Computerized tomography texture analysis of pheochromocytoma: relationship with hormonal and histopathological data.

OBJECTIVES: Pheochromocytomas are rare tumors which can present with heterogeneous secretion profiles, clinical manifestations, and radiologic appearance. Under a histopathological point of view, they can be characterized as more or less aggressive with the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score. The aim of this study is to analyze the texture analysis characteristics of pheochromocytoma and identify whether the texture analysis can yield information aiding in the diagnosis and the characterization of those tumors. METHODS: Radiological, biochemical, and histopathological data regarding 30 consecutive patients with histologically confirmed pheochromocytoma were analyzed. Images obtained in the unenhanced, late arterial, venous, and delayed phases were used for the texture analysis. RESULTS: Urinary epinephrine and metanephrine levels showed a significant correlation (R2 = 0.946; R2 = 699) in the multivariate linear model with texture features, as well as Ki-67 (R2 = 0.397), PASS score (R2 = 0.182), GAPP score (R2 = 0.705), and cellularity showed a significant correlation (R2 = 0.389). The cluster analysis based on radiomic features resulted in 2 clusters, with significative differences in terms of systolic and diastolic blood pressure values at the time of diagnosis (p = 0.025), GAPP score (4 vs 6, p = 0.05), histological pattern (1-2, p = 0.039), and comedonecrosis (0% vs 50%, p = 0.013). CONCLUSION: In conclusion, our study provides the proof of concept for the use of texture analysis on contrast-enhanced CT images as a noninvasive, quantitative tool for helping in the characterization of the clinical, biochemical, and histopathological features of pheochromocytoma.

Evaluation of fetal cardiac function in pregnancies with well-controlled gestational diabetes.

OBJECTIVE: To evaluate fetal ventricular diastolic function in pregnancies of women with gestational diabetes (GD), to determine whether minimal anomalies of glucose metabolism may influence fetal cardiac function. STUDY DESIGN: Fetal ventricular filling time was measured by transabdominal ultrasound in singleton pregnancies between 34 and 37 weeks of gestation. We used a measurement which consists in the ratio between the diastolic time and the whole cardiac cycle time. RESULTS: The study included 35 women with a GD and 217 non-diabetic. Right ventricular filling time (RVFT) was significantly lower in the GD group (mean of RVFT = 39.2 ± 4.4 vs 43.6 ± 4.6; p < 0.01). Likewise, left ventricular filling time (LVFT) was shorter in the GD group compared to the non-GD group, though the difference was not significant (mean of LVFT = 43.6 ± 4.6 vs 44.6 ± 5.5; p = 0.33). CONCLUSIONS: Fetal right cardiac function is altered also in pregnancies where gestational diabetes is well controlled.

Sphenofrontal distance on three-dimensional ultrasound in euploid and trisomy-21 fetuses at 16-24 weeks' gestation.

OBJECTIVE: To compare the distance between the sphenoid and frontal bones on three-dimensional (3D) ultrasound in euploid and trisomy-21 fetuses at 16-24 weeks' gestation. METHODS: We acquired 3D volumes of the fetal profile from 80 normal and 30 trisomy-21 fetuses at 16-24 weeks' gestation. We used the multiplanar mode to obtain the mid-sagittal plane and measured the sphenofrontal distance as the shortest distance between the most anterior edge of the sphenoid bone and the lowest edge of the frontal bone. RESULTS: In normal fetuses, the sphenofrontal distance increased linearly with gestational age, from 15.1 mm at 16 weeks to 18.2 mm at 24 weeks. In fetuses with trisomy 21, the mean sphenofrontal distance delta value was significantly smaller than in normal cases (-3.447 mm (95% CI, -5.684 to -1.211 mm); P < 0.01). The sphenofrontal distance was below the 5(th) and 1(st) percentiles of the normal range in 29 (96.7%) and 27 (90.0%) trisomy-21 fetuses, respectively. CONCLUSIONS: The sphenofrontal distance is shorter at 16-24 weeks' gestation in fetuses with trisomy 21 than in normal fetuses. A reduction in the growth of the anterior cranial base contributes to the mid-facial hypoplasia observed in fetuses with trisomy 21. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prognostic Impact of MCPyV and TIL Subtyping in Merkel Cell Carcinoma: Evidence from a Large European Cohort of 95 Patients.

Merkel cell carcinoma is a rare (∼ 2000 cases/year in the USA) but aggressive neuroendocrine neoplasm of the skin. In 2008, the Merkel cell polyomavirus (MCPyV) was found to be clonally integrated in approximately 80% of Merkel cell carcinomas. The remaining 20% have large numbers of UV-associated mutations. Importantly, both the UV-induced neoantigens in virus-negative Merkel cell carcinoma and the Merkel cell polyomavirus oncogenes that are required for virus-positive tumor growth are highly immunogenic. Indeed, antigen-specific T cells detected in patients are frequently "dysfunctional/exhausted," and the inhibitory ligand PD-L1 is often expressed by Merkel cell carcinoma cells. These data led to point our attention on the quantity and the quality of the immune response in Merkel cell carcinoma. Here, we found CD8+ lymphocytes are the only singly evaluated lymphocyte subclass that strongly influenced overall survival and disease-specific survival in Merkel cell carcinoma. In addition, we highlighted as Merkel cell polyomavirus is a strong prognostic factor and as it prompts a host immune response involving various lymphocyte subclasses (CD3, CD8, FoxP3, and PD-L1 positive) in MCC. For this reason, we proposed a novel eye-based "immunoscore" model, obtained by tumor infiltrating lymphocytes subtyping (CD3, CD8, FoxP3, and PD-L1) that could provide additional prognostic information in Merkel cell carcinoma.

Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre.

Objective and design A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome. Methods The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up. Results In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Conclusions Our data confirmed the validity of Trouillas' score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

Effects of acute benzodiazepine administration on growth hormone, prolactin and cortisol release after moderate insulin-induced hypoglycemia in normal women.

Benzodiazepines are known to affect pituitary hormone release, and it has recently been hypothesized that the adenohypophysial hormone response to stress may be modified by previous benzodiazepine treatment. We investigated, therefore, whether a single dose of triazolam, a short-acting benzodiazepine, and flurazepam, a long-acting one, could influence the response of prolactin (PRL), growth hormone (GH) and cortisol to a mild hypoglycemic stress in young healthy volunteers. Neither triazolam nor flurazepam pretreatment resulted in a significant effect on the pituitary response to hypoglycemic stimulus. The GH, PRL and cortisol peaks after both benzodiazepines were similar to those observed after placebo. Our results seem to exclude, therefore, any relevant effect of acute benzodiazepine administration on the neuroendocrine response to mild stress.

Is metformin safe enough for ageing type 2 diabetic patients?

We assessed the effect of adding low doses of metformin to sulfonylurea therapy in 76 elderly Type 2 diabetic patients by monitoring glycaemic control and blood lactate for one year. Metformin markedly improved glycaemic control. Fasting lactate concentrations were not affected and post-meal lactate peaks were minimally increased. Additional benefits included an improvement in some lipid parameters, a reduction in serum uric acid and a significant weight loss in overweight patients. Metformin was clinically well-tolerated. Instead of advanced age alone, renal function and/or any other age-related factor likely to contribute to lactate overproduction should be the basis for deciding on metformin therapy. No evidence indicated that metformin should be denied "a priori" to ageing Type 2 diabetic patients.

Meformin, plasma glucose and free fatty acids in type II diabetic out-patients: results of a clinical study.

Abnormalities in free fatty acid (FFA) metabolism are an intrinsic feature of type II diabetes mellitus and may even play a role in the development of glycaemic imbalance. This study investigated whether the anti-diabetic drug metformin can reduce FFA levels in clinical practice and whether this correlates with its anti-diabetic effect. For 6 months metformin was added to sulfonylurea therapy in 68 type II diabetic outpatients with poor glycaemic control, being administered before meals and at bed-time. Basal and daily area-under-the-curve (AUC) glucose levels dropped (both P < 0.0005) like basal and daily AUC FFA levels (P < 0.004 and P < 0.001 respectively) reductions were all correlated (P < 0.001 and P < 0.003 respectively). Reductions in fasting and daily AUC glucose correlated more closely with body fat distribution, expressed by waist-hip ratio (WHR) (P < 0.006 and P < 0.004 respectively), than with the body mass index (BMI) (P < 0.02 and P < 0.04 respectively). Similarly fasting and daily AUC FFA correlated with WHR (P < 0.007 and P < 0.01 respectively) but not with BMI (both P = ns). Subdividing male and female diabetic patients into groups with low and high WHRs, fasting and daily AUC glucose were reduced in men (P < 0.01 and P < 0.02) and in women (P < 0.02 and P < 0.04 respectively) with low WHRs less than in men and in women with higher WHRs (for each gender P < 0.0001 and P < 0.0002, respectively). Decreases in fasting and daily AUC FFA, which did not reach significance in either men or women with low WHRs, were statistically significant in men (P < 0.03 and P < 0.01 respectively) and in women (P < 0.02 and P < 0.005 respectively) with high WHRs. These findings suggest that an improvement in FFA plasma levels might contribute to metformin's anti-diabetic activity which appears to be more marked in patients with high WHRs. Moreover adding a bed-time dosage to the standard administration at meal times seems to be an effective therapeutical strategy.

Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic A- and B-cell function.

In the classical model of isolated perfused rat pancreas four commonly used sulfonylureas--tolbutamide, glibenclamide, gliquidone and gliclazide--were investigated at therapeutical concentrations at three different glucose levels (with 0, 2.22 and 5 mmol/l glucose surrounding) and in the presence of a metabolic stimulus with glucose at 8.33 mmol/l. All the sulfonylureas stimulated the B-cell function. Tolbutamide, gliquidone and gliclazide produced a prompt biphasic hormone release while glibenclamide induced a delayed monophasic insulin secretion. In all cases the amount of insulin released depended on the metabolic condition. As the environmental glucose levels fell, the sulfonylureas' stimulatory effect on the B-cell function decreased. At the therapeutical concentrations we tested, no sulfonylurea influenced A-cell activity whether directly or indirectly via an insulin-mediated paracrine inhibition of glucagon release.

Glucose modulates the amount, but not the kinetics, of insulin released by sulfonylureas.

This study compares the insulin-secretory profiles induced by therapeutical concentrations of four different sulfonylureas--tolbutamide, gliquidone, gliclazide, and glibenclamide--and the amount of hormone released by each under different ambient glucose concentrations, using the isolated perfused rat pancreas model. All four sulfonylureas stimulated B-cell function, but the kinetics varied. Tolbutamide, gliquidone, and gliclazide produced a quick, biphasic release, whereas glibenclamide stimulated a delayed monophasic insulin secretion. Dramatic falls in insulin release were observed when ambient glucose concentrations were lowered. Glucagon release was not influenced by any of the sulfonylureas whatever the metabolic condition, neither directly nor indirectly, via an insulin-mediated paracrine inhibition of A-cell activity.

Effects of glimepiride on insulin and glucagon release from isolated rat pancreas at different glucose concentrations.

The effects of glimepiride, the newest sulphonylureic compound, on pancreatic insulin and glucagon secretion were studied using the classical, isolated, perfused rat pancrease model. The influence of four different environmental glucose conditions (during a glycaemic stimulus with glucose increasing from 5 to 8.33 mM and at stable 0, 5 and 2.22 mM glucose levels) on the effects of glimepiride was also assessed. At a pharmacological concentration glimepiride strongly stimulated beta-cell activity, producing a characteristic biphasic insulin release with a sharp first-phase secretory peak, followed by a prolonged and sustained second phase. Environmental glucose concentrations markedly influenced the extent, but not the pattern of glimepiride-induced insulin secretion, as hormone release dropped significantly when the glucose level was reduced. Glimepiride failed to influence alpha-cell activity at any of the environmental glycaemic levels.

Hematologic reconstitution following high-dose and supralethal chemoradiotherapy using stored, noncryopreserved autologous hematopoietic stem cells.

Although cryopreservation is the standard for autotransplantation, it has logistic and financial disadvantages in undeveloped countries such as Colombia. In 47 patients, peripheral blood was refrigerated at 4 degrees C up to 144 h before autotransplantation. For mobilization, 27 men and 20 women of median age 37 years affected with hematologic malignancies received G-CSF. The 17 patients in Group 1 showed pre-refrigeration CFU-GM of 2.62 x 10(5)/kg (range 0.36 to 16.6 x 10(5)/kg) and at re-infusion, 1.36 x 10(5)/kg (range 0 to 6.32 x 10(5)/kg) of 83% viability (range, 78% to 96%). These patients showed >0.5 x 10(9)/L granulocytes on day +11 (range, 9 to 15) and >20 x 10(9)/L platelets on day +16 (range, 11 to 44). The 25 patients in Group 2 showed CD34 of 3.9 x 10(6)/kg (range, 0.16 to 9 x 10(6)/kg) and mononuclear cell count (MNC) of 8.7 x 10(8)/kg, reaching >0.5 x 10(9)/L granulocytes at day +13 (range, 10 to 17) and >20 x 10(9)/L on day +15 (range, 14 to 20). Among the 5 patients in Group 3, the average of MNC of 12.7 x 10(8)/kg was reached and >0.5 x 10(9)/L granulocytes on day 11 (range, 10 to 16) and >20 x 10(9)/L on day 14 (range, 10 to 18). No differences were observed between the groups. Refrigeration of stem cells appears to be a simple, effective, and inexpensive method that should be considered for autotransplants within a few days of harvesting when resources are limited for long-term storage.

[Antihypertensive efficacy of nitrendipine and its effects on carbohydrate metabolism. A controlled clinical study versus placebo]. / Efficacia anti-ipertensiva ed effetti sul metabolismo glucidico della nitrendipina. Studio clinico controllato versus placebo.

Hypertension and diabetes mellitus are both common conditions which frequently co-exist. The calcium channel blockers are potentially diabetogenic since insulin secretion may be impaired by their use. The aim of this study was to determine whether nitrendipine, a second generation dihydropyridine derivative calcium antagonist, is capable of interfering with carbohydrate metabolism and insulin secretion in hypertensive diabetics at the doses commonly used in therapy. In a 12-week double blind placebo-controlled randomized clinical trial, the effects of nitrendipine (20 mg/day) on arterial blood pressure, glycaemic homeostasis and other metabolic parameters were evaluated in 30 patients with mild to moderate essential hypertension and type II diabetes mellitus. The results showed nitrendipine to be an effective antihypertensive agent which neither impaired the overall glucose homeostasis nor caused any other potentially harmful metabolic side effect. In conclusion, these data suggest that the calcium channel antagonist nitrendipine is a metabolically safe drug to use in the treatment of hypertension, especially in patients with diabetes mellitus.

[Possible long-term effects on the respiratory system of exposure to yperite of fishermen]. / Possibili effetti a lungo termine sull'apparato respiratorio della esposizione ad iprite tra pescatori.

Yperite or mustard gas is a well known vesicant agent that was widely used in World War I, and so far it has been the cause of several accidental exposures from sulfur mustard bombs in the marine environment. In Apulia from 1946 to 1996, 236 exposures were identified when sulfur mustard shells were caught up in fishing nets. The long term effects on the respiratory tract due to the occupational exposure to sulfur mustard are well known. Sulfur mustard has been demonstrated to be causally related to COLD and respiratory tract cancer in many epidemiological studies conducted on workers exposed in manufacturing plants. This study describes chronic pulmonary diseases in fishermen acutely exposed to mustard gas.

[Health status of shift workers in oil refineries]. / Lo "stato di salute" dei lavoratori turnisti in raffinerie di petrolio.

Within a cross-sectional epidemiologic study in an oil refinery the "mean health score" in shift and daily workers was estimated, following a method developed by the authors and based on the mean health score technique processed by M. Koller for an Austrian refinery. No significant difference was observed in the mean health score between the shift-workers and the daily-workers. However analysis of the results shows, some meaningful trends to be considered: the mean health score would seen higher in shift-workers than in daily ones for lower class of age (30; 30-40 years), while an inverse trend is observed in higher class of age. In the Austrian refinery the shift-workers mean health score is uniformly lower in all class of age. The difference observed in the study refinery could be due to the lower class of length of employment of the young shift workers with regard to the young daily ones, while in the Austrian refinery the greater damage for the shift-workers state of health could be due to a greatly more irregular shift with less adaptability.

Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations.

Low doses of metformin (500 mg twice daily) were administered to 20 diabetic patients, combined with the original sulfonylurea treatment which had become ineffective even at full dosage. After 1 and 5 weeks, the effects of the drug on glycemic control, blood intermediate metabolites and monocyte insulin receptors were monitored. Metformin clearly improved glycemic control by reducing both fasting blood glucose from 189.88 +/- 21.11 mg/dl to 131.12 +/- 16.02 mg/dl after 1 week and to 130.11 +/- 13.29 mg/dl after 5 weeks (p less than 0.025 both after 1 and 5 weeks); the diurnal blood glucose average fell from 235.33 +/- 24.11 mg/dl to 174.66 +/- 23.45 mg/dl (p less than 0.0025) after 1 week and to 177.65 +/- 21.71 mg/dl (p less than 0.0005) after 5 weeks. Consequently both blood glycosylated hemoglobin (p = n.s. after 1 week, p less than 0.025 after 5 weeks) and serum fructosamine (p less than 0.0025 after both 1 and 5 weeks) also decreased after metformin treatment. No change in plasma insulin and C-peptide levels was reported and no modification in diurnal rhythms of blood lactate, pyruvate, alanine glycerol and beta-OH-butyrate was detected at any time during metformin treatment. All the changes documented in the binding values were already complete at the end of the first week; insulin binding to monocytes increased slightly but significantly (p less than 0.05) and the number of receptors per cell rose (p less than 0.05) but could not be correlated to any index of glycemic control. These data suggest that the antidiabetic action of metformin is neither related to its lactate-increasing activity nor does it depend upon its inducing an increase in insulin binding values. This metformin-related hypoglycemic effect might be the result, at least in part, of a reduced oxidative phosphorylation without inhibition of hepatic gluconeogenesis and/or of decreased hepatic glucose output. Moreover, our data are also consistent with the hypothesis that metformin might affect insulin action at a post-receptor level.

Catecholamines and pituitary function. VII: Effects of acute and chronic dopamine-receptor blockade on pituitary response to TRH-GNRH in normal women and in patients with hyperprolactinemic amenorrhea.

To investigate whether an enhanced dopamine (DA) inhibition on pituitary thyrotrophs and gonadotrophs may account for the abnormal TSH and LH dynamics in pathological hyperprolactinemia, we examined the effect of an acute lysis of the putative DA overinhibition, as obtained with continuous domperidone (DOM) infusion, on both basal and TRH-GnRH stimulated PRL, TSH and LH release in both normal cycling women and patients with pathological hyperprolactinemia. The effect of TRH-GnRH administration was also examined in women with DA-antagonist induced hyperprolactinemia, in order to evaluate the effect of a chronic lack of the physiological DA inhibition on pituitary hormone dynamics. Patients with both pathological and DA-antagonist induced hyperprolactinemia displayed an evident TSH and LH hyper-responsiveness to TRH-GnRH. The PRL response was reduced in the former but enhanced in the latter group. Domperidone infusion resulted in a marked increase in serum PRL levels in normal cycling women, but not in patients with pathological hyperprolactinemia. The abolition of the putative DA-overinhibition at the pituitary level with DOM infusion in patients with pathological hyperprolactinemia was followed by a slight increase in basal TSH output but did not modify the TSH and LH hyperresponsiveness to TRH-GnRH. The similarities in TSH and LH dynamics between patients with pathological and DA-antagonist induced hyperprolactinemia and the ineffectiveness of DOM infusion in modifying the TSH and LH hyper-responses to TRH-GnRH in the former group, seem to exclude the widely accepted idea that endogenous DA overactivity is responsible for the abnormal thyrotroph and lactotroph dynamics in women with hyperprolactinemic amenorrhea.