electromagnetic tomography (LORETA). Fluorodeoxyglucose positron emission tomography images were recorded only in the AD patients, and cortical hypometabolism was indexed by the so-called Alzheimer's discrimination analysis tool (PALZ) in the frontal association, ventromedial frontal, temporoparietal association, posterior cingulate, and precuneus areas. Results showed that compared with the Nold group, the AD group pointed to higher activity of delta sources and lower activity of low-frequency alpha sources in a cortical region of interest formed by all cortical areas of the PALZ score. In the AD patients, there was a positive correlation between the PALZ score and the activity of delta sources in the cortical region of interest (p < 0.05). These results suggest a relationship between resting state cortical hypometabolism and synchronization of cortical neurons at delta rhythms in AD patients with dementia.

Surgical treatment of elderly patients with meningioma is has proved to be safe, especially when patients are selected using dedicated surgical scores. These scores take into account tumor size, edema, location and patient's co-morbidities. Neuropsychological functioning (NPF) of this kind of patients has been poorly studied in literature and it is not taken into account by these scores. Aim of our study was to describe the long-term outcome in terms of NPF of elderly patients undergoing surgery. Patients older than 70 years of age affected by intracranial meningioma and selected with the Clinical-Radiological Grading Score were included in our study. Neuropsychological testing was performed using a dedicated battery of tests before surgery, 3 and 12 months after surgery. Clinical, neurological and radiological outcomes were studied as well. Forty-one patients with a median age of 74 years were included in this study. Preoperatively only 1/41 patients showed a normal NPF with all tests scoring normally. Four out of 39 patients showed a complete neuropsychological recovery after 3 months; while 10/37 patients had a complete recovery after 12 months. NPF showed a trend of progressive improvement after surgery. Our study is the first experience reported in literature describing a long term follow-up in elderly patients after surgery for intracranial meningioma. In our series, surgery determined an improvement of NPF over time; especially with a low complication rate related to the selection of patients obtained through the CRGS. Further studies need to be performed in order to understand how brain edema, tumor size, volume and tumor location affect NPF in both short and long term.

Background and aim of the study: Physical performance is the result of a complex combination of several factors such as genetic and anthropometric aspects, nutrition and hormonal status. In the past few years many studies have considered the impact of vitamin D on muscular strength and athletic performance. The aim of the present study was to assess the anthropometric measures impacting on physical performance in a group of professional rugby athletes. As a secondary aim we investigated a possible relationship between baseline vitamin D status and athletic performance status in these subjects. Methods: All rugby players completed a test–retest reliability study on performance measures, as 70kg jump squat and body weight (BW) jump squat to assess musculoskeletal performance. Additionally at the time point we collected a blood sample of every athletes for the assessment of serum vitamin D. Results: We found that lean mass was an important independent predictor of performance score in 70kg jump squat (p=0.007, R2=0.74) and BW jump squat (p=0.010, R2=0.66) in these well trained athletes. No statistically significant association was present between performance score and serum vitamin D in this specific setting. Conclusions: We demonstrate a positive interaction between lower limb lean mass and performance score, but we have not been able to identify any statistically significant association between worsening in performance measures and decrease of serum 25 OH Vitamin D. (www.actabiomedica.it)

Background: Obesity is a widespread problem in the elderly, being associated with severe comorbidities negatively influencing life expectancy. Integrated multidisciplinary metabolic rehabilitation aimed to reduce body weight (BW) and fatigue, increase physical autonomy and introduce healthy life style changes has been proposed as a useful intervention to improve the general health status and quality of life of the obese geriatric population. Methods: Six hundred-eighty four severely obese subjects (F/M = 592/92, age range: 61&ndash, 83 years, mean body mass index, BMI &plusmn, SD: 42.6 &plusmn, 5.6 kg/m2) were admitted to take part in a three-week in-hospital BW reduction program (BWRP), entailing energy restricted diet, psychological counselling, physical rehabilitation and nutritional education. Biochemical parameters, cardiovascular risk factors (throughout the Coronary Heart Disease Risk, CHD-R), fatigue (throughout the Fatigue Severity Scale, FSS) and lower limb muscle performance (throughout the Stair Climbing Test, SCT) were evaluated before and at the end of the BWRP. Results: A 4% BW reduction was achieved at the end of the BWRP. This finding was associated with a significant improvement of the metabolic homeostasis (i.e., decrease in total cholesterol and glucose) and a reduction of systolic blood pressure in both females and males, thus resulting in a reduction of CHD-R in the male group. Total FSS score and SCT time decreased in female and male obese patients. The effects of BWPR were comparable among all age-related subgroups (&gt, 60, 60&ndash, 69 and &gt, 70 years), apart from &Delta, CHD-R, which was higher in male subgroups. Finally, age was negatively correlated with &Delta, BMI and &Delta, FSS. Conclusions: Though only a relatively limited number of outcomes were investigated, the present study shows that a 4% BW reduction in severely elderly obese patients is associated with positive multisystemic effects, particularly, muscle-skeletal and cardiometabolic benefits, which can favorably influence their general well-being and improve the autonomy level in performing more common daily activities. The maintenance of a healthy life style, including controlled food intake and regular physical activity, after a BWRP is obviously recommended in all elderly obese patients to further improve their clinical condition.

Caroli's disease is a rare autosomal-recessive disorder caused by malformation of the ductal plate during embryonic development. Although it is present at birth, Caroli's disease is typically not diagnosed until between the second and fourth decades of life, as it was in the present patient. Here we report a rare case of Caroli's disease limited to one liver segment, which was initially misdiagnosed as an intraductal papillary neoplasm of the bile duct. The asymptomatic patient was treated with liver segmentectomy.

Objective.The aim of our study was to analyze the clinical and functional effect of the p.Q703K (p. Q705K, c. 2107C>A) variant of the NLRP3 gene in a population of patients screened for suspected cryopyrin-associated periodic syndrome (CAPS).Methods.Since 2002, 580 patients underwent molecular analysis for NLRP3. Data on clinical presentation, response to treatment, and longterm followup were collected using a uniform questionnaire. The pattern of cytokine secretion after lipopolysaccharide stimulation from isolated monocytes was analyzed in 3 patients carrying the p.Q703K variant and 1 patient with a chronic infantile neurologic, cutaneous, articular syndrome phenotype carrying both the p.M406I and p.Q703K, and compared with 7 patients with CAPS with sure pathogenic variants and 6 healthy controls.Results.The p.Q703K variant was found in 57 screened patients with an overall allelic frequency of 5%. The frequency in normal controls was 5.5%. Clinical data at the moment of molecular analysis and at followup were available in 36 patients. Two patients displayed additional mutations of NLRP3. The mean followup was 2.5 years. Thirteen patients (39%) had a final diagnosis different from the original suspicion of CAPS. The remaining 21 patients displayed a mild phenotype mainly characterized by recurrent episodes of urticarial rash and arthralgia. Only 8 patients were treated with anti-interleukin (IL)-1 treatment, with a complete response in 5 patients. The pattern of secretion of IL-1β and other cytokines (IL-6 and IL-1 receptor antagonist) in patients did not display the aberrancies observed in patients with CAPS and was similar to that observed in healthy controls.Conclusion.The present study confirms the weak clinical and functional effect of the p.Q703K variant.

International audience; Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter- and intra-familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra-familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well-known disease-associated genes, using reverse phenotyping.

Congenital intrahepatic bile duct dilatation (Caroli's disease) is a rare biliary disease. Although multiple reports exist describing its surgical treatment, relatively few have provided long-term follow-up. Prospective data about 25 cases of monolobular Caroli's disease, with liver resection between 1974 and 2016, were retrospectively analyzed. Patient demographics together with postoperative outcomes and long-term follow-up were assessed. Our 25-patient cohort (average age 53.4 years (range: 27-82)) included 20 cases with disease limited to the left lobe, and 5 to the right. The average time interval between first symptoms and final diagnosis was 5 years (range: 0-34 years). The surgical procedures included left lobectomy in 11 cases, left hepatectomy in 8 cases, right hepatectomy in 3, and sub-segmentectomy in 3 cases. Biliodigestive anastomosis was performed in 7 cases. Complications were observed in 3 patients (25%). Metachronous cholangiocarcinoma was observed in one single case, 10 years after initial operation. In conclusion, surgical treatment for monolobular Caroli's disease is effective, with good short-term results and few complications. Median long-term follow-up was 18 months (range: 3-132), with favorable clinical evolution in 96% of patients.

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

This article evaluates the results of portal vein (PV) stent placement in patients with malignant extrinsic lesions stenosing or obstructing the PV and causing symptomatic PV hypertension (PVHT). Fourteen patients with bile duct cancer (n = 7), pancreatic adenocarcinoma (n = 4), or another cancer (n = 3) underwent percutaneous transhepatic portal venous stent placement because of gastroesophageal or jejunal varices (n = 9), ascites (n = 7), and/or thrombocytopenia (n = 2). Concurrent tumoral obstruction of the main bile duct was treated via the transhepatic route in the same session in four patients. Changes in portal venous pressure, complications, stent patency, and survival were evaluated. Mean +/- standard deviation (SD) gradient of portal venous pressure decreased significantly immediately after stent placement from 11.2 mmHg +/- 4.6 to 1.1 mmHg +/- 1.0 (P < 0.00001). Three patients had minor complications, and one developed a liver abscess. During a mean +/- SD follow-up of 134.4 +/- 123.3 days, portal stents remained patent in 11 patients (78.6%); stent occlusion occurred in 3 patients, 2 of whom had undergone previous major hepatectomy. After stent placement, PVHT symptoms were relieved in four (57.1%) of seven patients who died (mean survival, 97 +/- 71.2 days), and relieved in six (85.7%) of seven patients still alive at the end of follow-up (mean follow-up, 171.7 +/- 153.5 days). Stent placement in the PV is feasible and relatively safe. It helped to relieve PVHT symptoms in a single session.

Background Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. Methods A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR 30% from baseline was evaluated. Results The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening. Electronic supplementary material The online version of this article (10.1186/s12882-018-1136-6) contains supplementary material, which is available to authorized users.

Background: The best chemotherapy regimen for well- differentiated pancreatic neuroendocrine tumours (pNETs) with a Ki-67 index ≥10% is still debated. We evaluated the antitumour efficacy of various first-line chemotherapy regimens (streptozocin based, platinum based, or dacarbazine/temozolomide based) in this situation. Methods: In this retrospective multicentre study of the French Group of Endocrine Tumours (GTE), we recruited consecutive patients with advanced well-differentiated pNETs and a Ki-67 index ≥10% receiving chemotherapy between 2000 and 2012. The primary endpoint was progression-free survival (PFS) according to RECIST. Results: Seventy-four patients (42 men, median age 55.5 years) were enrolled from 10 centres. Fifty-one patients (69%) had grade 2 NET and 61 (82%) were stage IV. Median overall survival was 36.3 months. Forty-four patients (59%) received streptozocin-based, 18 (24%) platinum-based, and 12 (16%) dacarbazine/temozolomide-based chemotherapy regimens. These 3 groups were similar regarding age, functioning tumours, grade, the number of metastatic sites, and surgery for primary tumours, but not regarding surgery for metastases and time since diagnosis. Grade 3 NET (HR 2.15, 95% CI: 1.18-3.92, p = 0.012) and age above 55 years (HR 1.84, 95% CI: 1.06-3.18, p = 0.030) were associated with shorter median PFS in the multivariate analyses. Compared to streptozocin-based chemotherapy, no difference was found in terms of PFS for the platinum-based or for the dacarbazine/temozolomide-based chemotherapy regimen: median PFS was 7.2, 7.5, and 7.2 months, respectively (p = 0.51). Conclusions: Patients with intermediate or highly proliferative well-differentiated pNETs may benefit from 1 of the 3 chemotherapy regimens. Increased age and grade 3 were associated with shorter median PFS. Randomised studies searching for response predictors and the best efficacy-tolerance ratio are required to personalise the strategy.

To assess clinical presentation and long-term results of surgical management of congenital intrahepatic bile duct dilatation (IHBDD) (Caroli disease and syndrome) in a multicenter setting.Congenital IHBDD predisposes to biliary stasis, resulting in intrahepatic lithiasis, septic complications, and cholangiocarcinoma. Although liver resection (LR) is considered to be the treatment of choice for unilobar disease extent into the liver, the management of bilobar disease and/or associated congenital hepatic fibrosis remains challenging.From 1978 to 2011, a total of 155 patients (median age: 55.7 years) were enrolled from 26 centers. Bilobar disease, Caroli syndrome, liver atrophy, and intrahepatic stones were encountered in 31.0%, 19.4%, 27.7%, and 48.4% of patients, respectively. A complete resection of congenital intrahepatic bile ducts was achieved in 90.5% of the 148 patients who underwent surgery.Postoperative mortality was nil after anatomical LR (n = 111) and 10.7% after liver transplantation (LT) (n = 28). Grade 3 or higher postoperative morbidity occurred in 15.3% of patients after LR and 39.3% after LT. After a median follow-up of 35 months, the 5-year overall survival rate was 88.5% (88.7% after LT), and the Mayo Clinic score was considered as excellent or good in 86.0% of patients. The 1-year survival rate was 33.3% for the 8 patients (5.2%) who presented with coexistent cholangiocarcinoma.LR for unilobar and LT for diffuse bilobar congenital IHBDD complicated with cholangitis and/or portal hypertension achieved excellent long-term patient outcomes and survival. Because of the bad prognosis of cholangiocarcinoma and the sizeable morbidity-mortality after LT, timely indication for surgical treatment is of major importance.

Background The thalamus is a deep-seated and crucial structure for the sensorimotor system. It has been long considered a surgically inaccessible area because of the morbidity associated with surgical resections. Astrocytomas of the thalamus are usually treated with bioptic procedures followed by adjuvant treatments. Intraoperative neurophysiologic monitoring (IONM) allows safe and satisfactory resections of lobar gliomas, but few data are available for thalamic lesions. The aim of this study was to review the outcome of a small series of patients with thalamic astrocytomas that were treated with surgical resection with the aid of IONM. Methods Surgical resection with IONM was performed in 5 patients with thalamic astrocytomas (1 grade I, 1 grade II, 2 grade III, 1 grade IV). Two astrocytomas were in the dominant hemisphere. Preoperative and postoperative neuropsychological assessments were performed in 3 patients. IONM was tailored to the individual patient and consisted of transcranial motor evoked potential monitoring, cortical motor evoked potential monitoring, somatosensory evoked potential monitoring, direct electrical stimulation, electroencephalography, and electrocorticography. Results None of the patients experienced permanent motor deficits; 2 patients had a transient hemiparesis requiring rehabilitation; 1 patient had a transient aphasia, and 1 patient had permanent aphasia. None of the patients had intraoperative seizures, but 1 patient experienced postoperative transient status epilepticus. The extent of resection on postoperative volumetric magnetic resonance imaging was >70% in all cases. Conclusions Surgical resection of thalamic astrocytomas appeared to be effective and relatively safe when guided by IONM. Larger series of patients are required to confirm these preliminary data.

Background In autosomal dominant polycystic kidney disease (ADPKD), total kidney volume (TKV) is regarded as an important biomarker of disease progression and different methods are available to assess kidney volume. The purpose of this study was to identify the most efficient kidney volume computation method to be used in clinical studies evaluating the effectiveness of treatments on ADPKD progression. Methods and findings We measured single kidney volume (SKV) on two series of MR and CT images from clinical studies on ADPKD (experimental dataset) by two independent operators (expert and beginner), twice, using all of the available methods: polyline manual tracing (reference method), free-hand manual tracing, semi-automatic tracing, Stereology, Mid-slice and Ellipsoid method. Additionally, the expert operator also measured the kidney length. We compared different methods for reproducibility, accuracy, precision, and time required. In addition, we performed a validation study to evaluate the sensitivity of these methods to detect the between-treatment group difference in TKV change over one year, using MR images from a previous clinical study. Reproducibility was higher on CT than MR for all methods, being highest for manual and semiautomatic contouring methods (planimetry). On MR, planimetry showed highest accuracy and precision, while on CT accuracy and precision of both planimetry and Stereology methods were comparable. Mid-slice and Ellipsoid method, as well as kidney length were fast but provided only a rough estimate of kidney volume. The results of the validation study indicated that planimetry and Stereology allow using an importantly lower number of patients to detect changes in kidney volume induced by drug treatment as compared to other methods. Conclusions Planimetry should be preferred over fast and simplified methods for accurately monitoring ADPKD progression and assessing drug treatment effects. Expert operators, especially on MR images, are required for performing reliable estimation of kidney volume. The use of efficient TKV quantification methods considerably reduces the number of patients to enrol in clinical investigations, making them more feasible and significant.

Our hypothesis was that pituitary macroadenomas show different areas of consistency detectable by enhanced magnetic resonance imaging (MRI) with Dynamic study during gadolinium administration. We analysed 21 patients with pituitary macroadenomas between June 2013 and June 2015. All patients underwent trans-sphenoidal surgery and neurosurgeon described macroadenomas consistency. Similarly, two neuroradiologists manually drew regions of interest (ROIs) inside the solid-appearing portions of macroadenoma and in the normal white matter both on dynamic and post-contrast acquisitions. The ratio between these ROIs, defined as Signal Intensity Ratio (SIR), allowed obtaining signal intensity curves over time on dynamic acquisition and a single value on post-contrast MRI. SIR values best differentiating solid from soft macroadenoma components were calculated and correlated with pathologic patterns. A two-sample T test and empiric receiver operating characteristic (ROC) curve of SIR was performed. According to ROC analysis, the SIR value of 1.92, obtained by dynamic acquisition, best distinguished soft and hard components. All the specimens from soft components were characterized by high cellularity, high representation of vascularization and micro-haemorrhage and low percentage of collagen content. The reverse was evident in hard components. We demonstrated that dynamic MRI acquisition could distinguish with good accuracy macroadenomas consistency.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited disorder of the kidneys. It is characterized by enlargement of the kidneys caused by progressive development of renal cysts, and thus assessment of total kidney volume (TKV) is crucial for studying disease progression in ADPKD. However, automatic segmentation of polycystic kidneys is a challenging task due to severe alteration in the morphology caused by non-uniform cyst formation and presence of adjacent liver cysts. In this study, an automated segmentation method based on deep learning has been proposed for TKV computation on computed tomography (CT) dataset of ADPKD patients exhibiting mild to moderate or severe renal insufficiency. The proposed method has been trained (n = 165) and tested (n = 79) on a wide range of TKV (321.2–14,670.7 mL) achieving an overall mean Dice Similarity Coefficient of 0.86 ± 0.07 (mean ± SD) between automated and manual segmentations from clinical experts and a mean correlation coefficient (ρ) of 0.98 (p

International audience; OBJECTIVE: Temozolomide (TMZ) is an alkylating agent frequently used in well-differentiated metastatic pancreatic neuroendocrine tumors (PNETs) with very variable responses. O-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose loss of expression has been suggested to be predictive of response to TMZ in various human tumors. We evaluated the predictive value of MGMT status, assessed by immunohistochemistry (IHC) and methylation-specific PCR (MS-PCR), in well-differentiated metastatic PNETs treated by a TMZ-based chemotherapy.PATIENTS AND METHODS: All patients with metastatic PNETs treated with TMZ-based chemotherapy between 2010 and 2016 in two academic centers, for whom the tumor samples were available, were included. Clinical data were collected and the MGMT status of the tumors was analyzed using MS-PCR and IHC.RESULTS: Twenty-two patients (nine men, median age 61 years) were included. The loss of MGMT protein expression detected by IHC was observed in 13 (59%) patients and MGMT promoter hypermethylation was detected by MS-PCR in three (15%) out of 20 interpretable cases. MGMT status did not correlate significantly with the best radiological response according to the Response Evaluation Criteria In Solid Tumors criteria or with progression-free survival. There was no correlation between MGMT protein expression and MGMT gene promoter methylation.CONCLUSION: These results indicate that a deficient MGMT status in PNETs, determined by loss of protein expression in IHC or by the presence of MGMT gene promoter methylation measured by MS-PCR, is not associated with a better response to TMZ-based chemotherapy and cannot be used as a predictive marker to lead treatment decisions.

BACKGROUND: Statistical Parametric Mapping (SPM) has been applied for single-subject evaluation of [18F]FDG uptake in Alzheimer Disease (AD). In a single-subject framework, the patient is compared to a dataset of [18F]FDG PET images from healthy subjects (HS) evaluating brain metabolic abnormalities. No studies exist that assess the effects on SPM analysis of HS [18F]FDG PET datasets acquired from different subjects and using different PET scanners including the same or different PET scanners than those used for patients. This work aims to elucidate this issue from a methodological perspective. METHODS: We considered six different [18F]FDG PET datasets, from different HS populations, acquired by different PET scanners. We applied SPM5 procedures for single-subject comparison with each of the six HS datasets in 10 probable AD patients showing the typical [18F] FDG pattern. We also implemented the same comparison in 3 probable AD patients and in 7 patients with a clinical diagnosis of Mild Cognitive Impariment (MCI), showing subtle changes on visual inspection of [18F]FDG distribution. RESULTS: Considering the 10 patients with the typical [18F]FDG pattern, the results were comparable for all the SPM maps. In the 3 probable AD patients with subtle changes in [18F]FDG distribution, no significant AD pattern emerged when a small number (50) HS image set was used. In the 7 considered MCI patients the use of a large (>50) HS image set allowed to assess significant hypometabolic patterns related to a probable neurodegenerative pathology. CONCLUSIONS: The use of large HS datasets of PET scans (>50) is recommended for single-subject SPM analysis. On condition that appropriate preprocessing steps are provided, large HS datasets can include HS images acquired with different PET systems, not including images from the same scanner of that used for patients

Vascular access dysfunction is one of the main causes of morbidity and hospitalization in hemodialysis patients. This major clinical problem points out the need for prediction of hemodynamic changes induced by vascular access surgery. Here we reviewed the potential of a patient-specific computational vascular network model that includes vessel wall remodeling to predict blood flow change within 6 weeks after surgery for different arteriovenous fistula configurations. For model validation, we performed a multicenter, prospective clinical study to collect longitudinal data on arm vasculature before and after surgery. Sixty-three patients with newly created arteriovenous fistula were included in the validation data set and divided into four groups based on fistula configuration. Predicted brachial artery blood flow volumes 40 days after surgery had a significantly high correlation with measured values. Deviation of predicted from measured brachial artery blood flow averaged 3% with a root mean squared error of 19.5%, showing that the computational tool reliably predicted patient-specific blood flow increase resulting from vascular access surgery and subsequent vascular adaptation. This innovative approach may help the surgeon to plan the most appropriate fistula configuration to optimize access blood flow for hemodialysis, potentially reducing the incidence of vascular access dysfunctions and the need of patient hospitalization.

Background: We wanted to determine the accuracy of transthoracic ultrasound in the prediction of chest wall infiltration by lung cancer or lung infiltration by chest wall tumours. Methods: Patients having preoperative CT-scan suspect for lung/chest wall infiltration were prospectively enrolled. Inclusion criteria for lung cancer were: obliteration of extrapleural fat, obtuse angle between tumour and chest wall, associated pleural thickening. The criteria for chest wall tumours were: rib destruction and intercostal muscles infiltration with extrapleural fat obliteration and intrathoracic extension. Lung cancer patients with evident chest wall infiltration were excluded.Transthoracic ultrasound was preoperatively performed. Predictions were checked during surgical intervention. Results: Twenty-three patients were preoperatively examined.Sensitivity, specificity, positive and negative predictive values of transthoracic ultrasound were 88.89%, 100%, 100% and 93.3%, respectively. Youden index was used to determine the best cut-off for tumour size in predicting lung/chest wall infiltration: 4.5. cm.At univariate logistic regression, tumour size (

Background Autism is an increasing neurodevelopmental disease that appears by 3 years of age, has genetic and/or environmental etiology, and often shows comorbid situations, such as gastrointestinal (GI) disorders. Autism has also a striking sex-bias, not fully genetically explainable. Objective Our goal was to explain how and in which predisposing conditions some compounds can impair neurodevelopment, why this occurs in the first years of age, and, primarily, why more in males than females. Methods We reviewed articles regarding the genetic and environmental etiology of autism and toxins effects on animal models selected from PubMed and databases about autism and toxicology. Discussion Our hypothesis proposes that in the first year of life, the decreasing of maternal immune protection and child immune-system immaturity create an immune vulnerability to infection diseases that, especially if treated with antibiotics, could facilitate dysbiosis and GI disorders. This condition triggers a vicious circle between immune system impairment and increasing dysbiosis that leads to leaky gut and neurochemical compounds and/or neurotoxic xenobiotics production and absorption. This alteration affects the ‘gut-brain axis’ communication that connects gut with central nervous system via immune system. Thus, metabolic pathways impaired in autistic children can be affected by genetic alterations or by environment–xenobiotics interference. In addition, in animal models many xenobiotics exert their neurotoxicity in a sex-dependent manner. Conclusions We integrate fragmented and multi-disciplinary information in a unique hypothesis and first disclose a possible environmental origin for the imbalance of male:female distribution of autism, reinforcing the idea that exogenous factors are related to the recent rise of this disease.

BACKGROUND: Non-small cell lung cancer (NSCLC) in young adults is uncommon. The objective of this study was to evaluate the clinicopathological characteristics, outcomes and prognosis of people younger than 50 years old treated surgically for NSCLC. METHODS: A retrospective study was conducted using the institutional database of four thoracic surgery units to collect patients with NSCLC younger than 50 years who had undergone surgery. These patients were compared with older patients (>75-years) operated in the same institutions and in the same period. RESULTS: We identified 113 young patients and 347 older patients. Younger patients were more likely to be female, non-smokers, with fewer comorbidities. Younger patients were more likely to be symptomatic at the time of diagnosis. Risk factors for poor prognosis in younger patients were T-stage, and disease-free-interval less than 548 days. Kaplan-Meier analysis showed a lower five-year survival in older patients compared with the younger ones (66% vs 38%, p=0.001). CONCLUSIONS: In conclusion NSCLC in younger patients has some distinct clinicopathological characteristics. The overall-survival of young patients is better than in older patients. Young patients receive more complete and aggressive treatment that could explain better survival. Further prospective studies with larger patient populations are required, to clarify the biological and genetic variance of NSCLC in younger patients. Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Introduction Proposed diagnostic criteria (international working group and National Institute on Aging and Alzheimer's Association) for Alzheimer's disease (AD) include markers of amyloidosis (abnormal cerebrospinal fluid [CSF] amyloid beta [Aβ]42) and neurodegeneration (hippocampal atrophy, temporo-parietal hypometabolism on [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and abnormal CSF tau). We aim to compare the accuracy of these biomarkers, individually and in combination, in predicting AD among mild cognitive impairment (MCI) patients. Methods In 73 MCI patients, followed to ascertain AD progression, markers were measured. Sensitivity and specificity, positive (LR+) and negative (LR−) likelihood ratios, and crude and adjusted hazard ratios were computed. Results Twenty-nine MCI patients progressed and 44 remained stable. Positivity to any marker achieved the lowest LR− (0.0), whereas the combination Aβ42 plus FDG-PET achieved the highest LR+ (6.45). In a survival analysis, positivity to any marker was associated with 100% conversion rate, whereas negativity to all markers was associated with 100% stability. Discussion The best criteria combined amyloidosis and neurodegeneration biomarkers, whereas the individual biomarker with the best performance was FDG-PET.

© 2014 Wolters Kluwer Health, Inc. All rights reserved. Background: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Methods: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. Results: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. Conclusion: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Caroli's syndrome is a rare congenital disorder that involves intrahepatic bile duct ectasia and congenital hepatic fibrosis, frequently seen with concomitant autosomal recessive polycystic kidney disease (ARPKD). Literature on infants with ARPKD is rare. Here, we present a case of a two month old boy who was diagnosed with Caroli's syndrome and ARPKD.

Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes (NPHP1–NPHP13) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7. This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.

We explored resting-state metabolic connectivity in prodromal Alzheimer's disease (pAD) patients and in healthy controls (CTR), through a voxel-wise interregional correlation analysis of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) by means of statistical parametric mapping. Baseline 18F-fluorodeoxyglucose-positron emission tomography of 36 patients with amnestic mild cognitive impairment who converted to Alzheimer's disease (AD) dementia after an average time of 2 years (pAD) and of 105 CTR were processed. The area of hypometabolism in pAD showed less metabolic connectivity in patients than in CTR (autocorrelation and correlation with large temporal and frontal areas, respectively). pAD patients showed limited correlation even in selected nonhypometabolic areas, including the hippocampi and the dorsolateral prefrontal cortex (DLFC). On the contrary, in CTR group correlation was highlighted between hippocampi and precuneus/posterior cingulate and frontal cortex, and between dorsolateral prefrontal cortex and caudate nuclei and parietal cortex. The reduced metabolic connections both in hypometabolic and nonhypometabolic areas in pAD patients suggest that metabolic disconnection (reflecting early diaschisis) may antedate remote hypometabolism (early sign of synaptic degeneration).

This Report intends to estimate the total number of people still alive in 2010 after cancer diagnosis in Italy, regardless of the time since diagnosis, and to project these estimates to 2015. This study is also aimed to estimate the number of already cured cancer patients, whose mortality rates have become undistinguishable from that of the general population of the same age and sex.The study took advantage of the information from the AIRTUM database, which included 29 Cancer Registries (covering 21 million people, 35% of the Italian population). A total of 1,624,533 cancer cases diagnosed between 1976 and 2009 contributed to the study. For each registry, the observed prevalence was calculated. Prevalence for lengths of time exceeding the maximum duration of the registration and of the complete prevalence were derived by applying an estimated correction factor, the completeness index. This index was estimated by means of statistical regression models using cancer incidence and survival data available in registries with 18 years of observation or more. For 50 types or combinations of neoplasms, complete prevalence was estimated at 1.1.2010 as an absolute number and as a proportion per 100,000 inhabitants by sex, age group, area of residence, and years since diagnosis. Projections of complete prevalence for 1.1.2015 were computed under the assumption of a linear trend of the complete prevalence observed until 2010. Validated mixture cure models were used to estimate: the cure fraction, that is the proportion of patients who, starting from the time of diagnosis, are expected to reach the same mortality rate of the general population; the conditional relative survival (CRS), that is the cumulative probability of surviving some additional years, given that patients already survived a certain number of years; the time to cure, that is the number of years necessary so that conditional survival in the following five years (5-year CRS) exceeds the conventional threshold of 95% (i.e., mortality rates in cancer patients become undistinguishable compared to those of the general population); the proportion of patients already cured, i.e., people alive since a number of years exceeding time to cure.As of 1.1.2010, it was estimated that 2,587,347 people were alive after a cancer diagnosis, corresponding to 4.4% of the Italian population. A relevant geographical heterogeneity emerged, with a prevalence above 5% in northern registries and below 4% in southern areas. Men were 45% of the total (1,154,289) and women 55% (1,433,058). In the population aged 75 years or more, the proportions of prevalent cases were 20% in males and 13% in females, 11% between 60 and 74 years of age in both sexes. Nearly 600,000 Italian women were alive after a breast cancer diagnosis (41% of all women with this neoplasm), followed by women with cancers of the colon rectum (12%), corpus uteri (7%), and thyroid (6%). In men, 26% of prevalent cases (295,624) were patients with prostate cancer, 16% with either bladder or colon rectum cancer. The projections for 1.1.2015 are of three million (3,036,741) people alive after a cancer diagnosis, 4.9% of the Italian population; with a 20% increase for males and 15% for females, compared to 2010. The cure fractions were heterogeneous according to cancer type and age. Estimates obtained as the sum of cure fractions for all cancer types showed that more than 60% of patients diagnosed below the age of 45 years will reach the same mortality rate of the general population. This proportion decreased with increasing age and it was30% for cancer diagnosed after the age of 74 years. It was observed that 60% of all prevalent cases (1,543,531 people or 2.6% of overall Italian population) had been diagnosed5 years earlier (long-term survivors). Time to cure (5-year CRS95%) was reached in10 years by patients with cancers of the stomach, colon rectum, pancreas, corpus and cervix uteri, brain, and Hodgkin lymphoma. Mortality rates similar to the ones reported by the general population were reached after approximately 20 years for breast and prostate cancer patients. Five-year CRS remained95% for25 years after cancer diagnosis in patients with liver and larynx cancers, non-Hodgkin lymphoma, myeloma, and leukaemia. Time to cure was reached by 27% (20% in men and 33% in women) of all people living after a cancer diagnosis, defined as already cured.The study showed a steady increase over time (nearly +3% per year) of prevalent cases in Italy. A quarter of Italian cancer patients alive in 2010 can be considered as already cured. The AIRTUM Report 2014 describes characteristics of cancer patients and former-patients for 50 cancer types or combinations by sex and age. This detailed information promotes the conduction of studies aimed at expanding the current knowledge on the quality of life of these patients during and after the active phase of treatments (prevalence according to health status), on the long-term effects of treatments (in particular for paediatric patients), on the cost profile of cancer patients, and on rare tumours. All these observations have a high potential impact on health planning, clinical practice, and, most of all, patients' perspective.

Diagnostic accuracy in FDG-PET imaging highly depends on the operating procedures. In this clinical study on dementia, we compared the diagnostic accuracy at a single-subject level of a) Clinical Scenarios, b) Standard FDG Images and c) Statistical Parametrical (SPM) Maps generated via a new optimized SPM procedure. We evaluated the added value of FDG-PET, either Standard FDG Images or SPM Maps, to Clinical Scenarios. In 88 patients with neurodegenerative diseases (Alzheimer's Disease—AD, Frontotemporal Lobar Degeneration—FTLD, Dementia with Lewy bodies—DLB and Mild Cognitive Impairment—MCI), 9 neuroimaging experts made a forced diagnostic decision on the basis of the evaluation of the three types of information. There was also the possibility of a decision of normality on the FDG-PET images. The clinical diagnosis confirmed at a long-term follow-up was used as the gold standard. SPM Maps showed higher sensitivity and specificity (96% and 84%), and better diagnostic positive (6.8) and negative (0.05) likelihood ratios compared to Clinical Scenarios and Standard FDG Images. SPM Maps increased diagnostic accuracy for differential diagnosis (AD vs. FTD; beta 1.414, p = 0.019). The AUC of the ROC curve was 0.67 for SPM Maps, 0.57 for Clinical Scenarios and 0.50 for Standard FDG Images. In the MCI group, SPM Maps showed the highest predictive prognostic value (mean LOC = 2.46), by identifying either normal brain metabolism (exclusionary role) or hypometabolic patterns typical of different neurodegenerative conditions., Highlights • Brain FDG-PET was evaluated with a new optimized SPM procedure in dementias. • We compared the diagnostic accuracy of clinical information, visual and SPM FDG-PET. • SPM had the best sensitivity (96%), specificity (84%) and positive and negative LR. • In an MCI subgroup, SPM had the highest predictive prognostic value.

International audience; The role of social norms in accounting for the different attitudes of men and women with respect to health is still an open issue. In this research, we investigate the role of social norms associated with specific gender environments in the workplace in accounting for differences in health-reporting behaviours across men and women. Using the 2010 European Working Conditions Survey, we build a database containing 30,124 observations. We first replicate the standard result that women report worse health than men, whatever the health outcome we consider. We then proxy social norms by the gender structure of the workplace environment and study how the latter affects self-reported health for men and women separately. Our findings indicate that individuals in workplaces where women are a majority tend to report worse health than individuals employed in male-dominated work environments, be they men or women. These results are robust to controlling for a large array of working condition indicators, which allows us to rule out that the poorer health status reported by individuals working in female-dominated environments could be due to worse job quality. This evidence suggests that social norms associated with specific gender environments play an important role in explaining differences in health-reporting behaviours across gender, at least in the workplace.

Typical and atypical carcinoids (TC and AC) represent 20 - 25 % of all neuroendocrine tumours. No standard therapeutic approach is available for patients with advanced disease. The aim of this phase II study was to investigate the efficacy and safety of peptide receptor radionuclide therapy with (177)Lu-DOTATATE (Lu-PRRT) and the role of thyroid transcription factor 1 (TTF-1) and (18)F-FDG PET as prognostic factors in patients with advanced TC or AC.A total of 34 consecutive patients with radiologically documented progressive disease were treated with Lu-PRRT at a therapeutic cumulative activity of 18.5 or 27.8 GBq in four or five cycles according to the patient's kidney function and bone marrow reserve. Information on TTF-1 was available in all patients. FDG PET studies prior to Lu-PRRT were available in 29 patients.The median follow-up was 29 months (range 7 - 69 months). The disease control rate (DCR) in patients with TC was 80 %: 6 % complete response, 27 % partial response and 47 % stable disease. The median progression-free survival (mPFS) was 20.1 months (95 % CI 11.8 - 26.8 months). Stable disease was achieved in 47 % of patients with AC with a mPFS of 15.7 months (95 % CI 10.6 - 25.9 months). No major acute or delayed toxicity occurred in either group or with either cumulative activity. mPFS in patients with TTF-1-negative TC was 26.3 months (95 % CI 12.9 - 45.2 months), but in patients with TTF-1-positive TC mPFS was 7.2 months (4.2 - 14.0 months; p = 0.0009). FDG PET was negative in 13 patients (10 TC and 3 AC) and positive in 16 patients (4 TC and 12 AC). The mPFS in the FDG PET-negative group was 26.4 months (95 % CI 14.2 - 48.9 months) and 15.3 months (11.7 - 31.1 months) in the FDG PET-positive group.Lu-PRRT showed antitumour activity in terms of DCR and PFS and proved safe, even in patients with a higher risk of side effects. TTF-1 would appear to be a prognostic factor. FDG PET positivity in bronchial carcinoids is a hallmark of aggressive tumour and is more frequent in patients with AC than in those with TC.

Background Leukemia/lymphoma cases reported in 2001 among United Nation soldiers or peacekeepers deployed to the Balkans aroused alert on the exposure to depleted uranium. Recent epidemiological studies carried out in different European countries among peacekeepers who served in the Balkans failed to demonstrate a higher than expected risk of all cancers but, mostly due to their limitations in size and follow up time, leave open the debate on health risk of depleted uranium. The aim of SIGNUM (Study of the Genotoxic Impact in Military Units) was to identify potential genotoxic risk associated with the exposure to depleted uranium or other pollutants in the Italian Army military personnel deployed in Iraq. Methods Blood and urine samples were collected before and after the deployment from 981 Italian soldiers operating in Iraq in 2004–2005. As, Cd, Mo, Ni, Pb, U, V, W, and Zr were determined in urine and serum. DNA-adducts, 8-hydroxy-2′-deoxyguanine and micronuclei frequency were evaluated in blood lymphocytes. Three different genetic polymorphisms, GSTM1 , XRCC1 , OGG1 were analyzed. Results Significant T 0– T 1 reduction in the total concentration of uranium, increases for Cd, Mo, Ni, Zr, and decreases for As, Pb, W, and V in urine and plasma were observed. Increases in oxidative alterations and in micronuclei frequency, included in the range of values of non-occupationally exposed populations, were observed at the end of the period of employment. Conclusions Our results did not detect any toxicologically relevant variation of DNA-damage biomarkers related to the deployment in the operational theater.

The calcifying cystic odontogenic tumor normally presents as a painless, slow-growing mass, involving both maxilla and mandible, primarily the anterior segment (incisor/canine area). It generally affects young adults in the third to fourth decades, with no gender predilection. Computerized tomography images revealed important characteristics that were not detected by panoramic radiography, such as fenestration, calcification and tooth-like structures. The typical microscopic feature of this lesion is the presence of variable amounts of aberrant epithelial cells, without nuclei, which are named "ghost cells". In addition, dysplastic dentine can be found and occasionally the cyst can be associated with an area of dental hard tissue formation resembling an odontoma. The treatment for calcifying cystic odontogenic tumor involves simple enucleation and curettage. The purpose of this article is to present two different manifestation of calcifying cystic odontogenic tumor in which computerized tomography, associated to clinical features, served as an important tool for diagnosis, adequate surgical planning and follow-up of patients.