Diagnostic, therapeutic and healthcare management protocols in parathyroid surgery: II Consensus Conference of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB).

AIM: To update the Diagnostic-Therapeutic-Healthcare Protocol (Protocollo Diagnostico-Terapeutico-Assistenziale, PDTA) created by the U.E.C. CLUB (Association of the Italian Endocrine Surgery Units) during the I Consensus Conference in 2008. METHODS: In the preliminary phase, the II Consensus involved a selected group of experts; the elaboration phase was conducted via e-mail among all members; the conclusion phase took place during the X National Congress of the U.E.C. CLUB. The following were examined: diagnostic pathway and clinical evaluation; mode of admission and waiting time; therapeutic pathway (patient preparation for surgery, surgical treatment, postoperative management, management of major complications); hospital discharge and patient information; outpatient care and follow-up. CONCLUSIONS: The PDTA for parathyroid surgery approved by the II Consensus Conference (June 2013) is the official PDTA of the U.E.C. CLUB.

Anaplastic thyroid cancer: prevalence, diagnosis and treatment.

UNLABELLED: Anaplastic thyroid cancer (ATC) is a rare aggressive tumor arising from the follicular cells of the thyroid gland (as does well differentiated thyroid cancer, WDTC), but ATC cells do not retain any of the biological features of the original follicular cells, such as uptake of iodine and synthesis of thyroglobulin. Prognosis is almost invariably fatal. In this article the Authors review the pathology, epidemiology, clinical presentation, diagnosis and treatment options of ATC. ATC incidence typically peaks at the 6-7th decade of life (mean age at diagnosis 55-65 years), women representing 55-77% of all patients. ATC represents 2-5% of all thyroid tumors, with a decreasing trend with respect to the incidence of WDTC. The histologic patterns of ATC include giant-cell, spindle-cell and squamoid-cell tumors; these subtypes frequently coexist and are not predictive of patients' outcome. Immuno-cyto-chemistry for thyroglobulin is usually negative or weakly positive and some cases are also negative for keratin, particularly in the spindle-cell areas. ATC may arise de novo, but in most cases it develops from a pre-existing WDTC, especially the follicular subtype. Most ATC patients complain of local compressive symptoms, such as dysphagia, dysphonia, stridor and dyspnea in addition to neck pain and tenderness; in over 70% of the patients the tumor infiltrates surrounding tissues, such as fat, trachea, muscle, esophagus, and larynx. The clinical course of a rapidly enlarging mass that is firm and fixed to surrounding structures in an elderly patient is quite suggestive for ATC. Diagnosis can be confirmed by fine needle aspiration cytology or, in doubtful cases, by histology on core biopsy. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are useful for defining the local extent of disease and for identifying distant metastases, as is also positron-emission tomography (PET) with [(18)F]FDG. Tracheoscopy and esophagoscopy should be performed every two months, or whenever patients refer the appearance or worsening of local symptoms. Bone scintigraphy may be included in the follow-up of patients with a longer survival and relatively good health. Because of its aggressive behavior, the latest American Joint Committee on Cancer Staging Manual classifies all ATCs as T4 and Stage IV tumors, regardless of their actual overall tumor burden. Treatment of ATC has not been standardized because it is not clear whether or not therapy is effective in prolonging survival; most patients die within six momths from diagnosis, primarily because of asphyxiation caused by local tumor invasion. When employed alone, surgery, radiotherapy, or chemotherapy are seldom adequate to achieve overall control of the disease, but a combination of these treatments may improve local control. Surgical treatment of local disease offers the best opportunity for prolonged survival if the tumor is intrathyroidal. When the tumor is extrathyroidal, the surgical approach to ATC is controversial. Some favourable results have recently been reported with newly developed chemotherapy agents and hyper-fractioned radiation therapy. Tracheostomy should be performed in patients with impending airway obstruction when death is not imminent from other sites of disease, and if patients are not candidates for local resection or chemoradiation. Interventional bronchoscopy, including Nd-YAG laser and airways stenting are alternatives to surgery in inoperable ATC-induced tracheal obstruction. Gene therapy is under investigation. Although very rare, ATC is a highly aggressive tumor that belongs to the group of killer tumors with median survival time not longer than 6-8 months. Surgery, chemotherapy and radiotherapy are the conventional therapeutic strategies performed in the attempt to improve survival. Unfortunately, very often they do not succeed any clinical benefit but only palliative RESULTS: New therapeutic strategies based on molecular approaches are desirable.

Vitamin K-induced modification of coagulation phenotype in VKORC1 homozygous deficiency.

BACKGROUND: Combined vitamin K-dependent clotting factor (VKCF) deficiency type 2 (VKCFD2) is a rare bleeding disorder caused by mutated vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) gene. METHODS AND RESULTS: An Italian patient with moderate to severe bleeding tendency was genotyped, and found to be homozygous for the unique VKORC1 mutation (Arg98Trp) so far detected in VKCFD2. The activity levels of VKCFs were differentially reduced, and inversely related to the previously estimated affinity of procoagulant factor propeptides for the gamma-carboxylase. The normal (factor IX) or reduced antigen levels (other VKCFs) produced a gradient in specific activities. Vitamin K supplementations resulted in reproducible, fast and sustained normalization of PT and APTT. At 24 h the activity/antigen ratios of VKCFs were close to normal, and activity levels were completely (factor VII and IX), virtually (prothrombin, factor X and protein C) or partially (protein S) restored. Thrombin generation assays showed a markedly shortened lag time. The time to peak observed at low tissue factor concentration, potentially mimicking the physiological trigger and able to highlight the effect of reduced protein S levels, was shorter than that in pooled normal plasma. At 72 h the thrombin generation times were normal, and the decrease in activity of procoagulant VKCFs was inversely related to their half-life in plasma. The improved coagulation phenotype permitted the uneventful clinical course after invasive diagnostic procedures. CONCLUSIONS: Modification of coagulation phenotypes in VKCFD2 after vitamin K supplementation was clinically beneficial, and provided valuable patterns of factor specific biosynthesis, half-life and decay.

Anticlastogenic effect of Ginkgo biloba extract in Graves' disease patients receiving radioiodine therapy.

BACKGROUND: Chromosomal damage, as assessed by clastogenic factors (CFs) and micronuclei (MN) appearance, after radioiodine therapy of Graves' disease has been reported. OBJECTIVE AND METHODS: Our objective was to evaluate the effect of Ginkgo biloba extract (EGb 761) supplementation on the time course (up to 120 d) of CFs and MN appearance in lymphocytes from patients with Graves' disease after iodine-131 ((131)I) therapy. Patients were randomly assigned to EGb 761 or placebo, in a blinded manner. RESULTS: In the placebo group, MN increased early (P < 0.001) after (131)I, peaking at the 21st day (P = 0.0003) and declining thereafter. In EGb 761-treated patients, MN increased early (P < 0.05), while returning toward baseline value thereafter. Therefore, mean MN increment was significantly higher in the placebo group as compared with EGb 761-treated patients (P < 0.01). Moreover, an early (P < 0.0001) and sustained (up to 35 d; P < 0.001) MN increase induced by CFs was observed in the placebo group. Conversely, in EGb 761-treated patients, MN increase induced by CFs never reached the statistical significance; therefore, the mean of the MN increments was significantly lower than in placebo (P < 0.05). A significant positive correlation between MN maximum increment and the bone marrow dose was observed in the placebo group only (P = 0.03). No significant difference was observed in clinical outcome between the two groups. CONCLUSIONS: EGb 761 supplementation neutralized genotoxic damage induced by radioiodine treatment, without affecting the clinical outcome. Although (131)I therapy is generally safe, our data suggest that Gingko biloba extracts may prevent genetic effects of radioiodine therapy for hyperthyroid Graves' disease.

Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers.

BACKGROUND AND OBJECTIVE: Little is known about the pharmacokinetics of allergens for local immunotherapy. Thus, we studied the pharmacokinetics in allergic volunteers of a commercial allergenic vaccine in orosoluble tablets (LAIS(R), Lofarma S.p.A). METHODS: The carbamylated monomeric allergoid derived from Parietaria judaica major allergen (Par j 1), characterized by maintenance of the original molecular size, and the native allergen, were radiolabelled with 123I, then incorporated into the commercial soluble tablets and administered to allergic subjects. Early sequential and late static scintigraphic acquisitions were performed, and plasma radioactivity was measured at different time intervals. RESULTS: No difference in local pharmacokinetics was observed between the allergen and the allergoid: part of the tracer was retained in the mouth for at least 2 h after swallowing. No direct absorption through the oral mucosa could be detected, as plasma radioactivity increased only after swallowing and peaked at 2 h. However, the plasma peak attained with the allergoid in tablets was significantly higher with respect to the native allergen. Finally, some undegraded allergoid, but not the allergen, could be constantly detected in the bloodstream at plasma peak. CONCLUSIONS: The results showed a similar behaviour of the allergoid and the allergen in tablets as far as their local kinetics are concerned, whereas plasma peak was higher with the allergoid than with the allergen. Therefore we conclude that the chemical modification of the allergen may affect its pharmacokinetics, by making it less susceptible to enzymatic degradation.

Hippocampal perfusion in mild Alzheimer's disease.

Perfusion and metabolic studies in patients with Alzheimer's disease (AD) have so far yielded conflicting results on the functional status of the hippocampal region, whose deep location in the brain makes it critical to optimize the image-reconstruction technique employed in emission tomography. We used a brain-dedicated device (CERASPECT) to perform single photon emission computed tomography (SPECT) studies with 99mTc-hexamethylpropylene-amine-oxime in 22 consecutive patients (mean age: 74+/-6.5 years) with mild [mini-mental status examination (MMSE) score > or =15, mean 20.8+/-3.2], probable AD. The control subjects were 11 healthy elderly people (mean age: 70.5+/-6.5 years). In patients, the total score on the selective reminding test (SRT) was used as an index of memory function. Counts from a hippocampal and a temporoparietal region of interest in each hemisphere were referred to the average thalamic counts. To optimize SPECT images, we used conventional filtered back-projection (FBP) reconstruction and a new iterative method of conjugate gradients (CG), which takes into account the geometrical and physical characteristics of the gamma-camera. Hippocampal perfusion in the two hemispheres was significantly lower in patients than in control subjects, regardless of which reconstruction method was used, and correlated with the MMSE score. The correlation between hippocampal perfusion and the SRT score was significantly (bootstrap procedure) higher with the CG method than with the FBP method (CG: r=0.52 and 0.54; FBP: r=0.39 and 0.47, for the right and left hemisphere, respectively). These results show hippocampal hypoperfusion in patients with mild AD, a correlation between hippocampal perfusion and the severity of cognitive impairment, and enhanced identification of these subtle perfusional changes with the use of an alternative image-reconstruction method that improves the spatial resolution of SPECT images.

Use of radioimmunoguided surgery after induction chemotherapy in locally advanced breast cancer.

Twenty-one patients with histologically proven locally advanced breast cancer (LABC) were treated with a combined modality approach based on primary chemotherapy and radical modified mastectomy followed by adjuvant chemotherapy. Surgery was performed by using radioimmunoguided surgery (RIGS) technique with the preoperative injection of Iodine-125 labeled monoclonal antibodies (MoAbs) B72.3 anti-TAG (11 patients, Group A) and FO23C5 anti-carcinoembryonic antigen (CEA; 10 patients, Group B). The role of RIGS was defined at surgery by using an intraoperative hand-held gamma-detecting probe (GDP) to locate the primary tumor, possible clinically occult multicentric foci and ipsilateral lymph node metastases. In Group A, RIGS correctly defined the primary tumor in seven out of 11 patients (63.3%) and was able to find multicentric tumors in two out of four patients (50%). Positive lymph nodes were identified by RIGS in three out of eight patients (37.5%). In Group B, patients RIGS correctly located the primary in 4/10 cases (40%); in two RIGS-positive cases, the tumor was clinically not evident after primary chemotherapy (yT0). RIGS correctly identified multicentric foci of tumor in one out of two cases (50%). Correct lymph nodal RIGS assessment was observed in three out of nine patients (33.3%). No RIGS false-positive findings occurred in the 21 patients included in the study. RIGS appears to be a reliable technique for the intraoperative diagnosis and staging of breast cancer with a potential role especially when conservative surgery is planned after primary chemotherapy in LABC.

Terminal megakaryocytic differentiation of TF-1 cells is induced by phorbol esters and thrombopoietin and is blocked by expression of PML/RARalpha fusion protein.

We have analyzed the differentiation program of growth factor-dependent TF-1 erythroleukemia cells as well as clones with inducible expression of the APL-specific PML/RARalpha protein. We have shown that TF-1 cells may be induced to megakaryocytic differentiation by phorbol ester (phorbol dibutyrate, PDB) addition, particularly when combined with thrombopoietin (Tpo). RT-PCR studies showed that Tpo induces Tpo receptor (TpoR or c-mpl), whose expression was further potentiated by PDB addition. When the cells are induced with both PDB and Tpo erythropoietin receptor (EpoR) expression was inhibited. In the absence of Zn2+-induced PML/RARalpha expression, PDB and Tpo induced megakaryocytic differentiation of TF-1 MTPR clones as observed in 'wild-type' TF-1 cells. Conversely, when PML/RARalpha expression was induced by Zn2+, PDB and Tpo treatment of these clones caused only a reduced level of megakaryocytic differentiation. These observations indicate that: (1) TF-1 cells as well as other erythroleukemic cells, possess the capacity to differentiate to megakaryocytic cells when grown in the presence of protein kinase (PKC) activators and more efficiently when combined with Tpo; (2) the PML/RARalpha gene has a wide capacity to interfere with the program of hematopoietic differentiation, including megakaryocytic differentiation. Finally, we also observed that PML/RARalpha expression in TF-1 cells induces an up-modulation of interleukin-3 receptor, c-kit and c-mpl, a phenomenon which may offer these cells a growth advantage.

[Feasibility of a cyclophosphamide methotrexate and 5-fluorouracil regime intravenously administered with and without granulocyte-colony stimulating factor in surgically treated breast carcinoma]. / Studio di fattibilità del regime ciclofosfamide methotrexate e 5-fluorouracile somministrati per via endovenosa con e senza "granulocyte-colony stimulating factor" nel carcinoma mammario operato.

The aim of this study was to evaluate the feasibility of CMF 1.8-28 regimen, with all three drugs administered intravenously (IV), and to compare the hematologic toxicity of this regimen with or without G-CSF. Patients aged 18 to 65 years with histologically proven breast cancer treated by surgery and without distant metastases were eligible for the study. All patients had to have normal white blood cells (WBC) count (WBC > or = 3000/mm3 and/or neutrophils > or = 2000), and platelets (Plt) counts (> or = 100,000/mm3), and adequate renal and hepatic function. The toxicity was recorded according to World Health Organization Scale. CMF 1.8 regimen was: cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2. The drugs were given IV on day 1 and 8, and cycles repeated every 28 days. G-CSF (5 micrograms/kg/day) was administered subcutaneously from day 9 to 20, starting from the second cycle of chemotherapy. A complete blood count with white-cell differential and platelet count was obtained twice a week. For each patient bone marrow toxicity variables recorded during the first cycle (without G-CSF) were compared with values during the second cycle (with G-CSF). One of 10 entered patients, 1 was not evaluated due to missing data on hematologic toxicity. All patients received chemotherapy with or without G-CSF at the scheduled 28th day. Treatment with G-CSF after CMF 1.8 regimen resulted in a significantly WBC's earlier nadir (average day of nadir 14 vs 17; p = 0.0005), while there was no difference in the average values of WBC at the nadir. Moreover, the average value of platelets recorded at the nadir was significantly lower with the use of G-CSF (average No. of platelets/mm3; 185,111 vs 116,000; p = 0.001). Complete hematologic recovery without and with G-CSF was reached on day 25 and 20 respectively (p = 0.001). CMF 1.8 with IV cyclophosphamide is a feasible regimen with and without G-CSF and can be used in adjuvant setting instead of "classic" CMF in order to improve the low compliance observed when cyclophosphamide is given by mouth. As reported by others, we observed that after standard chemotherapy G-CSF anticipated the nadir of WBC and hastened hematologic recovery (WBC > 3000 and Plt > or = 100,000).(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of polychlorinated dioxins and furans in samples of the toxic oil syndrome.

1 Polychlorinated dioxins (PCDDs) and furans (PCDFs) are known to produce a wide range of toxic effects. 2 PCDDs and PCDFs are typical contaminants of chlorinated phenols, and pentachlorophenol and related compounds have been shown to be widely distributed among selected oil samples taken from the 1981 Spanish toxic oil epidemic. 3 Six control and eight case oil samples were analysed using GC/MS for PCDDs and PCDFs. Only small concentrations, normally below 1 ng g-1, of the higher chlorinated PCDDs and PCDFs were detected. There were no statistical differences between the case and control oils. 4 These levels seem to be too low to elicit toxic effects, although they could be enough to potentiate the toxicity of other xenobiotics present in the oils. However, it is uncertain whether the levels of these compounds measured in 1990 reflect the levels present when the oils were consumed in 1981, or whether or not the levels measured in crude oils are representative of fried oils.

Transforming growth factor-beta potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines.

We have investigated the effects of 1,25-dihydroxyvitamin D3 (D3) and/or transforming growth factor (TGF)-beta on one monocytic (U-937) and two human promyelocytic (HL-60 and AML-193) leukemic cell lines. D3 addition induces a partial monocytic maturation of the cell lines, whereas TGF-beta treatment is largely ineffective. Combined treatment with TGF-beta and D3 causes terminal monocytic maturation, as evaluated both by assessment of a large spectrum of membrane Ag and by functional assays. Furthermore, sequential addition of the two inducers showed that pretreatment with TGF-beta 1 followed by incubation with D3, but not vice versa, induces monocytic maturation as effectively as simultaneous treatment with both agents. In liquid culture the proliferative activity of these cell lines is slightly decreased by D3 and virtually unaffected by TGF-beta, whereas combined treatment with D3 and TGF-beta induces a markedly potentiated inhibitory effect. Furthermore, TGF-beta/D3 treatment (but not D3 alone) elicits the expression of membrane CD14, FcRI, FcRII, CD11a, CD11b, CD11c, ICAM-1, and PECAM-1 Ag at a level comparable to that observed on normal human monocytes. It is noteworthy that several of these Ag play an important role in monocyte physiology (e.g., CD14 Ag mediates the binding of bacterial LPS to monocytes). Treatment with both TGF-beta and D3 (but not D3 alone) induces superoxide anions and H2O2 production similar to that of circulating monocytes. In semisolid culture, D3 and TGF-beta alone cause, respectively, a marked and slight loss of cloning efficiency of the cell lines, whereas their combined addition synergistically results in a complete loss of the cloning capacity. These findings suggest a physiologic role for TGF-beta in monocyte maturation. Furthermore, they may pave the way to the design of clinical protocols combining D3 and TGF-beta in the differentiation therapy of acute promyelocytic/myelomonocytic leukemia.

[Chronic renal insufficiency. Low-protein diet supplemented with essential amino acids and ketoanalogues]. / Insufficienza renale cronica. Dieta ipoproteica supplementata con aminoacidi essenziali e chetoanaloghi.

Conventional conservative treatment of chronic uremia is aimed at reducing protein intake to a minimum level compatible with nitrogen balance. A great progress in this field is represented by a low protein diet associated with some essential aminoacids and ketoanalogues. A group of 20 patients with chronic renal failure at an advanced stage has been studied and good results have been obtained with a low protein diet (0.2 g/kg/24 h vegetable proteins) associated with essential aminoacids and ketoanalogues.