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Objectives: Rapid and reliable exclusion of invasive fungal infections (IFI) by markers able to avoid unnecessary empirical antifungal treatment is still a critical unmet clinical need. We investigated the diagnostic performance of a newly available β-d-Glucan (BDG) quantification assay, focusing on the optimisation of the BDG cut-off values for IFI exclusion. Methods: BDG results by Wako β-glucan assay (lower limit of detection [LLOD]=2.16pg/mL, positivity≥11pg/mL) on two consecutive serum samples were retrospectively analysed in 170 patients, admitted to haematological wards (N=42), intensive care units (ICUs; N=80), or other wards (N=48), exhibiting clinical signs and/or symptoms suspected for IFI. Only patients with proven IFI (EORTC/MSG criteria) were considered as true positives in the assessment of BDG sensitivity, specificity and predictive values. Results: Patients were diagnosed with no IFI (69.4%), proven IFI (25.3%) or probable IFI (5.3%). Two consecutive BDG values7.7pg/mL, could be a promising diagnostic approach to confidently rule out an IFI in both ICU and non-ICU patients. The poor specificity in the ICU setting remains a concern, due to the difficulty to interpret positive results in this fragile population.

Background Many Eastern reports attempted to identify predictive variables for esophago-jejunal anastomosis leakage (EJAL) after total gastrectomy for cancer. There are no definitive answers about reliable risk factors for EJAL. This retrospective study shows the largest Western series focused on this topic. Methods This is a multicenter retrospective study analyzing patients’ datasets collected by 18 Italian referral Centres of the Italian Research Group for Gastric Cancer (GIRCG) from 2000 to 2018. The inclusion criteria were pathological diagnosis of gastric and esophageal (Siewert III) carcinoma requiring total gastrectomy. The primary end point of risk analysis was the occurrence of EJAL; secondary end points were post-operative (30-day) morbidity and mortality, length of stay (LoS), and survival. Results Data of 1 750 patients submitted to total gastrectomy were collected. EJAL developed in 116 (6.6%) patients and represented the 26.3% of all the 441 observed post-operative surgical complications. EJAL diagnosis was followed by a reoperation in 39 (33.6%) patients and by an endoscopic/radiological procedure in 30 cases (25.9%). In 47 patients (40.5%) EJAL was managed with conservative approach. Post-operative LoS and mortality were significantly higher after EJAL occurrence (27 days versus 12 days and 8.6% versus 1.6%, respectively). At risk analysis, comorbidities (particularly, if respiratory), minimally invasive surgery, extended lymphadenectomy, and anastomotic technique resulted significant predictive factors for EJAL. EJAL did not significantly affect survival. Conclusions These results were consistent with Asian experiences: the frequency of EJAL and its higher rate observed in patients with comorbidities or after minimally invasive approach were confirmed.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Background. In 2014, the Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC) reviewed the previous cytological classification proposed in 2007 including the subdivision of TIR 3 category into low risk (TIR 3A) and high risk (TIR 3B). In Italian literature, different rates of malignancy have been correlated to these subcategories. Objectives. The aim of the study is to present our experience on this subclassification for the assessment of the malignancy risk of indeterminate thyroid nodules. We correlated the subdivision into TIR 3A and TIR 3B with the histological report by highlighting the rates of malignancy detected in the two subcategories. On the one hand, we aimed to check if the groups are associated with a real and significant difference risk of malignancy. On the other hand, we evaluated the use of this subdivision in the choice of the appropriate treatment. Study Design. This is a retrospective review of all the patients with an indeterminate nodule who underwent US-FNA and had surgery at ASL Città di Torino between January 2005 and May 2018. Results. 150 patients have been analyzed for the research; 62 (41.3%) had a malignant histological report. Rates of malignancy between TIR 3A (20.8%) and TIR 3B (60.3%) were significantly different (p<0.0001). The subclassification had high sensitivity (75.8%; CI 63.3–85.8%) and NPV (79.3%; CI 68–87.8%) and low specificity (64.8%; CI 53.9–74.7%) and PPV (60.3; CI 48.5–71.2%). The measurement of the accuracy (AUC = 0.7) classified the test as “moderately accurate.” Conclusions. Obtained data show a great rate of false negative (20.8%) and limited AUC (0.7). According to our logistic regression, we argue that the 2014 subclassification into TIR 3A and TIR 3B should be considered for the choice of patient treatment, but at the same time, we believe that the association with other screening tests is necessary to increase the accuracy in the future.

Background Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

The aims of this study were to define in a cohort of 310 liver transplant recipients, the incidence of post-liver transplantation (LT) non-carbapenem-resistant Klebsiella pneumoniae (CRKP) and CRKP infections, pre- and post-LT CRKP colonization, CRKP-associated mortality, and risk factors for non-CRKP and CRKP infections. Every patient was screened for CRKP immediately before and after LT. The 6-month survival rate was 95%. Fifty-two patients became infected (16.5%): 8 by CRKP (2.5%) and 44 (14%) by a non-CRKP micro-organism. Median onset of CRKP infections occurred at postoperative (POD) 12 (range, 4-70). CRKP colonization occurred in 20 patients (6%): 10 before LT (3 infected and died) and 10 after (5 infected, 3 died). CRKP- versus non-CRKP-infected patients had higher rates of intensive care unit (ICU) and hospital mortality (50% vs 20% and 62.5% vs 36%; P ≤ .001), septic shock (87% vs 34%; P = .0057; confidence interval [CI], 9.8-71.5), prolonged mechanical ventilation (100% vs 64%; P = .043, CI, 3.5-51.9), and renal replacement therapy (87% vs 41%; P = .0177; CI, 2.8-65). The small number of CRKP-infected patients did not allow the definition of specific risk factors for CRKP infection. At univariate analysis, pre- and post-LT colonization (odds ratio [OR], 10.76; CI, 2.6-44; OR, 14.99; CI, 3.83-58.66, respectively), relaparotomy (OR, 9.09; CI, 4.01-20.6), retransplantation (OR, 7.45; CI, 3.45-16), bile leakage (OR, 61.28; CI, 9.23-80), and early allograft dysfunction (EAD; OR, 5.7; CI, 3-10.7) were significantly associated with infections, making CRKP colonization (any time) and post-LT surgical and medical complications critical factors for post-LT CRKP infections.

Major improvements in perioperative care and immunobiology have not abated the risk for severe pulmonary complications after solid-organ transplantation. The aim of this study is to update information on infectious and noninfectious pulmonary complications after solid-organ transplantation, addressing epidemiology, risk factors, diagnostic workup, and management.Infectious and noninfectious postoperative pulmonary complications depend on the grafted organ and the anatomical site of transplantation. Kidney transplants have the lowest incidence of pulmonary complications, the highest being reported for heart, lung, and liver recipients. Respiratory tract infections, ranking first in heart and lung transplants and second in liver recipients, are a common cause of mortality. Risk factors include end-stage organ disease, comorbidities, perioperative procedures, and graft function. Factors specific for infections are timeline, state of immunosuppression, and graft dysfunction. Nosocomial multi-drug resistant pathogens are frequently responsible for the most severe infections. Aggressive diagnostic workup, early and broad empiric antiinfective therapy, and deescalation policy are the mainstays of their management. The role of intraoperative protective ventilation is under scrutiny.Pulmonary complications after solid-organ transplantation, and particularly infections, are able to compromise the extremely good results of the transplant procedures. Solid-organ transplantation recipients challenge the ICU physician with unique aspects of their post-transplant course, adding, in an already critical patient, the immunosuppressed state and the quality of the functional recovery of the graft.

The LUMIRA trial evaluated the effectiveness of radiofrequency (RFA) and microwave ablation (MWA) in lung tumours ablation and defining more precisely their fields of application. It is a controlled prospective multi-centre random trial with 1:1 randomization. Fifty-two patients in stage IV disease (15 females and 37 males, mean age 69 y.o., range 40–87) were included. We randomized the patients in two different subgroups: MWA group and RFA group. For each group, we evaluated the technical and clinical success, the overall survival and complication rate. Inter-group difference was compared using Chi-square test or Fisher’s exact test for categorical variables and one-way ANOVA test for continuous variables. For RFA group, there was a significant reduction in tumour size only between 6 and 12months (p value=0.0014). For MWA group, there was a significant reduction in tumour size between 6 and 12months (p value=0.0003) and between pre-therapy and 12months (p value=0.0215). There were not significant differences between the two groups in terms of survival time (p value=0.883), while the pain level in MWA group was significantly less than in RFA group (1.79&nbsp

Background: The goal was to understand factors leading to prolonged wait times for neurological assessment of children with new onset seizures. A second objective was to develop an innovative approach to patient flow through and achieve a reduction in waiting times utilizing limited resources.Methods:Audit of the referrals, flow through, wait timesIdentification of bottlenecksDevelopment of triaging strategy:Suspected Febrile seizures and non-epileptic events;Suspected benign and absence epilepsies;Suspected other Focal epilepsies, generalized epilepsies, epilepsy under 2 yearsInitiation of early telephone contact and supportDevelopment of a ketogenic dietResults: Using a triaging strategy and focusing on timely access to investigations, wait times for clinic evaluations were shortened despite larger numbers of referrals (mean wait time reductions from 179 to 91 days). Limiting factors such increase in referral numbers, attrition in support staff, interfered with sustainability of reduced wait times achieved in the initial phase of the program. Conclusions: This pilot study highlights the effectiveness of an innovative triaging strategy and improvements in patient flow through in achieving the goals of reduction in wait times for clinical evaluation and timely investigations to improve care for children with new onset seizures. Insights into limitations of such strategies and factors determining sustainability are discussed.

Acute liver failure (ALF) is defined as a severe, sudden liver dysfunction that induces encephalopathy and coagulopathy (prothrombin time [PT/INR] > 1.5) within 26 weeks of the onset of symptoms (usually jaundice) in patients without previous liver disease. Quantitative and qualitative platelet dysfunction, reduced synthesis of clotting factors, increased consumption of factors (mainly II, V, VII, X), reduced clearance of both activated factors, and/or factor inhibitor complexes are among the most important proposed pathogenetic factors. A possible role might be also played by the diminished degradation of anticoagulants. Plasminogen activator inhibitor 1 (PAI-1) is increased, shifting the balance toward hypofibrinolysis, despite the elevated levels of tissue plasminogen activator (tPA). Although changes in coagulation parameters provide crucial information for the management of the patient with ALF, the optimal management of the hemostatic defects is far from being defined. Because spontaneous bleeding occurs rarely during ALF, measures to improve the bleeding diathesis (fresh frozen plasma, cryoprecipitate, platelet transfusion) are recommended only in patients with clinically significant bleeding or before placement of invasive devices. Antifibrinolytic drugs are used in some cases, but often empirically. The role of rFVIIa, even if promising, is still under debate.

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

Background Carcinoid tumours of the extrahepatic biliary tree are exceedingly rare. We report a case of primary carcinoid tumour arising in the distal portion of the common bile duct. Case outline A 30-year-old man was admitted with watery diarrhoea and symptoms of biliary obstruction. Abdominal ultrasound scan showed a normal gallbladder without stones, mild dilatation of the intra- and extrahepatic biliary tree and a 2 cm solid lesion in the head of pancreas compressing the distal common bile duct. Computed tomography confirmed these findings and showed that the tumour was hypervascular. Gastrointestinal hormone screening showed an increase in plasma serotonin. The patient underwent a standard pylorus-preserving proximal pancreatoduodenectomy (PPPD). Results Pathological examination showed a neuroendocrine tumour (carcinoid) of the distal bile duct. The postoperative plasma serotonin decreased to normal levels. One year later the patient is well without evidence of disease. Discussion Primary carcinoid tumours of the extrahepatic biliary tree are rare, accounting for 0.2–2% of all digestive carcinoids. This is the fifth report of a tumour arising from the distal common bile duct. Surgical treatment for neoplasms of the distal common bile duct can be problematic because of the site of the lesion and the difficulty in differentiating them from periampullary neoplasms lesions. Pancreatoduodenectomy (PD) is therefore the treatment of choice.

OBJECTIVE The aim of the present study was to measure dehydroepiandrosterone-sulphate (DHEA-S) levels in obesity and assess the relationships between DHEA-S and anthropometric, metabolic and hormonal variables. SUBJECTS AND METHODS We evaluated the serum DHEA-S levels in 217 obese but otherwise normal female subjects (age (mean ± SEM): 39.4 ± 0.9, range 18–67 years, body mass index (BMI) = 36.1 ± 0.4, range 27.1–57.1 kg/m2). RESULTS DHEA-S levels showed an age-dependent fall similar to that observed in normal women (n = 156, age 46.2 ± 1.2, range 22–69 years, BMI

Kidney transplantation is now recognized as the treatment of choice for patients with chronic renal failure. Despite the extension of indications to patients suffering severe hypertension, ischemic heart disease, and chronic heart failure, the worldwide results are superb. However, perioperative cardiac complications occur in 6% to 10% of transplanted patients. Aggressive intraoperative volume expansion is still recommended to maximize graft functional recovery (up to 30 mL/kg/h, central venous pressure [CVP] > 15 mm Hg), but patients with preexistent cardiac disease or poor myocardial function are exposed to the risk of fluid overload, acute respiratory failure, and prolonged ventilation. Among the last 90 cases performed at our institution, good functional recovery of the graft was present in 94% of the patients within 2 weeks, despite a much more conservative intraoperative hydration policy (crystalloids 2400 +/- 1000 mL, 15 mL/kg/h, CVP 7-9 mm Hg). Graft failure which occurred in 5 patients was significantly correlated only with donor age, while perioperative cardiovascular complications had been present in 9 cases (10%) who were coronary artery disease patients (55%). Age above 50 years was the only significant risk factor. Supranormal volume loading is probably not always warranted in kidney transplantation.

Background Gastroesophageal reflux is frequently associated with abnormal motility in the body of the esophagus. Concern for dysphagia has led surgeons to perform less competent procedures in this group, or to avoid surgery altogether. The current study was undertaken to evaluate our experience with the laparoscopic Hill repair in patients with reflux-associated abnormal motility. Methods A retrospective review of 338 laparoscopic Hill repairs was performed; 253 patients had adequate information for analysis, and 8 patients were excluded because of hypertensive motility. The remaining 245 patients were divided into group I (175) with normal esophageal body peristalsis, group MA (37) with moderate dysmotility, and group IIB (33) with severe dysmotility. All patients underwent standard laparoscopic Hill repair. Follow-up included postoperative manometry and 24-hour pH studies and interview by an independent physician. Dilation for dysphagia was performed when necessary. Statistical analysis was performed using the F test. Results Mean follow-up was 11.0 months (range 1 to 41). Early dysphagia (3 months) occurred in 4.0% of group I patients and 12.9% of group II patients. Late dysphagia (>3 months) occurred in 1.1% of group I patients and 1.4% of group II patients. Postoperative motility returned to normal in 43% of group IIB patients studied. Twenty-four hour pH evaluation showed fractional pH 4 an average of 4.8% in group I (median 2.1%) and 6.4% in group II (median 4.0%; P = 0.57). Patient rating of results was good to excellent in 91.0% with no statistical difference between the two groups. No patient required reoperation for dysphagia. Conclusion The laparoscopic Hill repair can be safely performed in patients with reflux-associated dysmotility, with excellent results. Even severely disordered motility will return to normal in a high percentage of cases. Manometric control of the repair and secure distal fixation of the gastroesophageal junction are advantages. Abnormal motility may be an indication for, rather than a contraindication to, laparoscopic Hill repair.

We studied 316 patients undergoing cardiopulmonary bypass for coronary artery surgery in order to determine perioperative risk factors for postoperative renal dysfunction A preliminary univariate analysis was performed by χ2 analysis for categorical data and Mann-Whitney U-test for continuous variables to detect significant correlations between each risk factor and the occurrence of moderate or severe renal dysfunction. Subsequently, a multiple logistic regression was applied to the three risk factors identified as predictive for severe renal dysfunction. Low cardiac output syndrome and need for banked blood transfusions combined with a low haematocrit value during cardiopulmonary bypass increase the probability of severe renal dysfunction in the postoperative course.

A blunted growth hormone (GH) response to several stimuli, including growth hormone-releasing hormone (GHRH), has been shown in obesity. Arginine (ARG) has been demonstrated to potentiate the GHRH-induced GH increase in normal subjects, likely acting via inhibition of hypothalamic somatostatin release. To shed further light onto the mechanisms underlying the blunted GH secretion in obesity, we studied the effect of ARG (0.5 g/kg infused intravenously [IV] over 30 minutes) on both basal and GHRH (1 micron/kg IV)-stimulated GH secretion. Eight obese subjects (aged 26.4 +/- 3.9 years; body mass index, 39.0 +/- 1.9 kg/m2) and eight normal control volunteers (aged 27.0 +/- 1.7 years; body mass index, 22.3 +/- 0.5 kg/m2) were studied. In obese subjects, the GH response to both GHRH and ARG was lower (P less than .01 and P less than .002, respectively) than in controls. ARG potentiated the GH response to GHRH in obese patients (P less than .0003). However, in these patients, the GH secretion elicited by GHRH, even when coadministered with ARG, persisted at reduced levels (P less than .005) when compared with controls. Basal insulin-like growth factor-1 (IGF-1) levels did not significantly differ in obese subjects and in normal subjects (161.1 +/- 37.0 v 181.0 +/- 12.8 micrograms/L). In conclusion, ARG enhances the blunted GHRH-induced GH increase in obese patients, but the GH responses to ARG alone and to ARG + GHRH persist at lower levels than in normals. Thus, our results suggest the existence of a reduced pituitary GH pool in obesity.

Administration of cholinergic agonists increases both basal and GH-releasing hormone (GHRH)-induced GH secretion, probably acting via inhibition of endogenous somatostatin release. The aim of our study was to verify in two groups of children with idiopathic short stature the effect of intranasal administration of neostigmine (inNS; 3 mg), a cholinesterase inhibitor, on basal GH levels as well as on the somatotroph response to GHRH when the peptide was administered either iv (ivGHRH; 1 microgram/kg) or intranasally (inGHRH; 10 micrograms/kg). In group A (n = 6; age, 10.6-16.0 yr) inNS induced a significant GH increase [inNS vs. saline, area under the curve (AUC; mean +/- SEM), 263.7 +/- 60.2 vs. 73.8 +/- 3.1 micrograms/L.h; P less than 0.03] and potentiated the somatotroph response to ivGHRH (inNS with ivGHRH vs. ivGHRH, 1316 +/- 183.0 vs. 644.9 +/- 154.5 micrograms/L.h; P less than 0.03). In group B (n = 6; age, 11.5-15.9 yr) ivGHRH induced a GH rise clearly higher than that induced by inGHRH (604.2 +/- 154.3 vs. 137.1 +/- 28.2 micrograms/L.h; P less than 0.03). Administration of inNS induced a GH rise similar to that occurring after inGHRH (AUC, 239.2 +/- 69.5 micrograms/L.h) and markedly increased the inGHRH-induced GH response (482.4 +/- 103.6 micrograms/L.h; P less than 0.05 and 0.03 vs. inNS and inGHRH, respectively), so that it overlapped with that induced by ivGHRH alone. In conclusion, cholinergic agonists such as neostigmine are able to increase both basal and GHRH-induced GH secretion in short children even when given intranasally. Combined intranasal administration of neostigmine and GHRH (10 micrograms/kg) is able to induce a GH rise similar to that induced by ivGHRH alone (1 microgram/kg), suggesting the potential usefulness of this combination cocktail and route of administration for the treatment of short stature.

Antithyroid drugs may be proposed as the first-line therapy for hyperthyroidism due to Graves’ disease since some patients undergo prolonged remission after drug withdrawal. On the other hand, some studies, though controversial, indicated that methimazole (MMI) has some immunomodulating activity. We retrospectively analyzed 384 consecutive patients newly diagnosed with Graves’ disease in the years 1990–2002 to ascertain whether long-term therapy with low doses of MMI may prevent relapse of thyrotoxicosis. Two hundred and forty-nine patients were included in our study. The date of reduction of MMI dose to 5 mg/day was considered time 0 for survival analysis. In 121 MMI was discontinued in less than 15 months after time 0 (group D), while in the remaining 128 a daily MMI 2.5–5 mg dose was maintained (group M). One hundred and thirty-five patients were excluded for inadequate response to MMI, relapse of thyrotoxicosis that could be related to an improper withdrawal or reduction of MMI, inadequate or too short follow-up, iodide contamination, steroid or interferon therapy, pregnancy or post-partum. D and M groups did not differ for clinical and hormonal parameters except age, which was lower in D (p=0.019). Age > vs < 35 yr was relevant in survival analysis; therefore patients were divided in 2 groups according to this age cut-off. In younger patients relapse of thyrotoxicosis occurred in 15 patients of group D 2.4–39.6 months (median 19.0) after time 0, and 8 M after 5.9–40.0 (21.3) months, while 14 D and 5 M maintained euthyroidism until the end of the observation after 31.8–95.3 (56.6) months and 30.4–62.1 (46.5) months, respectively. Survival analysis indicated that the risk of relapse was similar in group D and M. In older patients relapse of thyrotoxicosis occurred in 40 patients of group D after 8.2–65.8 (25.4) months and 29 M after 5.8–62.5 (22.4) months, while 52 D and 86 M maintained euthyroidism until the end of the observation, 20.1–168.0 (46.7) months and 24.1–117.4 (53.4) months respectively. Survival analysis indicated that the risk of relapse was increased in group D. Therefore long-term treatment with low doses of MMI seems to prevent relapse in Graves’ disease in patients above 35 yr of age. This should be confirmed in a prospective study.

Indwelling central venous catheters (CVCs) are used in the management of hematologic patients. However, insertion and maintenance of CVCs are susceptible to complications. Study design and methods data concerning 388 consecutive catheterisations, performed in oncohematologic patients between April 2003 and December 2004, were prospectively collected. At insertion thrombocytopenia was present in 109 cases (28.1%) and neutropenia in 67 (17.3%). Hemorrhage after CVC insertion occurred in five thrombocytopenic patients (1.3%). The median duration of catheterisation was 18.8 days (range 1-89), longer in the 7-French CVCs utilised in leukemic patients (24.3 days) and shorter in 12-French CVCs (11 days), used for PBSC harvesting. Deep venous thrombosis was diagnosed in 13 cases (3.3%). Ninety-two catheterisations (12.6/1000 days-catheter) were complicated by infections: 19 local infections (4.8%) and 73 (18.8%) bacteraemias of which 45 (11.6%) were catheter-related, mainly due to Gram positive germs (32/45, 71.1%). The frequency of catheter-related bacteraemia was 7.2 events/1000 days-catheter. Thirteen CVCs were removed due to thrombosis, 15 due to infections, 20 due to malfunction, the remaining 333 at patients discharge. At univariate analysis high-dose chemotherapy (p = 0.013), 7-Fr lumen (p = 0.023), acute myeloid leukemia (AML) (p = 0.001), duration of neutropenia10 days and length of catheterisation were significantly correlated to infection. Multivariate analysis confirmed the duration of catheterisation, AML and high-dose chemotherapy as risk factors. Even though hematological in-patients are at increased risk for bleeding and infections, non-tunnelled CVCs offer a safe venous access also in patients affected by severe thrombocytopenia and prolonged neutropenia.

At present, the mechanism(s) underlying the reduced spontaneous and stimulated GH secretion in aging is still unclear. To obtain new information on this mechanism(s), the GH responses to both single and combined administration of GH-releasing hormone (GHRH; 1 microgram/kg iv) and arginine (ARG; 30 g infused over 30 min), a well known GH secretagogue probably acting via inhibition of hypothalamic somatostatin release, were studied in seven elderly normal subjects and seven young healthy subjects. Basal GH levels were similar in both groups, while insulin-like growth factor-I levels were lower in elderly subjects (76.7 +/- 9.2 vs. 258.3 +/- 29.2 micrograms/L; P = 0.01). In aged subjects GHRH induced a GH increase (area under the curve, 314.9 +/- 91.9 micrograms/L.h) which was lower (P = 0.01) than that in young subjects (709.1 +/- 114.4 micrograms/L.h). On the other hand, the ARG-induced GH increase in the elderly was not significantly different from that in young subjects (372.8 +/- 81.8 vs. 470.6 +/- 126.5 micrograms/L.h). ARG potentiated GH responsiveness to GHRH in both elderly (1787.1 +/- 226.0 micrograms/L.h; P = 0.0001 vs. GHRH alone) and young subjects (2113.0 +/- 444.3 micrograms/L.h; P = 0.001 vs. GHRH alone). The potentiating effect of ARG on the GHRH-induced GH response was greater in elderly than in young subjects (1013.0 +/- 553.5% vs. 237.9 +/- 79.1%; P = 0.0001); thus, the GH increase induced by combined administration of ARG and GHRH overlapped in two groups. In conclusion, these results show that, differently from the GHRH-induced GH increase, the somatotroph response to combined administration of ARG and GHRH does not vary with age. Our finding suggests that an increased somatostatinergic activity may underlie the reduced GH secretion in normal aging.

To investigate the mechanism underlying the GH-releasing effect of arginine (ARG), we studied the interactions of ARG (0.5 g/kg infused i.v. over 30 min) with GHRH (1 microgram/kg i.v.) and with pyridostigmine (PD, 60 mg orally) on GH secretion in 15 children and adolescents with familial short stature (5.1-15.4 years). In a group of eight subjects ARG induced a GH increase not statistically different to that observed after GHRH (peak, mean +/- SEM: 38.0 +/- 10.4 vs 64.0 +/- 14.4 mU/l). The combined administration of ARG and GHRH led to GH levels (101 +/- 15.2 mU/l) higher than those observed after GHRH (P less than 0.025) or ARG alone (P less than 0.001) and overlapping with those recorded after combined PD and GHRH administration (111 +/- 22.4 mU/l). In the other seven subjects, ARG and PD administration induced a similar GH response either when administered alone (25.2 +/- 13.6 and 27.8 +/- 4.0 mU/l, respectively) or in combination (33.8 +/- 5.4 mU/l). In conclusion, our results show that in children ARG administration potentiates GHRH- but not PD-induced GH increase. These findings agree with the hypothesis that the GH-releasing effect of both ARG and PD is mediated via the same mechanism, namely, by suppression of endogeneous somatostatin release. Combined administration of either ARG or PD with GHRH has a similar striking GH-releasing effect which is clearly higher than that of GHRH alone.

The aim of this study was to verify that the stimulatory effect of cholinergic agonists on both basal and stimulated GH release observed in the morning persists in the night. The effects of pyridostigmine (120 mg orally), a cholinesterase inhibitor, on both basal and GHRH (1 μg/kg iv) - induced GH secretion were studied in 8 healthy volunteers, aged 22-30 years. In the morning, administration of pyridostigmine induced a significant increase in basal GH levels compared with saline (area under the response curve, mean ± SEM: 277.0 ± 54.0 vs 49.7 ± 8.2 μg·l−1·h−1, p < 0.02) as well as a strong potentiation of the GHRH-induced GH release (2117.6 ± 353.0 vs 427.9 ± 87.0 μg·l−1·h−1, p < 0.02). In the night, GH secretion after pyridostigmine did not differ from saline (194.5 ± 21.9 vs 89.4 ± 28.7 μg·l−1·h−1). Moreover pyridostigmine failed to potentiate the GHRH-induced GH increase (1071.9 ± 170.4 vs 740.2 ± 150.9 μg·l−1·h−1). The pyridostigmine + GHRH-induced GH rise during the night was lower (p < 0.05) than in the morning. All together, these data seem to indicate that cholinergic neurons controlling GH secretion are already maximally stimulated at night. As cholinergic activity negatively modulates SRIH secretion, our findings suggest that a reduced somatostatinergic tone in the hypothalamus is present during the night.

Background Indwelling central venous catheters (CVCs) are essential devices in the management of patients with hematological disorders treated with chemotherapy. However, their nature predisposes patients to unwanted complications. Methods CVC-related complications were retrospectively analyzed in 227 hematologic patients who were consecutively admitted to our hematology department between May 2002 and April 2004. Patients’ diagnoses comprised acute myeloid leukemia (36.8%), acute lymphoid leukemia (7.3%), lymphoproliferative disorders (28.3%), multiple myeloma (19.5%), myeloproliferative syndromes (5%) and others (3.1%). The CVCs used were polyurethane three lumen 7-Fr (111 patients) for chemotherapy and 12-Fr (114 patients) for chemotherapy and peripheral blood stem cell apheresis, plus two tunneled catheters. Results The pathological events were: bacteriaemias (n=46); occlusions (n=10); exit tunnel infections (n=8); thrombosis (n=6); lung emboli (n=2). Among febrile patients the bacteriemia frequency was 20%, of which 13.6% were CVC-related (with a higher incidence in leukemia patients (p=0.027). Among the isolates, gram-positive bacteria were found in 29 cases (23 CVC-related cases), and gram-negative bacteria in 16 cases (8 CVC-related cases). Only one patient had Candida albicans sepsis. At univariate and multivariate analysis significant risk factors for infection (pConclusions In our hematologic patients, the CVC complications were mainly septic, with only 10.1% of CVC-related bacteriemias, despite prolonged catheterization duration. Acute leukemia patients were at major risk for sepsis, probably due to a more severe neutropenia and prolonged catheterization duration.

Studies have estimated that 5–10% of all fractures are associated with impaired healing, resulting in delayed union or non-union. Bone defects can result from a high-energy traumatic event, from large bone resection for different pathologies such as tumours or infections or from the treatment of complex non-unions. A large bone defect represents a challenge for the orthopaedic surgeon. This clinical condition is considered critical in relation to the skeletal segment involved: 3 cm for the forearm, 5 cm in the femur and tibia, 6 cm in the humerus. Excluding the traditional surgical techinques (distraction osteogenesis, autologous bone grafts or arthrodesis), the use of biotechnology can be very useful. We treated a 42 years old patient, that came to our observation through the ambulatory of nonunion of our Institute with a diagnosis of “humeral large bone septic defect”; this patient had in his history multiple previous osteosynthesis surgeries. The patient therefore underwent corrective surgery according to the Masquelet’s technique in two surgical times. The postoperative course was uneventful; during the follow-up the patient showed a good functional recovery with great satisfaction.

Sex and age are the major determinants of serum levels of dehydroepiandrosterone sulfate (DHEA-S): they are about twice in men than in women and show a progressive reduction from the end of the puberty to aging in both sexes. It has been reported that DHEA-S levels are also negatively influenced by insulin. Moreover, DHEA-S levels reduction has been associated to increased risk for cardiovascular disease, which connotes hyperinsulinemic states, such as obesity. We have evaluated serum levels of DHEA-S and insulin as function of age and body mass index (BMI) in 376 adult women (age 18.1–89.6 yrs, median 42.2; BMI 15.7–57.8 kg/m2, median 32.7) by multiple regression and piecewise regression analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S levels negatively associated with age (p=0.000001). Considering the whole population, DHEA-S levels were related positively with BMI (p=0.0013) independently of age. DHEA-S were also directly related to insulin levels independently of age (p=0.042), but this association disappeared after correction for BMI. Piecewise regression analysis did not reveal a threshold level for the increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively associated before but not after menopause. Taking into account only obese population, (no.=143, age 18.7w–67.3 yrs, mean 39.0, median 39.4) DHEA-S levels were again related negatively with age and positively with BMI, while were unrelated with waist to hip ratio (p=0.391). Our data show that increasing body mass and insulin secretion is not associated to DHEA-S reduction in women. This evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of cardiovascular disease in obese women.

To investigate whether early postoperative changes in blood lactate concentration indicate the functional recovery of the newly grafted liver, changes in oxygen supply, oxygen consumption, acid-base equilibrium, and blood lactate concentrations were prospectively studied in a group of 53 postnecrotic cirrhotic patients during the various phases of orthotopic liver transplantation (preanhepatic, anhepatic, neohepatic) and for the first 48 h following reperfusion. The patients were divided into two groups according to the quality of the early graft function, as indicated by alanine aminotransferase, bile flow, and prothrombin activity: group A (49 patients), good immediate graft function and group B (4 patients), immediate graft non-function. Lactate levels rose in the same manner during the preanhepatic and anhepatic stages and peaked after revascularization of the graft. Following reperfusion, however, distinctly different blood lactate profiles were recorded in the two groups of patients. A fall in lactate concentration was recorded in group A patients, whereas a continuous rise occurred in group B patients: the difference becoming significant by the end of surgery (Por = 0.05). During the first 48 h following revascularization of the graft, opposite trends in lactate concentration, bile flow, alanine aminotransferase, and prothrombin activity were evident in the two groups of patients: 24 h after reperfusion, lactate levels were below 2 mmol/l in 47 of 49 patients from group A, while they plateaued above 4 mmol/l in all patients from group B. Group A patients had lower alanine aminotransferase levels (Por = 0.001), higher prothrombin activity, (Por = 0.01), and greater bile flow (Por = 0.02). If validated in larger series, the blood lactate profile, probably more than the absolute level, appears to be a useful indicator of the early recovery of liver metabolic capacities in the immediate postoperative period of orthotopic liver transplantation.

Rare cases of myelolipomas associated with adrenocortical lesions responsible for Cushing or Conn syndromes have been described. We report two additional cases of extensive lipomatous changes in incidentally discovered adrenocortical adenomas, which were preoperatively interpreted as myelolipomas on the basis of radiologic findings. Microscopically, the adenomas were composed of sheets and nests of adrenocortical cells, and extensive areas of mature adipose tissue admixed with a bland stromal infiltration of small cells. The impression was that myeloid cells were present, featuring a myelolipoma associated with a clear cell adenoma of the adrenal cortex, but specific immunocytochemical markers of myeloid lineage were not reactive in the small cell component, and these cells consisted of small lymphocytes. The lipomatous tissue may represent a degenerative phenomena within an adrenocortical adenoma or may be an additional neoplastic component of the tumor. Irrespective of their origin, extensive (myelo)lipomatous changes in adrenocortical tumors can lead to misinterpretations in the preoperative work-up of patients with adrenal masses.

The occurrence of tumors originating from aberrant adrenocortical tissue in ectopic site is very rare. Up to now only two cases of ectopic aldosterone-producing adenoma have been described. We have observed another case of ectopic aldosteronoma, located in the retrocaval region, laterally to the body of the 12th thoracic vertebra. This ectopic tumor was associated to another adrenocortical adenoma, in the adrenal gland of the same side. The diagnostic implications of this observation are discussed.

Summary BACKGROUND AND OBJECTIVE Reduced serum levels of dehydroeplandrosterone sulphate (DHEAS) have been shown In patients with Cushing's syndrome resulting from adrenocortical adenoma, In contrast with normal DHEAS levels In patients with Cushing's disease. The elm of this study was to verify whether patients with incidentally discovered adrenocortical adenomas also have reduced levels of DHEAS. DESIGN Evaluation of serum DHEAS, serum and urinary cortisol, plasma ACTH and low dose dexamethasone suppression test In patients with adrenal Incidentaloma and Cushing's syndrome. PATIENTS Thirty-two patients with adrenal Incidentaloma and, as controls, 17 patients with overt Cushing's syndrome, were studied. RESULTS Serum DHEAS levels lower than normal were found In 21/24 (81.5 %) patients with adrenocortical Incidentaloma, but In only 1/8 patients with a mass of non-adrenocortical origin. This patient had massive bilateral metastatic infiltration of both adrenal glands and primary adrenal failure. The prevalence of low DHEAS levels in the two groups was significantly different (P= 00001). In patients with adrenocortical Incidentaloma, the prevalence of low DHEAS levels was significantly higher (P= 00001) than that found for some hormonal alterations Indicating pre-clinical hypercortlsoilsm (high urinary cortisol, unsuppressed serum cortisol after low dose dexamethasone administration and low plasma ACTH). Low DHEAS levels were found in all patients with Cushing's syndrome due to adrenocortical adenoma but in none of those with Cushing's disease. CONCLUSIONS Our results Indicate that the finding of low DHEAS levels can be considered a marker of the adrenocortical origin of an adrenal Incidentaloma, provided adrenal failure has been excluded.

Mazza E, Goffi S, Barchi P, Arvat E, Bellone J, Limone P, Ghigo E, Camanni F. Enhanced adrenocorticotrophic hormone and cortisol responses to corticotrophin-releasing hormone in central idiopathic diabetes insipidus. Eur J Endocrinol 1994;130:121–4. ISSN 0804–4643 It is well known that arginine vasopressin (AVP) exerts a stimulatory effect on adrenocorticotrophic hormone (ACTH) secretion. Moreover, there is consistent evidence that the hypothalamic AVP-secreting neurons are involved in the neuroregulation of ACTH secretion. With the aim to throw further light on the interaction between AVP and corticotrophin-releasing hormone (CRH) in the neuroregulation of ACTH secretion, in this study we compared the ACTH and cortisol responses to human CRH (100 μg iv as a bolus) in 18 normal subjects (15 females and three males, age 22–35 years) and seven patients with central isolated diabetes insipidus (six females and one male, age 16–40 years). Two patients were newly diagnosed and five had discontinued substitution therapy with desamino-D-AVP 24 h before testing. All had free access to water before and during the test period. The ACTH and cortisol responses to CRH were higher in subjects with diabetes insipidus than in controls, either when evaluated as peak values (ACTH, mean±sem: 17.0±1.2 vs 7.7±0.7 pmol/l, p=0.0003; cortisol: 611.3±59.4 vs 450.7±21.2 nmol/l, p=0.01) or area under curve values (ACTH: 672.5±75.7 vs 364.0±33.6 pmol·1−1·h−1. p=0.002; cortisol: 29158.0±2937.0 vs 23236.7±1052.1 nmol·l−1 · h−1, p=0.03). These results show that patients with diabetes insipidus have an exaggerated pituitary-adrenal response to CRH. This may be due to the fact that in diabetes insipidus AVP secretion from parvocellular neurons of the paraventricular nucleus in the hypophysial portal system is not impaired. Alternatively, AVP secretion may be defective in both magnocellular and parvocellular hypothalamic AVP-secreting neurons. In this case, it could be hypothesized that adjustment is made to the feedback regulatory mechanisms of the hypothalamic–pituitary–adrenal axis, so that the CRH–ACTH axis assumes a main role with respect to the AVP–ACTH axis. Franco Camanni, Divisione di Endocrinologia, Ospedale Molinette, corso Dogliotti 14, 10126 Torino. Italy

Cholinergic pathways in the central nervous system positively influence growth hormone (GH) secretion. In fact pyridostigmine, a cholinesterase inhibitor, enhances both basal and GH-releasing hormone (GHRH)-induced GH secretion while, conversely, pirenzepine, an antagonist of muscarinic M 1 receptors, inhibits the GH response to GHRH and to other physiological and pharmacological stimuli. The effect of the cholinergic system on GH secretion probably takes place via inhibition of the release of endogenous somatostatin. In this study in 36 normal adults (26 males and 10 females, age 22–35 years) we compared the effects of three cholinesterase inhibitors (pyridostigmine, 120 mg p.o., n = 19; neostigmine, 10 μg/kg i.v., n = 6; physostigmine, 12.5 μg/kg i.v., n = 6) and bethanechol, a direct muscarinic receptor agonist that is mainly active on muscarinic M 3 receptors (25 μg/kg i.v., n = 5), on both basal and GHRH (1 μg/kg i.v.)-stimulated GH secretion. Pyridostigmine, neostigmine and physostigmine induced a significant GH increase (peak vs. basal levels, mean ± S.E.: 10.4 ± 1.6 vs. 0.6 ± 0.2 μ g/l, P = 0.0001; 13.3 ± 1.2 vs. 0.5 ± 1.1 μ g/l, P = 0.004; and 14.9 ± 3.1 vs. 2.7 ± 1.1 μ g/l, P = 0.025;, respectively). These drugs also induced a similar potentiation of the GH response to GHRH (peak: 48.3 ± 5.6 vs. 16.2 ± 2.2 μ g/l, P = 0.0001; 49.2 ± 2.2 vs. 19.9 ± 5.1 μ g/l, P = 0.006; and 76.9 ± 12.4 vs. 18.1 ± 5.3 μ g/1, P = 0.001, respectively). By contrast, bethanechol neither enhanced basal GH secretion (peak vs. basal level: 3.3 ± 1.2 vs. 2.6 ± 1.2 μ g/l) nor potentiated the GH response to GHRH (peak: 16.3 ± 1.3 vs. 15.4 ± 1.6 μ g/l). The present findings strongly confirm the stimulatory role of aetylcholine on GH secretion in man, showing that indirect acetylcholine receptor agonists stimulate GH secretion, while the muscarinic M 3 agonist bethanechol does not. The results exclude that cholinergic stimulation of GH secretion is mediated by muscarinic M 3 receptors, in keeping with the hypothesis that muscarinic M 1 receptors play the main role in the neuroregulation of GH secretion.

A hypothalamic pathogenesis for the reduced GH secretion in aging has been reported for both animal and man. To further address this issue we studied in 31 elderly normal subjects (6 males and 25 females, aged 66–90 yr) and in 22 young healthy controls (13 males and 9 females, aged 20–35 yr) the GH responses to GHRH test (GHRH29, 1 μg/kg iv as a bolus at 0 min) alone and combined with pyridostigmine, a cholinesterase inhibitor (PD, 120 mg po 60 min before GHRH), or with arginine (ARG, 30 g in 100 ml infused from 0 to 30 min). Serum IGF-I levels were lower in elderly than in young subjects (mean±SE: 86.9±7.2 vs 288.7±22.1 μg/L, p

To clarify the mechanism by which galanin, a 29-amino-acid peptide, increases GH secretion in man.We studied the GH-releasing effect of this neurohormone (galanin, 15 micrograms/kg) infused over 60 minutes after 120 minutes of saline, following a previous GHRH bolus (GHRH 1 microgram/kg i.v. at 0 minutes, galanin infused from 120 to 180 minutes) and coadministered with the second of two consecutive GHRH boluses (GHRH every 120 minutes, galanin infused from 120 to 180 minutes).Fourteen healthy male subjects, aged 20-34 years, in two groups (group A, 20-31 years (n = 8); group B, 25-34 years (n = 6)) were studied.Blood samples were drawn every 15 minutes of 255 minutes. Serum GH was measured in duplicate by IRMA. Statistical analysis of the data was carried out by non-parametric ANOVA test.The GH response to galanin infused 120 minutes after saline overlapped with that induced by the neuropeptide infused following previous GHRH bolus (AUC, mean +/- SEM: 317.3 +/- 73.2 vs 326.8 +/- 54.2 micrograms/l/h). The GH-releasing effect of the second GHRH bolus (126.9 +/- 32.3 micrograms/l/h) was lower than that of the first one (503.4 +/- 41.3 micrograms/l/h; P = 0.0002). Galanin markedly enhanced the GH responses to the second GHRH bolus (1118.0 +/- 212.7 micrograms/l/h; P = 0.0002 vs second GHRH bolus alone) so that it did not significantly differ from the first one (710.9 +/- 107.8 micrograms/l/h).Our results show that the GH-releasing effect of galanin is not modified by GHRH pretreatment and that the neuropeptide reinstates the GH response to the repeated GHRH stimulation in man. They suggest that these effects are due to the inhibition of hypothalamic somatostatin release.