Executive functions and adaptive behaviour in individuals with Down syndrome.

BACKGROUND: Previous research has explored executive functions (EFs) and adaptive behaviour in children and adolescents with Down syndrome (DS), but there is a paucity of research on the relationship between the two in this population. This study aims to shed light on the profile of EFs and adaptive behaviour in DS, exploring the differences by age and investigating the relationship between these two domains. METHOD: Parents/caregivers of 100 individuals with DS from 3 to 16 years old participated in the study. The sample was divided into preschoolers (3-6.11 years old) and school-age children (7-16 years old). Parents/caregivers completed either the Preschool Version of the Behaviour Rating Inventory of Executive Function (for children 2-6.11 years old) or the Second Edition of the same Inventory (for individuals 7 + years old). Adaptive behaviour was assessed with the Vineland Adaptive Behaviour Scale - Interview, Second Edition. RESULTS: Findings suggest that individuals with DS have overall difficulties, but also patterns of strength and weakness in their EFs and adaptive behaviour. The preschool-age and school-age children's EF profiles differed slightly. While both age groups showed Emotional Control as a relative strength and Working Memory as a weakness, the school-age group revealed further weaknesses in Shift and Plan/Organise. As concerns adaptive behaviour, the profiles were similar in the two age groups, with Socialisation as a strength, and Communication and Daily Living Skills as weaknesses, but with a tendency for preschoolers to obtain intermediate scores for the latter. When the relationship between EFs and adaptive behaviour was explored, Working Memory predicted Communication in the younger group, while in the older group the predictors varied, depending on the adaptive domains: Working Memory was a predictor of Communication, Inhibit of Daily Living Skills, and Inhibit and Shift of Socialisation. CONCLUSION: As well as elucidating the EF profiles and adaptive behaviour in individuals with DS by age, this study points to the role of EFs in adaptive functioning, providing important information for targeted interventions.

Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer.

PURPOSE: Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy. METHODS: Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient's response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment. RESULTS: At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib. CONCLUSIONS: In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues.

Bone represents the second most common site of distant metastases in differentiated thyroid cancer (DTC). The clinical course of DTC patients with bone metastases (BM) is quite heterogeneous, but generally associated with low survival rates. Skeletal-related events might be a serious complication of BM, resulting in high morbidity and impaired quality of life. To achieve disease control and symptoms relief, multimodal treatment is generally required: radioiodine therapy, local procedures-including surgery, radiotherapy and percutaneous techniques-and systemic therapies, such as kinase inhibitors and antiresorptive drugs. The management of DTC with BM is challenging: a careful evaluation and a personalized approach are essential to improve patients' outcomes. To date, prospective studies focusing on the main clinical aspects of DTC with BM are scarce; available analyses mainly include cohorts assembled over multiple decades, small samples sizes and data about BM not always separated from those regarding other distant metastases. The aim of this review is to summarize the most recent evidences and the unsolved questions regarding BM in DTC, analyzing several key issues: pathophysiology, prognostic factors, role of anatomic and functional imaging, and clinical management.

Interplay between serum osteocalcin and insulin sensitivity in primary hyperparathyroidism.

Osteocalcin (OC) has been proposed as a regulator of insulin sensitivity in both humans and other animals. Primary hyperparathyroidism (PHPT) is characterized by high OC levels and insulin resistance. The aim of this study was to evaluate whether in PHPT the link between OC levels and blood markers of insulin resistance was maintained. In a consecutive series of 219 adult PHPT patients, serum OC as well as fasting insulin and glucose levels were measured. Insulin sensitivity was estimated by homeostatic model assessment (HOMA2-S%). The same parameters were evaluated in a subgroup of 45 patients after parathyroidectomy (PTX). PHPT patients were characterized by markedly high OC levels. After subdividing them according to glucose tolerance, it was found that OC was similar in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), while diabetic subjects had lower serum OC than those with NGT (P < 0.02) or IGT (P < 0.04). OC was negatively associated with fasting glucose and positively associated with HOMA2-S%. OC independently predicted HOMA2-S% in a multivariate analysis. In the subgroup of surgically cured PHPT patients, OC levels significantly decreased after PTX, while HOMA2-S% did not change. Our findings indicate that in PHPT there is a positive relationship between OC and glucose metabolism, OC being one of the predictors of insulin sensitivity. However, data in surgically cured patients, showing OC normalization in spite of unchanged HOMA2-S%, suggest that OC does not likely play a major role in affecting insulin sensitivity in PHPT.

Surgical treatment of anaplastic thyroid carcinoma. Our experience.

BACKGROUND: In anaplastic thyroid carcinoma (ATC) surgical resection associated to radiotherapy and chemotherapy can ameliorate local disease control with occasional long-term survivals. PATIENTS AND METHODS: Resection of the tumor was accomplished in 20 ATC patients, with no macroscopic (13 cases) or minimal residual neck disease infiltrating vital structures (7 cases). Ten of these patients (50%) had distant metastases. Sixteen cases were also treated with radiotherapy and chemotherapy, while in one patient only chemotherapy was possible; 2 patients refused further therapy; the last one is starting adjuvant treatment. Morbidity and survival were analysed, and compared with other 15 ATCs submitted to partial tumor debulking or not operated at all (control group). RESULTS: Function of at least one laryngeal recurrent nerve was preserved in all 20 patients; none experienced permanent hypoparathyroidism. At last follow-up examination 17 patients had died and 3 were alive 1, 6 and 80 months after the operation, the latter being free of disease. Survival of dead patients ranged from 3 to 28 months (mean: 8 months). In the control group all patients died, survival ranging from 1 to 13 months (mean: 4 months). Actuarial analysis of survival showed a significant difference between the two groups (p = 0.0112); multivariate analysis of several prognostic factors confirmed that complete or near complete tumour resection was the most relevant. CONCLUSIONS: Surgical resection is an important component of the multimodal treatment of ATC and should be attempted whenever possible.

Amylose molecular fine structure dictates water-oil dynamics during deep-frying and the caloric density of potato crisps.

The fine structure of extractable amylose (E-AM) in potato flakes dictates oil uptake during the production of deep-fried crisps from dough made from the flakes, and thus their caloric density. High levels of short E-AM chains increase the extent of amylose crystallization during dough making and increase water binding. Time-domain proton NMR analysis showed that they also cause water to be released at a low rate during deep-frying and thus restrict dough expansion and, most importantly, oil uptake. X-ray micro-computed tomography revealed that this results in high thickness of the crisp solid matrix and reduced pore sizes. Thus, the level of short E-AM chains in potato flakes impacts amylose crystal formation, dough strength and expansion, as well as the associated oil uptake during deep-frying. Based on these results, we advise potato crisp manufacturers to source potato cultivars with high levels of short amylose chains for the production of reduced-calorie crisps and to make well-reasoned process adaptations to control the extractability of potato amylose.

Clinico-pathological features, treatments and survival of malignant insulinomas: a multicenter study.

INTRODUCTION: Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. AIM OF THE STUDY: To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. MATERIALS AND METHODS: Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. RESULTS: The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. CONCLUSIONS: Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.

Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy.

BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

Multifocal renal allograft biopsy: impact on therapeutic decisions.

OBJECTIVE: There are no data to support the suggestion that samples removed from one segment of the transplanted kidney are representative of the whole graft. The aim of this study was to compare the histological differences between biopsies obtained from different portions of the renal allograft and their impact on treatment recommendations. PATIENTS AND METHODS: Two hundred percutaneous biopsies were performed on kidney allografts and samples were collected from the upper and lower poles (100 kidneys). All samples were randomized and blindly reviewed. We obtained the discordance rates between the poles for the grading of acute rejection and for the diagnosis of nephrotoxicity due to immunosuppression. We also checked if the differences found were sufficient to call for different clinical recommendations. These values were compared with the intrapathologist variation rates. RESULTS: In 70 kidneys adequate sampling was obtained from both poles. The diagnosis of acute rejection were made in 17. The discordance rate between the upper and lower poles was 82.3% (kappa = 0.34), higher than the intrapathologist variation (P = .002). Nephrotoxicity was found in 14 kidneys. The discordance rate between the upper and lower poles was 28.6% (kappa = 0.88), with no difference compared with the intrapathologist variation. In 14 of the 70 kidneys (25.7%), discordances between poles had impact on clinical recommendations, most of these cases due to different gradings of acute rejection (78%). This number was higher than the intrapathologist variation (P = .04). CONCLUSIONS: The histopathological changes in the kidney allograft are not always homogeneous. This heterogeneity may affect the therapeutic recommendations.

Donor transmission intestinal carcinoma after kidney transplantation: case report.

Tumor transmission is a rare complication of organ transplantation. Despite several improvements in excluding donor malignant disease, there continue to be reports of unknown tumors in the donors. The risk of having a donor with an undetected malignancy ranges between 1.3% and 2%. The cases of two kidney transplant recipients who had intestinal carcinoma transmitted from the same deceased donor are described. The clinical presentation, previous data, and management options are discussed. As a result of the increase in the overall donor pool, using extended criteria donors, donors of extreme ages, donors with prolonged intensive care admission, and donors who may potentially transmit disease to their recipients, the risk of tumor transmission and also infections should be considered.

Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas)

Since 1989, 45 patients [pts; 26 females and 19 males, aged 19-79 yr (median, 58)] bearing incidentally discovered adrenal masses were studied. The aim of the study was to verify the prevalence of hormone activity in clinically silent adrenal masses. Endocrine work-up included determination of urinary catecholamines and their metabolites, measurement of PRA and aldosterone levels in clino- and orthostatic posture, and basal and dynamic [dexamethasone (dex) suppression and ovine CRH stimulation] evaluation of hypothalamic-pituitary-adrenal axis. The most frequent finding was the reduction of dehydroepiandrosterone sulfate (DHEA-S) levels below the third percentile of controls in 19 (42%) pts. DHEA-S levels were significantly lower in pts than in controls [68 (range, 5-1000) vs. 208 (34-326) micrograms/dL; 1.8 (0.1-27.1) vs. 5.6 (0.9-8.8) mumol/L; P < 0.001]. Three pts (7%) had high 24-h mean serum cortisol levels, and 6 (14%) had blunted day-night amplitude of cortisol rhythm. Defective dex suppressibility was found in 15% of pts vs. 8% of controls (P < 0.05). ACTH and cortisol responses to ovine CRH did not significantly differ between pts and controls, although blunted ACTH responses were found in 22% of the cases. The above-mentioned endocrine alterations could be accounted for by autonomous cortisol secretion by the adrenal nodule at a rate not sufficient to give clinical expression, but able to inhibit to some extent the hypothalamic-pituitary-adrenal axis. These results indicate that silent cortisol hypersecretion is frequently observed in pts with adrenal incidentaloma even if progression to overt Cushing's syndrome seems unlikely. Indeed, the size of the mass and the hormone pattern remained substantially unchanged in 9 pts followed up for 12 months. From merely a cost/benefit ratio, the evaluation of DHEA-S levels and dex suppression has sufficient sensitivity to identify the occurrence of silent hypercortisolism.

Serum markers of bone and collagen turnover in patients with Cushing's syndrome and in subjects with adrenal incidentalomas.

The aim of this study was to assess serum levels of some markers of bone turnover and collagen synthesis in 22 patients with adrenal incidentalomas (AI), a model of silent glucocorticoid excess, and to compare the results with those obtained in 18 patients with Cushing's syndrome (CS). Osteocalcin (BGP), bone isoenzyme of alkaline phsophatase, carboxy-terminal propeptide of type I procollagen, and carboxy-terminal cross-linked telopeptide of type I collagen were measured as biochemical indexes of bone turnover, and amino-terminal propeptide of type III procollagen was determined as an index of collagen synthesis. Two groups of healthy volunteers evenly matched for sex, age, and menstrual status were used for a case-control analysis of AI and CS groups, respectively. Patients with AI showed a slight, albeit significant, reduction in serum BGP and a mild increase in carboxy-terminal cross-linked telopeptide of type I collagen levels compared with controls [median, 6.6 vs. 7.8 ng/mL (P < 0.05) and 4.2 vs. 3.1 micrograms/L (P < 0.01), respectively]. No significant differences were found when comparing the other markers. Patients with CS had BGP, bone isoenzyme of alkaline phosphatase, and amino-terminal propeptide of type III procollagen levels significantly lower than control values [median, 3.0 vs. 7.3 ng/mL (P < 0.0001); 4.4 vs. 11.5 micrograms/L (P < 0.01); 2.2 vs. 4.3 micrograms/L (P < 0.0001), respectively], but no significant difference in the other markers. These results confirm a clear inhibition of osteoblastic activity in CS and could suggest an enhanced bone metabolism in patients with AI. The degree of impairment of bone turnover in patients with AI does not seem enough to recommend surgery (removal of the adrenal adenoma) in the absence of other indications.

B lymphocytes in newborns.

B lymphocyte markers in 24 full term newborn infants were evaluated within four days after birth. It was demonstrated that the percentage of cells with surface immunoglobulins (SmIg) in the blood of these subjects was normal when the lymphocytes were stained with polyvalent as well as monospecific antisera. The percentage of cells bearing Fc receptors were found to be slightly, but not significantly, reduced. The ability of newborn lymphocytes to form rosettes with mouse erythrocytes was significantly reduced. The hypothesis that the B dependent system reaches complete maturity already at the first days after birth is discussed.

Biochemical picture of bone metabolism in breast cancer patients with bone metastases.

A panel of bone turn-over markers was assessed in 75 normocalcemic patients bearing bone metastases from breast cancer (BC), and in 25 advanced/metastatic BC patients without clinical appearance of bone involvement. 115 healthy women, stratified in three subgroups according to age served as controls. Bone formation was investigated by measuring serum carboxyterminal propeptide of type I procollagen (PICP), Bone Gla Protein (BGP, osteocalcin), bone isoenzyme of alkaline phosphatase (BALP); bone resorption by measuring serum carboxyterminal telopeptide of type I collagen (ICTP), fasting urinary hydroxyproline/creatinine (OHPro/Cr) and calcium/creatinine (Ca/Cr). In patients with bone metastases the percent of supranormal values (higher than mean plus 2 SD of the age-matched controls) ranged between 25% and 40% for indices of bone formation, about 73% for both ICTP and OHPro/Cr and about 30% for Ca/Cr. The median levels of all bone turn-over markers were higher in bone metastatic patients than in those without apparent skeletal involvement, but significance was attained only for OHPro/Cr, Ca/Cr and BALP. Supranormal levels of ICTP and OHPro/Cr were also found in about 65-70% of patients without apparent skeletal involvement. ICTP and Ca/Cr significantly correlated with bone pain score, BALP, ICTP, Ca/Cr significantly correlated with the number of tumour appearances in bone. In conclusion, the bone resorption indices, ICTP and OHPro/Cr, are much more frequently elevated than bone formation indices in BC patients with or without skeletal involvement. Their potential use in the early detection of bone metastases is hampered by the insufficient knowledge on specificity. Among the biochemical markers evaluated, Ca/Cr, ICTP and BALP, due to correlation with clinical aspects, appear the most interesting for follow-up studies.

Serum levels of carboxyterminal propeptide of type I procollagen in cancer patients with osteoblastic and osteolytic bone metastases.

Serial monitoring of serum and urinary markers of bone regeneration may provide an indirect assessment of the activity of bone metastases. We measured serum levels of carboxyterminal propeptide of type I procollagen (PICP), a new marker of bone formation, in 236 control subjects, stratified according to age and sex, and in 122 cancer patients: 80 with breast cancer (BC) (42 with osteolytic bone metastases) and 42 with prostate cancer (PC) (31 with osteoblastic bone metastases). An inverse correlation between age and serum PICP levels was found in healthy men (r = -0.30), but not in women, PICP levels were significantly higher in patients with osteoblastic metastases compared to age-matched control subjects and patients with advanced disease not involving the skeleton. The sensitivity of PICP was 64% for detecting osteoblastic metastases, and 12% for detecting osteolytic metastases. Serum PICP determination may have a diagnostic role for osteoblastic activity.

Circadian profile of serum melatonin in Cushing's disease and acromegaly.

We evaluated the circadian profiles of serum melatonin (MT) and cortisol in 6 patients with Cushing's disease while those of serum MT and GH were evaluated in 8 patients with acromegaly. The control group consisted of 15 healthy subjects in whom MT, cortisol and GH were determined. The presence of a circadian rhythmicity was validated by the cosinor method, while the diurnal and nocturnal amount of MT secretion were expressed in terms of area under the curve. Gross alterations of MT rhythm were not apparent in Cushing's patients. In acromegalics, we observed a blunted day-night oscillation of MT accounted for by a significant increase of its secretion during the day-time period.

24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities.

We monitored the circadian profiles of cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P less than 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.

24-hour profiles of blood pressure and heart rate in Cushing's syndrome. Evidence for differential control of cardiovascular variables by glucocorticoids.

We monitored the circadian profile of cortisol, systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) in 33 normotensive subjects aged 20-40 years, 20 normotensive subjects aged 40-60, 32 patients with essential hypertension and 13 patients with Cushing's syndrome (6 pituitary adenomas, 5 adrenal adenomas and 2 adrenal carcinomas). All controls and patients underwent serial blood drawings at 4-h intervals during the 24-h cycle. BP and HR were recorded every 30 min by an automatic, room-restricted instrument. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry) to quantify rhythm parameters such as the MESOR (rhythm-adjusted average), amplitude (difference between maximum and MESOR) and acrophase (timing of the crest of the rhythm). Both the control and essential hypertensive subjects showed a BP and HR circadian profile characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: p less than 0.001). The chronobiological analysis did not reveal any significant difference between healthy young and aged subjects. BP rhythmicity was disrupted in patients affected by Cushing's syndrome, whereas the 24-h oscillation of HR was preserved (p less than 0.001). Patients with pituitary-dependent Cushing's syndrome had higher BP levels than adrenal-dependent subjects (p less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.