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Background: Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis. Methods: In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up. Results: In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories. Conclusions: The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class. Keywords: 7-gene test; cancer; cytopathology; fine-needle aspiration; molecular diagnostics; thyroid.

The efficacy and safety of low dose oral valgancyclovir (VGCV) as cytomegalovirus (CMV) reactivation prophylaxis was retrospectively evaluated in 32 consecutive patients which underwent allogeneic HLA-matched related and unrelated hematopoietic stem cell transplantation (HSCT). Thirty HSCT recipients showed pretransplant CMV seropositivity. Fifteen received a myeloablative conditioning regimen, while seventeen patients received a reduced-intensity conditioning regimen. Twenty-one patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporin A (CsA) and methotrexate (MTX), and the others CsA with MTX and anti-thymocyte globulin. CMV infection was monitored weekly using polymerase chain reaction (PCR). VGCV was administered orally at a dose of 450 mg daily for six months. Six patients developed a positive CMV-PCR on average 56 days after HSCT successfully treated with VGCV at 1800 mg/day, except one who developed fatal gastrointestinal CMV disease. At the time of CMV reactivation, four patients had been affected by grade II-IV acute GVHD and two by an extensive chronic GVHD. No significant specific VGCV-related toxicity was encountered. Seven patients presented hematological toxicity which did not require drug discontinuation. Our data suggest that low dose VGCV is safe and effective as CMV reactivation prophylaxis in allogeneic HSCT recipients. These results require further validation in prospective randomized studies.

Technetium-99m-sestaMIBI is a reliable positive tracer of skeletal lesions in multiple myeloma (MM), while bone scintigraphy by 99mTc-MDP and 67Ga scanning are considered of negligible value. We report the case of a young patient with a 5-year history of light chain MM, which was not eradicated by chemotherapy, radiotherapy, allogeneic bone marrow transplantation, α-interferon and donor lymphocyte infusion. In the final phase of the disease a CT scan showed a 14 cm mediastinal mass (Figure 1A). The neoplastic tissue took up 67Ga more avidly than 99mTc-sesta MIBI (Figures 1B-C), and focal bone lesions showed 67Ga uptake even in areas negative by MIBI scan. The patient died of disease progression in a few months. It seems that a 67Ga scan can identify patients with very aggressive MM.

Schwannoma originating from the cervical vagus nerve is an extremely rare neoplasm. Vagal nerve schwannoma usually occurs between the third and fifth decades of life, it does not show sex predilection both sexes being equally affected and it most often presents as a painless, slow-growing, lateral neck mass. The treatment of choice is complete surgical excision with preservation of the neural pathway, when it is possible. These tumours, in fact, are almost always benign and a conservative surgical approach is emphasized by most of the Authors. A case of a cervical vagal schwannoma, in a 33-year old male with a previous medical history of malignant lymphoma, is described. The clinical features, diagnosis, management and pathological findings of cervical vagal schwannoma are discussed.

The frequency of neuromonitoring during thyroid surgery is underreported in Italy. The present survey depicts and describes the patterns of use, management, documentation for IONM devices of IONM during thyroid surgery by surgeons in Italy. A point prevalence survey was undertaken. Source data were mixed from Italian surgeons attending the 2014 International Neuromonitoring Study Group (INMSG) meeting, four IONM manufacturers available in Italy and surgical units were identified from Company sales data. Qualitative and quantitative data were used to analyze. Questions probed IONM prevalence, surgeon background, hospital geographic practice locations, type of hospital, rationale for IONM use, sources of initial capital investment for IONM acquisition, type of equipment, use of continuous IONM, monitoring management, use of distinctive standards, and IONM documentation. IONM is currently delivered through 48 units in Italy. In 2013, the distribution of IONM by specialties included: general (50 %), ENT (46 %), and thoracic surgery (4 %). Overall, 12.853 IONM procedures were performed in the period from 2006 to 2013: 253 were performed in 2007 and about 5,100 in 2013. Distribution according to the type of hospital is: public 48 %, academic setting 37 %, and private maintenance 15 %. The use category of high volume thyroid hospitals represented 33 %. Initial capital investment for the acquisition of the monitoring equipment was 67 % public and 33 % with charitable/private funding. Audio plus graphic and EMG electrodes surface endotracheal tube-based monitoring systems accounted for the majority. Continuous IONM was introduced in 5 Academic Centers. Overall motivations expressed are legal (30 %), RLN confirmation (20 %), RLN identification (20 %), prognosis (10 %), helpful in difficult cases (10 %), decrease surgical time (5 %), and educational (5 %). The survey revealed that participants had few experience with the standardized approach of IONM technique (28 %). General IONM information to patients and/or subsequent specific IONM informed consent was initiated in 8 % of centers. EMG determinations were included in medical chart in 20 %. There were no significant associations found between all parameters considered. The present study describes an increased utilization of IONM in Italy. We highlighted areas for improvement in the management and documentation of IONM.

Functional inactivation of the tumor suppressor p27(kip1) in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration. Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27(kip1) is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells. Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27. Results obtained with phospho-specific antibodies and with transfection of nonphosphorylable p27(kip1) mutant constructs demonstrated that PI3K/AKT-dependent regulation of p27(kip1) mislocalization in thyroid cancer cells occurred via phosphorylation of p27(kip1) at T157 and T198 (but not at S10 or T187). Finally, we evaluated whether these results were applicable to human tumors. Analysis of 100 thyroid carcinomas indicated that p27(kip1) phosphorylation at T157/T198 and cytoplasmic mislocalization were preferentially associated with activation of the PI3K/AKT pathway. Thus the PI3/AKT pathway and its effector p27(kip1) play major roles in thyroid carcinogenesis.

Large granular lymphocytes derive from two major lineages: one expressing the CD3 surface antigen (T-lymphocytes), and the other lacking this marker (NK-cells). Although developmental overlaps between natural killer cells and T-cells have been described, malignancies derived from these two cell types are considered as distinct lymphoid disorders.We report the case of a 30-year old man affected by a lymphoma/leukemia syndrome presenting with hepatosplenic lymphoma which rapidly transformed into aggressive NK-leukemia. Extensive flow cytometry studies and molecular analysis were repeated during the course of the disease, and showed an unexpected changing pattern.At diagnosis, flow cytometry analysis showed the co-existence of two cell populations, one CD56(+), CD3(+), TcRgd(+), and the other CD56(+), CD3(-) and TcRgd(-). Molecular analysis showed that the TcR genes had the same clonally rearranged pattern involving b, g and d genes in both populations. At disease relapse and during the terminal refractory phase, only CD3(-) cells were present.This is an unusual case of CD56(+) aggressive lymphoma/leukemia characterized by the clonal expansion of two phenotypically different cell populations, variably balanced during the course of the disease. The presence of the same TcR genomic rearrangement suggests the origin from a common progenitor able to differentiate along both T- and NK-pathways.

Cerebral toxoplasmosis is a rare late complication in allogeneic bone marrow transplanted patients. Neuroradiological findings may suggest the correct diagnosis. We report a patient in whom cerebral magnetic resonance imaging (MRI) showed a lesion characteristic of toxoplasmosis. Anti- toxoplasma treatment led to clinical and radiological improvement. MRI seems to be a valid tool for detection and follow-up of cerebral toxoplasmosis.

The authors described a case of hernia of Morgagni-Larrey in aged patients with an acute sub-occlusive symptomatology. This type of diaphragmatic hernia is uncommon and characterized by an aspecific symptomatology which realize different problems in children and adult patients, in whom diagnosis can be made incidentally, executing analysis for other pathologies. Using Marlex mesh to repair hernia represents an improvement of surgery, because it enables to repair a great hernia with a better result, and no recurrence.

The aim of the study was to draw up a management protocol in thyroid surgery promoted by the Italian Association of Endocrine Surgery Units (Club delle UEC), shared by the experts and applied by the operators in the sector. The management protocols already presented in February 2002 and drawn up by the first Author of the present publication on the occasion of the current review were examined by the I Consensus Conference called on the topic by the Italian Endocrine Surgery Units. The conference comprised two distinct sessions, the first on 18 June 2005 within the framework of the 4th National Congress of the Club delle UEC in Naples, and the second on 17 September 2005 within the framework of the 8th Multidisciplinary Scanno Prize Meeting. A selected board of endocrinologists and endocrine surgeons, chaired by Aldo Pinchera and comprising the first nine Authors of this paper, examined the individual chapters in close collaboration with the other Authors, comparing their findings with the opinions of the experts cited in the text and submitting the consensus text for the approval of all those present. The diagnostic, therapeutic and healtcare management protocols in thyroid surgery approved by the I Consensus Conference are officially those proposed by the Italian Association of Endocrine Surgery Units (Club delle UEC) and are subject to review by October 1, 2007.

In the surgical treatment of rectal cancer, local recurrence has a high incidence up to 40% of cases. The introduction of stapling techniques permit the execution of conservative surgery with increasing frequency, to which are wrongly associated a major rate of local recurrence. In effect in the localization of midrectal cancer, at the same stage, the abdominoperineal resection and the anterior low resection have the same long term results. Residual disease is due to no removing lymphatic perivisceral tissue (mesorectum, pelvic lymphatic cell tissue), when is respected a distal clearance from the tumour's margin of 2 cm. The authors on the base of their experience and reported data, examine pathogenetic factors responsible for local recurrence and curative surgical principles. Anterior resection remains the elective operation in midrectal cancer when it is realized with completely removal of mesorectum and with "en bloc" abdominopelvic lymphadenectomy in selected cases. In Duke's C-D stages the preservation of sphincters is always to be preferred, because abdominoperineal resection doesn't assure a curative result with a better quality of life in low anterior resection.

Rectal Prolapse is a rare and distressing condition, with a multifactorial etiopathogenesis. Often, this pathology is associated with fecal incontinence. The recommended approach to the patient with rectal prolapse and fecal incontinence is to repair the prolapse first, then deal particularly with fecal incontinence at a second operation. A retrospective, clinical and manometric study has varying degrees of fecal incontinence. Clinically five of their operation, and a further three patients improved, in two patients the degree of fecal incontinence remained invariable. One patient was worsened after surgery. Manometrically resting and pressure (RAP) was significantly higher in continent patients than in voluntary contraction pressure (MVCP) (p0.05) in preoperative testing. Postoperatively, there was a significant increase in the resting anal pressure as well as in maximum voluntary contraction pressure. Patients who remained incontinent had a significantly lower RAP and MVCP than patients who improved our regained continence. In conclusion this study shows an alteration of internal and external sphincteric function in patients with rectal prolapse. The surgical treatment of this disease improves sphincteric function. Incontinent patients with RAP10 mmHg and MCVP20 mmHg, probably they would be better treated simultaneously either for rectal prolapsus and incontinence. In this kind of patients the perianal proctectomy with total sphincteroplasty could be the elective treatment.

Parathyroid carcinoma is a rare malignancy. We report the case of a 66 years old man referred to our department for a large substernal goiter suspected as a thyroid cancer associated with severe hyperparathyroidism. After normalization of serum levels of calcemia, total thyroidectomy and subtotal parathyroidectomy was performed. Histopathology revealed a parathyroid cancer of 450 g.

Two cases of a right non-recurrent laryngeal nerve were encountered during the performance of 992 thyroid operations. In its abnormal non-recurrent course the nerve passes transversely from under the carotid sheat hand takes a position which is at right-angles to the normal recurrent laryngeal nerve.

Leydig's cells tumor account for 1-2% of all testicular tumors. The authors report a rare case of benign Leydig's cells tumor in a young man with gynecomastia. They examine the embryogenesis, the hormonal modifications, the criteria of malignancy, the treatment and results. They present a review of the literature pertaining to this rare tumors.

The authors discuss the problems in the diagnosis and treatment of pancreatic pseudocysts; they emphasize the risk of complication. The authors discuss their personal experience in the treatment of 31 pancreatic pseudocysts using the different techniques, and the very good results they observed in their own series.

Overexpression of thymosin beta-10 (TB10) has been shown in rat thyroid transformed cell lines, and in human thyroid carcinoma tissues and cell lines. To investigate whether TB10 detection could be a valid tool in the diagnosis of human thyroid neoplasias, we extended the analysis of TB10 expression to a large number of thyroid hyperproliferative and neoplastic tissues using an immunohistochemical assay. Our analyses showed a TB10 positive staining in all human thyroid carcinomas particularly in the anaplastic histotypes, whereas no TB10 immunostaining was observed in normal thyroid, in adenomas and the majority of the goiters. These results suggest that the evaluation of TB10 gene expression may be considered a promising means of diagnosis of human thyroid hyperproliferative disorders.

BACKGROUND: Intrathyroid metastases (ITM) are rare and usually have a dismal prognosis. The aim of this study was to detect which neoplasms metastasize most often to the thyroid gland, their clinical features and treatment options. MATERIALS AND METHODS: Retrospective analysis of clinical files of 17,122 patients submitted to surgery for thyroid disease between 1995 and 2005. Twenty-five patients (median age 61 years) were affected by ITM. RESULTS: The site of the primary tumor was: kidney (15), lung (4), colon (3), breast (1), melanoma (1), and unknown in 1 patient. Ten patients (40%) complained of preoperative symptoms, in the others, thyroid involvement was incidentally discovered during the follow-up for the primary cancer. Twenty patients (80%) underwent total thyroidectomy, 3 received thyroid lobectomy and 2 palliative procedures. Morbidity was 16%, mortality was nil. The median follow-up was 24 months. CONCLUSION: ITM should always be suspected in any patient with a previous history of malignancy. Fine-needle agobiopsy (FNAB) with immunohistochemical stains may help in preoperative workup. A long delay between the primary tumor and the recurrence warrants surgery and total thyroidectomy seems to be the treatment of choice because of the multifocality of metastasis to the thyroid gland

Drainage in thyroid surgery is still an area of controversy. We analysed the results of a prospective randomised trial conducted in our institution in order to assess the utility of drainage after thyroid surgery. Sixty patients were entered into the study, thirty of whom were drained after surgery and thirty who received no drainage. The two groups were well matched with regard to most characteristics. There was no difference between the two groups in terms of early or late postoperative complications. We therefore conclude that, in our experience, drainage after uncomplicated thyroid surgery is of no benefit.

Merkel cell carcinoma (MCC) is a rare, malignant skin cancer, exhibiting neuroendocrine differentiation, with a significant incidence of locoregional lymph nodal involvement (40%-73%). The accepted staging system classifies MCC as: stage I, localized skin disease; stage II, regional lymph node disease; stage III, metastatic disease. The clinical differentiation of stage I and II patients is difficult and understaging is frequent. Surgery, as first approach, represents the leading treatment for this neoplasm and, depending on stage consists in: local wide excision for stage I patients and local excision and lymphadenectomy for stage II. In our experience, lymphadenectomy, included in the initial treatment of all stage II patients, seemed to influence positively the prognosis. In comparing stage related recurrence and survival rates the results we obtained were better in stage II patients, where lymphadenectomy was included in the initial treatment than in stage I subjects, who received local excision alone as first treatment and lymphadenectomy as secondary treatment for nodal recurrence (overall recurrence rate 86% vs 20%, survival rate 71% vs 80% in stage I vs stage II patients). The performance of lymphadenectomy for stage I MCC could be reconsidered both for a more reliable staging of the disease and for a positive impact on recurrence and survival rates.

The purposes of this article are to review the history and evolution of neck dissections, including an update on node levels and their anatomical landmark. A number of classification systems were proposed and subsequently established for neck dissection procedures. The system most often employed was published in 1991 by the American Head and Neck Society and American Academy of Otolaryngology- Head and Neck Surgery and revised in 2002 and 2008. According to this classification, neck dissections are grouped into four broad categories: radical neck dissection (RND), modified radical neck dissection (MRND), selective neck dissection (SND) and extended neck dissection (ERND). The choice between different surgeries depends on type and site of head and neck tumor as well nodal involvement.

Introduction: Lymph node (LN) fine needle aspiration cytology (FNAC) is a safe, quick, inexpensive, reliable, and minimally invasive technique for the diagnosis of lymphadenopathies. Recently, an international committee of experts proposed guidelines for the performance, classification, and reporting of LN-FNAC: the Sydney System. We set out to analyse the diagnostic performance of the Sydney System in a retrospective study. Methods: We retrieved 1458 LN-FNACs, reformulated the diagnoses according to the Sydney System, and compared them to the histological control where available (n = 551, 37.8%). Results: The risk of malignancy for each of the five categories was 66.7% for inadequate/insufficient, 9.38% for benign (overall: 0.84%), 28.6% for atypical, 100% for suspicious and 99.8% for malignant. LN-FNAC showed a sensitivity of 97.94%, a specificity of 96.92%, a positive predictive value of 99.58%, and a negative predictive value of 86.30%. Conclusions: These data support the usage of LN-FNAC as an agile first-level technique in the diagnosis of lymphadenopathies. The Sydney System supports and enhances this role of LN-FNAC, and its adoption is encouraged. In negative cases, coupled with ancillary techniques, LN-FNAC can reassure the clinician regarding the benignity of a lymphadenopathy and indicate the need for clinical follow-up, which will catch possible false negatives. In positive cases, LN-FNAC can provide sufficient information, including predictive biomarkers, to initiate management and obviate the need for subsequent, more invasive procedures. Given its speed, minimal invasiveness, and low cost, LN-FNAC can be performed in most cases, even when more invasive techniques are not feasible.

Background Ruxolitinib (Ruxo), an orally bioavailable and selective inhibitor of JAK1 and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea (HU) might improve hematological response. Aims: To evaluate the efficacy and safety of Ruxo and HU combination. Methods This observational multicenter study, conducted from April 2012 to April 2017, enrolled 20 adult patients with a confirmed diagnosis of primary myelofibrosis (PMF), post-polycythemia vera (PPV-MF), or post-essential thrombocythemia (PET-MF) with hyperproliferative manifestations of the disease not controlled by Ruxo therapy. All patients we enrolled into the study had received Ruxo at a starting dose based on baseline platelet count. Patients were included into the study when Ruxo proved to be unable to reduce WBC and/or platelet count to within normal range (WBC Results The addition of HU was started after a median time of ruxolitinib monotherapy of 6.5 months (range 1-49.6 months): 17 patients (85%) started HU treatment due to lack of WBC control, whereas the remaining 3 patients (15%) started for the lack of platelet control. While on Ruxo monotherapy, ten patients (50%) needed a dose reduction due to hematological toxicity and three patients temporarily discontinued Ruxo due to severe thrombocytopenia (15%). After 14.5 months (range 2-195) median time of combination therapy in 8 patients the Ruxo daily doses increased (mean increase = 5.1 mg BID), in 9 the dose was unchanged despite the addition of HU, and only in three cases the ruxolitinib dose had to be reduced (mean reduction = 3.4 mg BID). Overall, the mean daily dose of Ruxo administered to the whole cohort of patients increased by 1.8 mg BID (P=.013), and only one patient had to discontinue Ruxo, due to severe thrombocytopenia. Non-hematological adverse events were not observed. Among the 17 patients who started combination therapy to control WBC count, 14 (82.3%) obtained a WBC response, whereas, among the three patients who started HU in association with Ruxo in order to reduce platelets count, two (66.6%) achieved a platelet response. In addition, 12 patients of the whole study cohort had clinical improvement in MF-associated symptomatic burden, with 9 of them showing spleen and symptoms response and the remaining three only spleen response. Thus, a clinical response of any type was obtained in 8 patients (40%) during Ruxo monotherapy and in 17 patients (85%) during Ruxo-HU combination (P=.003). Of note, all 8 patients in which Ruxo dose was increased during combination had at least one type of drug-related clinical response. Conclusion In conclusion, the combination of HU with Ruxo yielded a high clinical response rate and increased Ruxo exposure in patients with hyperproliferative forms of MF. The association was very well tolerated, and the hematological toxicities mostly and were generally manageable with dose reductions and/or supportive treatment. Disclosures Pane: AMGEN: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau.

The most appropriate surgical management of "follicular neoplasm/suspicious for follicular neoplasm" lesions (FN), considering their low definitive malignancy rate and the limited predictive power of preoperative clinic-diagnostic factors, is still controversial. On behalf of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB), we collected and analyzed the experience of 26 endocrine centers by computerized questionnaire. 1379 patients, surgically treated after a FN diagnosis from January 2012 and December 2103, were evaluated. Histological features, surgical complications, and medium-term outcomes were reported. Total thyroidectomy (TT) was performed in 1055/1379 patients (76.5 %), while hemithyroidectomy (HT) was carried out in 324/1379 cases (23.5 %). Malignancy rate was higher in TT than in HT groups (36.4 vs. 26.2 %), whereas the rates of transient and definitive hypoparathyroidism following TT were higher than after HT. Consensual thyroiditis (16.8 vs. 9.9 %) and patient age (50.9 vs. 47.9 %) also differed between groups. A cytological FN diagnosis was associated to a not negligible malignancy rate (469/1379 patients; 34 %), that was higher in TT than in HT groups. However, a lower morbidity rate was observed in HT, which should be considered the standard of care in solitary lesions in absence of specific risk factors. Malignancy could not be preoperatively assessed and clinical decision-making is still controversial. Further efforts should be spent to more accurately preoperatively classify FN thyroid nodules. The most appropriate surgical management of “follicular neoplasm/suspicious for follicular neoplasm” lesions (FN), considering their low definitive malignancy rate and the limited predictive power of preoperative clinic-diagnostic factors, is still controversial. On behalf of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB), we collected and analyzed the experience of 26 endocrine centers by computerized questionnaire. 1379 patients, surgically treated after a FN diagnosis from January 2012 and December 2103, were evaluated. Histological features, surgical complications, and medium-term outcomes were reported. Total thyroidectomy (TT) was performed in 1055/1379 patients (76.5 %), while hemithyroidectomy (HT) was carried out in 324/1379 cases (23.5 %). Malignancy rate was higher in TT than in HT groups (36.4 vs. 26.2 %), whereas the rates of transient and definitive hypoparathyroidism following TT were higher than after HT. Consensual thyroiditis (16.8 vs. 9.9 %) and patient age (50.9 vs. 47.9 %) also differed between groups. A cytological FN diagnosis was associated to a not negligible malignancy rate (469/1379 patients; 34 %), that was higher in TT than in HT groups. However, a lower morbidity rate was observed in HT, which should be considered the standard of care in solitary lesions in absence of specific risk factors. Malignancy could not be preoperatively assessed and clinical decision-making is still controversial. Further efforts should be spent to more accurately preoperatively classify FN thyroid nodules.

We have analysed the expression of the HMGA2 gene in a panel of normal and neoplastic thyroid tissues by immunohistochemistry and quantitative RT-PCR. HMGA2 protein was detectable in four out of 21 follicular carcinomas, 30 out of 45 papillary carcinomas, and 11 out of 12 undifferentiated carcinomas. As far as follicular thyroid adenomas are concerned, only three cases of the 31 analysed showed HMGA2 protein expression, whereas it was absent in seven normal thyroid tissues and in 12 hyperplastic nodules. Quantitative RT-PCR showed that almost all the papillary thyroid carcinomas and 13 out of 16 follicular thyroid carcinomas express much higher HMGA2 specific mRNA levels in comparison to normal thyroids and adenomas. Therefore, our data support the quantitative RT-PCR analysis of HMGA2 expression, rather than immunohistochemistry, as a powerful tool for the diagnosis of thyroid neoplasias. (c) 2008 Elsevier Ltd. All rights reserved.

The CDC73 gene, encoding parafibromin, has been identified as a tumour suppressor gene both in hyperparathyroidism-jaw tumour (HPT-JT) syndrome and in sporadic parathyroid carcinoma. While the vast majority of CDC73 mutations affect the N-terminus or the central core of the encoded protein, as yet few mutations have been reported affecting the C-terminus. Here, we report a case (Caucasian female, 28 years) with an invasive ossifying fibroma of the left mandible and hyperparathyroidism (sCa = 16 mg/dl, PTH = 660 pg/mL) due to a parathyroid lesion of 20 mm, hystologically diagnosed as carcinoma. The whole CDC73 gene was screened for the presence of mutations by Sanger sequencing. Immunohistochemistry, in vitro functional assays, Western blotting, MTT assays and in-silico modelling were performed to assess the effect of the detected mutation. Sequence analysis of the CDC73 gene in the proband revealed the presence of a novel deletion affecting the C-terminus of the encoded protein (c.1379delT/p.L460Lfs*18). Clinical and genetic analyses of the available relatives led to the identification of three additional carriers, one of whom was also affected by a parathyroid lesion. Immunohistochemistry, Western blotting, MTT and in-silico modelling assays revealed that the deletion leads to down-regulation of the mutated protein, most likely through a proteasome-mediated pathway. We also found that the deletion may cause a conformational change in the C-terminus of the protein, possibly affecting its interaction with partner proteins. Finally, we found that the mutant protein enhances cellular growth. We report a novel mutation in the CDC73 gene that may underlie HPT-JT syndrome. This mutation appears to affect the C-terminal moiety of the encoded protein, which is thought to interact with other protein partners. The identification of these partners may be instrumental for our understanding of the CDC73-associated phenotype.

Introduction: Kinase inhibitors (KIs) are a class of anticancer drugs that inhibit activity of the enzymes protein kinases, which regulate crucial cellular processes and have a demonstrated role in human oncogenesis. Treatment of advanced forms of endocrine cancer which are not responsive to cytotoxic chemotherapies is challenging and use of KIs is gaining a growing role in this field. Areas covered: The authors summarize the main genetic alterations known to be linked to endocrine tumors, indicating the rationale for utilizing KIs. Furthermore, they present an updated analysis of clinical trials available on PubMed Central, which were pertinent to the activities of KIs in aggressive endocrine cancer. The authors also discuss the adverse effects of KIs and summarize likely involved underlying mechanisms. Expert opinion: KIs are effective in obtaining a radiological disease control and an improvement of progression-free survival in several forms of endocrine cancer but will never deliver a knockout blow of the disease, due to mechanisms of adaptation to circumvent the specific molecular blockade. The new frontier of KIs treatment is to identify agents that could synergize activity of KIs. The true goal will be to perform an overall genotyping of each tumor, thus predicting the impact of combined targeted therapies in the context of a particular constellation of mutant genes.

CONTEXT AND OBJECTIVES: The prognosis of medullary thyroid carcinoma (MTC) depends on the completeness of the first surgical treatment. To date, it is not possible to predict whether the tumor has been completely removed after surgery. The aim of this study was to evaluate the reliability of an intraoperative calcitonin monitoring as a predictor of the final outcome after surgery in patients with MTC. PATIENTS AND METHODS: Twenty patients underwent total thyroidectomy and central lymph node dissection on the basis of a positive pentagastrin test. In six cases a preoperative diagnosis of MTC was achieved at the cytological examination. During the surgical intervention, calcitonin was measured at the time of anesthesia, at the time of manipulation, and 10 and 30 min after surgical excision. At the histological examination, 10 patients had MTC and 10 had C cell hyperplasia. RESULTS: As compared with calcitonin levels before thyroidectomy, a decrease of calcitonin greater than 50% 30 min after surgery was able to significantly distinguish patients who were cured from those who experienced persistence of disease. It was not possible to find a similar result when the decrease of calcitonin 10 min after surgery was considered. CONCLUSIONS: A rate of calcitonin decrease less than 50% 30 min after thyroidectomy plus central neck lymph node dissection suggests the persistence of tumor tissue in patients operated for MTC. These results indicate that intraoperative calcitonin monitoring may be a useful tool to predict the completeness of surgery in patients with MTC.

AML patients (total 129; median age =50 years; range 16-72) in first CR received BU and melphalan (BU/Mel) as conditioning regimen before auto-SCT. In all, 82 patients (63.6%) received PBSCs and 47 patients (36.4%) received BM cells. The distribution of cytogenetic categories was conventionally defined as favorable (15.5%), intermediate (60.1%) and unfavorable (24.3%). With a median follow-up of 31 months, the 8-year projected OS and disease-free survival (DFS) was 62 and 56% for the whole population, respectively. The relapse rate was 46% and the non-relapse mortality was 4.65%. Although PBSC transplantation led to a faster hematological recovery than BM transplantation, in univariate analysis the stem cell source, cytogenetics and different BU formulations did not significantly affect OS and DFS, whereas age and the number of post-remission chemotherapy cycles did have a significant effect on the clinical outcome. Multivariate analysis identified age

Summary Background and Objectives Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-secreting neuroendocrine tumour originating from thyroid C cells. Serum CT concentrations are helpful in the early detection of MTC, while it is still unclear whether they can be used also for the differential diagnosis between MTC and C-cell hyperplasia (CCH), a precancerous condition in familial MTCs but with unclear clinical significance in sporadic MTCs. Nowadays, surgery is recommended in all patients with basal or pentagastrin (PG)-stimulated CT value of 100 pg/ml or more, without discriminating if they are affected with MTC or CCH only. The objective of this study was to investigate the utility of the PG test for CT in distinguishing CCH from MTC before surgery. Patients and Methods Sixteen of 20 patients with thyroid nodules and basal CT levels between 15 and 100 ng/l had a positive PG test (>100 ng/l PG CT peak) and form the basis of the data analysis. A diagnosis of MTC was histologically proved on surgical samples in seven patients and of CCH in nine other patients. Four patients with neither FNAB nor PG test consistent with a diagnosis of MTC did not undergo thyroidectomy. Results A peak of CT of 275 ng/l after PG was able to significantly distinguish patients with MTC from patients with CCH, with 100% sensitivity and 89% specificity (P = 0·002). PG-stimulated calcitonin levels >275 ng/l had a positive predictive value (PPV) value for diagnosis of MTC of 100%, and PG-stimulated calcitonin levels

Ta k i n g h e r b a l - e x t ra c t s t o l o s e w e i g h t i s a n underestimated health hazard. Often, these products contain active agents that can cause acute liver damage. In this case report, a 22-year-old female patient, who presented with a feature of cholestatic syndrome, was so sure that the “natural products” were not dangerous that she did not inform her physicians that she had taken them, making their task that much more challenging. Clinical presentation mimicked acute cholecystitis and the patient underwent a cholecystectomy. Surgery was without any consequences and complications, although it did not completely cure the illness. She later admitted to having taken herbal remedies and this led to the correct diagnosis of phytotherapy-related hepatotoxicity and a successful therapeutic approach. The true incidence of phytotherapy-related hepatotoxicity and its pathogenic mechanisms are largely unknown. It is important to increase the awareness of both clinicians and patients about the potential dangers of herbal remedies.

The aim of the study was to draw up a management protocol in parathyroid surgery promoted by the Italian Association of Endocrine Surgery Units (UEC Club), based on the guidelines of the main international scientific societies and shared by the experts and applied by the operators in the sector.The management protocols, already presented in 2003, on the occasion of the current review were examined by the 1st Consensus Conference called on the topic by the Italian Association of Endocrine Surgery Units (UEC). The Conference comprised two distinct sessions, the first in November 2006 within the framework of the 5th National Congress of the UEC Club in Verona, and the second in September 2007 within the framework of the 10th Multidisciplinary Scanno Prize Meeting. A selected board of endocrinologists and endocrine surgeons examined the individual chapters and submitted the consensus text for the approval of several experts.The diagnostic, therapeutic and healthcare management protocols in parathyroid surgery approved by the 1st Consensus Conference are officially those proposed by the Italian Association of Endocrine Surgery Units (UEC Club) and are subject to review by October, 2009.

To report an unusual case of persistent thyrotoxicosis after treatment of Graves' disease, because of coexistence of struma ovarii.We report the clinical history, imaging studies, laboratory and pathologic data, and treatment in a patient with persistent hyperthyroidism after surgical treatment of Graves' disease. In addition, we discuss some aspects of the pathogenesis of hyperthyroidism due to functioning struma ovarii.A 42-year-old woman underwent near-total thyroidectomy for treatment of Graves' disease. Post-operatively, hyperthyroidism was still present. Methimazole was administered again, and performance of a 131I whole-body scan demonstrated a focus of intense uptake in the pelvis. Pelvic ultrasonography revealed a mass (11 by 8 by 7.1 cm) arising from the right ovary, with both solid and cystic components. Abdominal surgical exploration was performed, and the final histologic diagnosis was struma ovarii. The symptoms of hyperthyroidism diminished, and 3 weeks postoperatively, the thyroid hormone levels were in the hypothyroid range.In patients with refractory hyperthyroidism after thyroid surgical treatment, radioiodine scanning should be performed to diagnose or exclude the functioning profile of ovarian masses.

Context: We previously showed that BAG3 protein, a member of the BAG (Bcl-2-associated athanogene) co-chaperone family, modulates apoptosis in human leukemias. The expression of BAG3 in other tumor types has not been extensively investigated so far. Objective: The objective of this study was to analyze BAG3 expression in thyroid neoplastic cells and investigate its influence in cell apoptotic response to TNF-related apoptosis-inducing ligand (TRAIL). Design, Setting, and Patients: We investigated BAG3 expression in human thyroid carcinoma cell lines, including NPA, and the effect of BAG3-specific small interfering RNA on TRAIL-induced apoptosis in NPA cells. Subsequently, we analyzed BAG3 expression in 30 benign lesions and 56 carcinomas from patients of the Naples Tumor Institute Fondazione Senatore Pascale. Main Outcome Measures: The main outcome measures were: analysis of BAG3 protein in NPA cells by Western blot and immunocytochemistry; analysis of apoptosis in TRAIL-stimulated NPA cells by flow cytometry; and evaluation of BAG3 expression in specimens from thyroid lesions by immunohistochemistry. Results: BAG3 was expressed in human thyroid carcinoma cell lines; small interfering RNA-mediated downmodulation of its levels significantly (P < 0.0195) enhanced NPA cell apoptotic response to TRAIL. The protein was not detectable in 19 of 20 specimens of normal thyroid or goiters, whereas 54 of 56 analyzed carcinomas (15 follicular, 28 papillary, and 13 anaplastic) were clearly positive for BAG3 expression. Conclusions: BAG3 downmodulates the apoptotic response to TRAIL in human neoplastic thyroid cells. The protein is specifically expressed in thyroid carcinomas and not in normal thyroid tissue or goiter.

Liver disease is a frequent complication in bone marrow transplant recipients and may occur early or late in the post-transplant period. Using ultrasound-guided fine needle (1.2 mm, 18 G) cutting biopsy, we studied six patients with undefined late post-BMT liver disease. No procedure-related complications occurred and all liver biopsies were informative, leading to changes in therapeutic approach. In our small series, the most frequent cause of hepatic damage was drug toxicity. US-guided fine needle cutting biopsy is a useful and easy tool for the work-up of unexplained post-BMT liver disease.

The risk of severe hepatic damage in patients with chronic hepatitis B virus (HBV) infection is well known; more effective treatments for this infection are needed. Lamivudine is being studied in immunocompetent and immunosuppressed HBV infected patients. We report a patient suffering from chronic replicative HBV infection after allogeneic BMT, who responded to lamivudine therapy. A 24-year-old woman with CML received an allogeneic BMT from her HLA-identical sister in June 1992. Before transplant, her HBV status demonstrated viral contact without active infection (HBsAb+, HBcAb+ IgG, HBeAb+). Four months after BMT mild chronic liver GVHD appeared, requiring immunosuppressive treatment. Antibodies to HBV completely disappeared post-transplant. Acute icteric hepatitis occurred 2 years later, with HBsAg+, high level of HBV-DNA, HBeAg+ and HBcAb IgM+. Lamivudine 100 mg/day rapidly reduced transaminase levels and effected HBV-DNA disappearance within 2 months. The treatment was well tolerated; no hematological side-effects occurred. This preliminary observation warrants further investigation of lamivudine treatment in bone marrow transplanted patients with active HBV infection.

A variety of immunohematological complications may occur after ABO-incompatible BMT. We report a CML patient (blood group O) who received a BMT from an HLA-identical sibling (blood group AB). The transplant was followed by normal myeloid and megakaryocytic engraftment, but erythroblastopenia persisted for more than 200 days after BMT. By bone marrow culture studies, a complement-dependent serum inhibitor of hemopoiesis was detected, suggesting immunological inhibition of erythropoiesis. The patient was resistant to a number of treatments such as intravenous gamma-globulins, prednisolone and high-dose erythropoietin. Full engraftment with normal blood counts and marrow cellularity was achieved after two dose-escalating CD34+-enriched donor lymphocyte infusions (DLI). This experience suggests that CD34+-enriched DLI may be an effective treatment for patients with delayed engraftment or late graft failure due to major ABO-incompatibility.

The present management of onco-haematologic patients may require continuous infusion of cytotoxic drugs, use of drugs or concentrated ion solutions which are toxic for the endothelial wall of small vessels, infusion of large amounts of antibiotics or antimycotics, red blood cell and platelet transfusion, and not rarely parenteral nutrition. Such a complex therapy needs a vascular access by a central vein catheter (CVC) insertion. Many types of CVC are available at present: tunnelled Hickman or Hickmanlike catheters, subcutaneous ports, tunnelled catheters with Groshong valve, external untunnelled catheters.

The pressure profile of the anal canal results from the effects of several muscles mainly the internal and external anal sphincter and the puborectalis. The preliminary results of radial manometric study of the anal canal carried out in 36 healthy volunteers, are reported. Based on the obtained results it is concluded that the anal canal shows a statistically significant difference in the radial distribution of pressure. The anatomo-physiologic mechanisms underlying this phenomenon, are discussed.