HMGB1-Induced Cross Talk between PTEN and miRs 221/222 in Thyroid Cancer.

High mobility group box 1 (HMGB1) is an ubiquitous protein that plays different roles in the nucleus, cytoplasm, and extracellular space. It is an important DAMP molecule that allows communication between damaged or tumor cells and the immune system. Tumor cells exploit HMGB1's ability to activate intracellular pathways that lead to cell growth and migration. Papillary thyroid cancer is a well-differentiated tumor and is often used to study relationships between cells and the inflammatory microenvironment as the latter is characterized by high levels of inflammatory cells and cytokines. Anaplastic thyroid cancer is one of the most lethal human cancers in which many microRNAs and tumor suppressor genes are deregulated. Upregulation of microRNAs 221 and 222 has been shown to induce the malignant phenotype in many human cancers via inhibition of PTEN expression. In this study we suggest that extracellular HMGB1 interaction with RAGE enhances expression of oncogenic cluster miR221/222 that in turn inhibits tumor suppressor gene PTEN in two cell lines derived from human thyroid anaplastic and papillary cancers. The newly identified pathway HMGB1/RAGE/miR221/222 may represent an effective way of tumor escape from immune surveillance that could be used to develop new therapeutic strategies against anaplastic tumors.

Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrast-enhanced ultrasound for the evaluation of thyroid nodules: preliminary experience.

PURPOSE: To assess the effectiveness of semiquantitative elastosonography (Q-elastography) compared with contrast-enhanced ultrasound (CEUS) in differentiating the nature of thyroid nodules. METHODS AND MATERIALS: Forty-eight consecutive patients (35 males, 13 females, range: 34-69 years, mean: 49.4 years), candidate to surgery, previously detected at color-Doppler ultrasound (CDUS), were prospectively examined with elastosonography with dedicated semiquantitative software (Q-Elastography, Toshiba XG) and CEUS (Technos Mylab 70 Gold X, and Toshiba XG) before surgery. CEUS and elastosonography were evaluated by two investigators in consensus. Comparison between the CEUS pattern and elastonographic strain ratio observed and expected frequencies for the diagnoses was evaluated with χ(2) test or with Fisher exact test. RESULTS: Fifty-three nodules (19 papillary carcinoma, 32 hyperplasia, and 2 follicular adenoma) in 48 patients were available for analysis. Regarding echogenicity score, sensitivity, specificity, PPV and NPV of conventional US were 81%, 50%, 56%, 77%; according to Q-elastography, sensitivity, specificity, PPV and NPV were 95%, 88%, 97% and 91% respectively; whereas concerning CEUS, sensitivity specificity PPV and NPV were 79%, 91%, 83% and 89% respectively. Both CEUS and Q-elastography were more specific than US (p<0.01), with not statistical significant difference with regard to sensitivity. CONCLUSIONS: The results of the present study suggest that Q-elastography is a valuable tool in the characterization of thyroid nodules and it seems to be more sensitive than CEUS.

Increasing diagnostic accuracy for thyroid nodules by an integrated multivariate approach: a methodological study.

OBJECTIVES: Current guidelines for diagnostic management of thyroid nodules are based on a linear approach, using categorial classifications to cluster diagnostic findings and they still lead to unnecessary surgery. A diagnostic scoring system, based on clinical, cytological and ultrasound findings is described. MATERIALS AND METHODS: Two groups of patients (168 and 55 pts) were used to compute a multivariate model and the discriminating threshold by ROC curves. The performance of the derived scoring system was assessed by a simulation on a third group of 60 patients, who had undergone surgery according to current guidelines. RESULTS: The scoring system displayed a sensitivity of 100%, specificity 53.3%, positive and negative predictive values of 68.1% and 100%. According to the scoring system, 16 out of 60 operations would have been saved. CONCLUSIONS: A scoring system can take into account in a more accurate way the full informative content of the fine-grained description of diagnostic and clinical features.

Risk of malignancy from thyroid nodular disease as an element of clinical management of patients with Hashimoto's thyroiditis.

BACKGROUND: Many studies have investigated the association between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC), but clinical management of this condition has never been addressed specifically, even in recent guidelines. Surprisingly the likelihood of a nodule as being cancerous in a CLT has never been explicitly expressed in terms of relative risk. METHODS: This study was based on a retrospective analysis of 404 patients undergoing total thyroidectomy. RESULTS: Sixty-nine patients (17.1%) had histological findings of true CLT, and 36.2% had concurrent PTC versus 22.6% of patients in the non-CLT group (p < 0.05), with a tumour risk in the CLT group of ×1.6 (95% CI = 1.21-1.94, likelihood ratio = +1.63). CONCLUSIONS: Patients with CLT and a nodular condition have a ×1.6 increased risk of harbouring a PTC. Moreover, these patients develop multicentric PTC more frequently, and, as a result, total thyroidectomy should always be considered.

[FT3 value is a possible risk indicator for patients undergoing vascular surgery]. / Il valore di FT3 è un possibile indicatore di rischio per pazienti sottoposti a chirurgia vascolare.

A study on 28 patients undergoing vascular surgery was performed with the aims to confirm the postoperative decrease of serum FT3 value, to study the correlation between Euthyroid Sick Syndrome (ESS) and postoperative complications, to detect a possible correlation between markers of severity of atherosclerosis and ESS. A slight but significant decrease in postoperative FT3 value was observed (3.88 +/- 0.73 vs 3.32 +/- 1.07 p < 0.05), while we could not find any difference in pre-postoperative FT4 and TSH values. Six patients developed inflammation-related complications (Systemic Inflammatory Response Syndrome--SIRS) and they all showed a deeper postoperative decrease of FT3 value than non complicated subjects, even if the difference was not statistically significant (1st postop day 3.60 +/- 1.05 vs 2.47 +/- 0.61 p = 0.06). Finally, a strong negative linear correlation was observed between preoperative fibrinogen value and FT3 (r = -0.48). FT3 value could be a good predictor of risk for inflammatory-related postoperative complications. Preoperative FT3 value in patients with atherosclerosis is inversely correlated with markers of inflammation activity, mainly with fibrinogen.

[Two centers with a native fistula prevalence higher than 90%: organization and activity]. / Due centri accomunati da una prevalenza di fistole con vasi nativi maggiore del 90%: attività e modelli organizzativi a confronto.

Vascular access (AV) dysfunction is a major cause of morbidity and hospitalisation in hemodialysis population. Despite of guidelines statements which consider native arteriovenous fistula (nAVF) the gold standard, epidemiological studies still show a decline in their prevalence with an increase of central venous catheters (CVC). In this study we compared the activity of two Dialysis Units both characterized by a high prevalence (> 90%) of nAVF, in order to highlight the possible reasons. No collaboration existed between the two centres until the decision to design this work. The "policy" on creation and management of vascular access and organizational models of the two centres were assessed, in particular focusing on surgeons, presence of dedicated nephrologists, preoperatory ultrasound evaluation, follow-up and diagnosis of complications, resort to interventional radiology, complications management, in particular the timing of intervention after AVF thrombosis. Of the two dialysis populations were analysed: age, time on dialysis, coexistence of diabetes and the prevalence of various types of vascular access to 31 December 2007. It was evaluated the AV incidence in the last 4 years. The statistical analysis was performed by T student and Chi square tests. There were no substantial differences in the organizational models of the two centres, which had both a routine ECD use in preoperatory mapping and in monitoring of complications; in case of thrombosis both centres performed surgery within 12-24 hours; in case of stenosis both centres performed the correction, surgical or by angioplasty, within 15 days from the diagnosis. Another common element was the presence of a multidisciplinary team with a interventionist nephrologist, a vascular surgeon and a vascular interventional radiologist, where nephrologist has the coordination role. The data analysis showed a prevalence of nAVF in the two centres of 92.5% and 96.1%, Pescara and Lecce respectively, with a prevalence of forearm nAVF of more than 80% and 90% respectively. The analysis of incident interventions showed high percentage of forearm AVF in case of revisions for complications (stenosis, thrombosis), and a little recourse to proximal AVF and graft.

[Clearances in automated intermittent peritoneal techniques: a new formula to use morning blood sampling]. / Clearances in tecniche peritoneali automatizzate intermittenti: una nuova formula per utilizzare il prelievo ematico del mattino.

According to the main guidelines, dialysis adequacy monitoring is fundamental in the management of patients on peritoneal dialysis. In order to avoid mistakes in the calculation of the peritoneal urea and creatinine clearance in patients on dialysis with intermittent techniques, the collection of blood samples about 6 hours after the end of the dialysis session is advised. In fact, because the creatinine and urea values at the end of dialysis (the morning values in NIPD) are the lowest, the resulting clearances could be overestimated. The mean values between the start and the end of the dialysis session are considered the gold standard. However, collecting a blood sample at 2.00 p.m. may be difficult and uncomfortable both for the nurse and the patient. In this paper we present two formulas (the first for urea and the second for creatinine) which, starting from the values at the end of dialysis, predict the values at the beginning of the session and consequently the mean values. The aim of this study was to validate the formulas by evaluating their capability to predict the mean urea and creatinine values when only end-of-dialysis blood sampling was performed. Statistical analysis was carried out using the Bland-Altman test. The two formulas proved able to predict the mean urea and creatinine values; the differences between the measured and calculated values were not statistically significant.

The use of different Peg-interferon alpha-2b regimens plus ribavirin in HCV-1b-infected patients after rapid virological response does not affect the achievement of sustained virological response.

In patients with chronic hepatitis C, rapid virological response (RVR) at week 4 of treatment seems to be strongly associated with a high probability of achieving a sustained virological response (SVR). The aim of this study was to investigate the outcome of different pegylated interferon-alpha2b (Peg-IFN-alpha2b) dosages plus ribavirin (RBV) in patients with RVR. Forty-five naïve patients chronically infected with hepatitis C virus (HCV)-1b started Peg-IFN-alpha2b (1.5 microg/kg/week) in combination with weight-based RBV doses (800-1200 mg/day). Thirty-one patients (68.9%) attained RVR at week 4 of therapy, while four further patients showed negative HCV-RNA values for the first time at week 12 and were considered early virological responders (EVR). The 31 RVR patients were randomized to receive either RBV plus 1.5 microg/kg/week (17 pts) or 1.0 microg/kg/week (14 pts) of Peg-IFN-alpha2b for the remaining 44 weeks. The two groups were matched for age, sex, baseline alanine aminotransferase levels, viral load and fibrosis score. After 6 months of post-treatment follow-up, the prevalence of SVR was 94.1% (16/17) among RVR patients treated with 1.5 microg/kg/week and 92.8% (13/14) in RVR patients treated with 1.0 microg/kg/week (P = not significant). A high-baseline viral load (P = 0.01) and bridging fibrosis/cirrhosis (P = 0.02) negatively influenced the likelihood of achieving RVR. On the contrary, the ability of RVR patients to achieve SVR did not correlate with these baseline characteristics in either of the treatment group. Finally, the SVR rate among EVR patients who responded after more than 4 weeks of treatment was significantly lower than among RVR patients (1/4 = 25%vs 29/31 = 93.5%; P = 0.0058), because of a high prevalence of post-treatment relapse among patients with EVR.

Microcarcinoma and incidental carcinoma of the thyroid in a clinical series: clinical behaviour and surgical management.

OBJECTIVES: Papillary thyroid microcarcinomas (PTM) have not yet an agreed clinical management. The Authors compared PTMs with papillary thyroid carcinoma of larger size (LPTC) and incidental and not-incidental carcinomas. MATERIALS AND METHODS: Review of clinical data of 67 patients (54 women, 13 men) prospectively stored in a standardised way in an electronic patient record system. RESULTS: There were 36 cases of microcarcinoma (53.7%). Differences were not significant between PTM and LPTC groups as to patients personal data, TNM and MACIS staging, nodal involvement (8.3% vs 19.3%) and multifocality (25% vs 38.7%) while capsular invasion was significantly higher in LPTC (25% vs 54.8%). Nineteen incidental tumors were detected at pathological examination and they were all microcarcinomas. They were smaller than the remaining 17 not-incidental microcarcinomas but showed a similar clinical behaviour. There were not cancer related deaths nor recurrences in the follow up period in any group. CONCLUSIONS: Despite the excellent prognosis of PTM, a subset of these tumours shows aggressive biological and clinical features, like nodal or capsular invasion and multifocality. Actually, with the exclusion of size, they do not show any relevant difference from differentiated thyroid carcinoma of larger size. Since predictive cytogenetic markers are still missing, their treatment should then be the same as for conventional thyroid cancers.

Lung metastases from differentiated thyroid carcinoma. A 40 years' experience.

AIM: Retrospective studies have been carried out to estimate the survival of 96 patients with lung metastases from differentiated thyroid carcinoma, observed from 1958 to 2000. METHODS: All patients had undergone total thyroidectomy. Case histories were analysed with respect to age at diagnosis, sex, histology, local lymph node involvement, size of lung metastases and 131I uptake by metastases. Survival functions were calculated. Cox regression was performed. RESULTS: There was no statistically significant difference in histological type and lymph node involvement, whereas a significantly longer survival time was observed in patients under 45 years of age at diagnosis (p= or <0.0001), in those with metastases concentrating 131I (p= or <0.0001) and in those with fine miliaric metastases (p=0.0037). Multi-variate analysis revealed that the risk of death increases about 5.4-fold in patients over 45 years old, whereas 131I treatment is likely to reduce this risk to nearly 1/6. Conclusion. In conclusion, in patients with lung metastases from differentiated thyroid carcinoma, young age at diagnosis and 131I uptake by metastases are the most important factors positively affecting survival time. Radioiodine therapy, also with high cumulative 131I activity, can lead to longer survival time or complete recovery.

[Clinical significance of thyroid nodule calcification]. / Significato clinico delle calcificazioni nei noduli tiroidei.

To confirm the predictive value of calcifications in thyroid nodules as a risk factor for malignancy and to detect specific aspects for tumours, in a set of 175 patients--30 papillary carcinoma (PC) and 145 multinodular goiters (MNG) with dominant nodule--calcifications were detected by ultrasound scan. Calcifications were significantly more frequent in PC than in MNG (40% vs 20.7% p < 0.05) but their considered characteristics (size, number, position, location in the gland, sonographic features of the nodule) did not show any particular difference between PC and MNG. The frequency of calcifications in our series was higher in older patients (mean age 58.7 +/- 13.3 vs 51.1 +/- 12.7 in patients without calcifications, p < 0.001) and this could imply that their onset is time-dependent. Calcifications can be a useful indicator of enhanced risk, to be considered in the overall process of surgical decision making.

What sedation to use during endoscopic procedure.

Many endoscopists sometimes prefer to perform endoscopies without anaesthetic support, using only benzodiazepines. Endogenous opioid peptides are believed to play an important role in the modulation of pain within the endogenous analgesic system. A group of 40 patients undergoing diagnostic and therapeutic Endoscopic Retrograde Cholangiography and Pancreatography (ERCP) was recruited. Patients were divided into 2 groups according to Visual Analog Scale: pain 1-5 (Group A) and pain 6-10 (Group B). The beta-endorphin baseline values were significantly different between patients of Group A and Group B. Our data show that patients with levels of beta-endorphin over 8 pmol/L were less sensitive to pain, so that they become candidates for a traditional utilization of the benzodiazepines. However in the patients with beta-end levels less of 8 pmol/L should be suitable an anaesthetic as propofol because strong pain might provoke neurohumoral reflexes, cardiovascular alterations, and even a heart attack.

Multiple viral infections in a group of intravenous drug users: hepatitis B virus exposure is the risk factor.

OBJECTIVE: Infection with hepatotropic viruses is associated with a variable degree of liver disease, and there is evidence that more severe lesions are related to the association with another viral infection. The aim of this investigation is to establish the relationship between different viral infections occurring in the same individual and the presence and progression of liver disease. DESIGN: The study population comprises 754 intravenous (IV) drug abusers exposed to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or cytomegalovirus (CMV). All individuals were followed for an average of 2 years. Liver disease was assessed by liver function tests, 99m-technetium (99mTc) liver scintigraphy, and also by liver biopsy in a subset (n = 136) of patients. The different viral patterns and presence of disease were analysed by logistic regression, and the risk factors were calculated. Contingency tables of patients with single or associated infections were drawn up to evaluate progression of liver disease. RESULTS: Association of HIV with at least one other viral infection was constant. Surface antigens of HBV (HBsAg) were always associated with HIV (n = 19); in this group, 18 patients had signs of liver disease. A past infection with HBV, as revealed by the presence of at least antibodies against the surface antigen (HBsAb) and antibodies against the core antigen of HBV (HBcAb), was detected in 463 patients (61.4%). The overall prevalence of HCV antibodies was 63.91% (n = 482). In 96.8% of the 406 patients tested, HCV-RNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The majority of patients with high alanine transaminase (ALT) had anti-HBV antibodies in the presence of HCV (56.1%). At the end of follow-up, all of these patients showed signs of active liver disease, and scoring was significantly worse than in patients with either HBV or HCV alone. An infection/reactivation of CMV was found in patients previously exposed to HBV and with increased ALT values. CONCLUSIONS: Data emerging from this study reveal the association of HCV or CMV, or both, with a previous HBV infection, as demonstrated by HBsAb and HBcAb, and rapid progression of the disease in this group of patients. A previous HBV infection therefore appears to be an important risk factor for subsequent viral-related liver disease.

Single brain metastasis from thyroid cancer: report of twelve cases and review of the literature.

Brain metastases from thyroid carcinoma is unusual, with a frequency of 1%. We report twelve patients, with single brain metastases and with a karnofsky performance scale score >60 at admission. No metastasis was seen during the uptake of iodine-131, even in the cases from differentiated thyroid carcinoma, suggesting absence of differentiation between primary and metastasic disease. The histopathology of thyroid carcinomas was anaplastic in five cases, differentiated in six, and medullary in one. Only in four patients, brain was the unique site of metastatic spread; in others, bones and lungs were also involved. All metastases were surgically removed, and all patients were treated with radiotherapy (45 Gy) in the postoperative course. The survival average was 19.8 months, and the quality of life was satisfactory in all patients. One patient remained alive till 5 years. Anaplastic histopathology and size of the primitive, and also bone involvement of thyroid disease were significant risk factors in our cases (p < 0.05). According to the literature, surgery is the best therapeutical choice. Alternative strategies in the management of brain metastasis, such as iodine-131 therapy, are discussed, paying particular attention to the relevant side effects.

Expression of bcl-2, c-erbB-2, p53, and p21 (waf1-cip1) protein in thyroid carcinomas.

The study was carried out on 53 patients who had thyroid cancer with various degree of differentiation. We studied the expression of bcl-2, a-erbB-2, p53, and p21 ras protein. The protein encoded by bCL-2 proto-oncogene is implicated in the prolongation of cell survival by blocking programmed cell death, i.e. apoptosis. The role of p53 and bcl-2 genes in the regulation of apoptosis has important implications in oncogenesis. Wild-type p53 is thought to promote apoptosis, whilst mutant p53 has a similar effect on apoptosis as bcl-2 that is inhibition of programmed cell kinase activity. C-erb-2 protein overexpression is currently being evaluated as a potential risk factor in breast cancer patients? The ras gene family codes for a 21 kD protein (p21), which binds guanine nucleotides and possesses GTPase activity. Through this mechanism, the ras p21 protein participates in the control of cell proliferation, possibly as a signal transducer from cell surface receptors to the nucleus. Activation of ras genes has been implicated in neoplastic transformation of cells. The aim of our study is to evaluate the expression of these markers in thyroid carcinomas. All immunohistochemical study was performed in paraffin-embedded tissues pathology specimen. Any well differentiated tumor in our study was positive for bcl-2 protein. C-erb-2 immunostaining was present in tumor samples in 60% of cases. In most cases, specific membrane staining as well as a weak cytoplasmic positivity of tumor cells were seen. Immunoreactivity for p53 was positive only in 10% of cases. By immunostaining, p21 protein was expressed in 55% of the 53 tumors tested, with different degree of expression. Only some poorly differentiated tumours were positive for bcl-2, furthermore all markers tested were strongly positive in these tumours. In conclusion, our results indicate that bcl-2, c-erbB-2, p53, and p21 ras protein are differently expressed in thyroid carcinomas in relation to the degree of aggressiveness and differentiation.

Cytological and immunocytochemical evaluation of thyroid and breast masses in patients with a previous neoplasm: case reports.

The diagnosis of secondary tumours represents one of the most important fields in the application of fine needle aspiration cytology (FNAC). We studied two patients, one with a history of breast cancer and one with a previous tumour of the thyroid, who showed a second mass, in the thyroid and in the breast, respectively, during follow up. The aim of our study was to evaluate if cytology, performed on FNAC smears, may distinguish a metastatic lesion from a second primary tumour, or if further immunocytochemistry should be performed. Our data demonstrate that, while cytology may be indicative of a second primary tumour, the histotype should be confirmed by immunocytochemical staining.

Vitiligo, autoimmune thyroiditis: a rare thyroid cancer arising with bone metastates on maxillofacial area.

An association between vitiligo and autoimmune thyroid disorders had previously been postulated. Thyroid disorders were found in 18.5% of 15,126 patients with vitiligo, on the basis of the anamnestic data. Then, we investigated 255 healthy relatives in whom we tested only T3, T4 and TSH. With the immunological investigation we detected a higher incidence of TMA in vitiligo patients and in the family members. Therefore, on the basis of the immunologic and thyroid pathology functional data, we observed a thyroid pathology in 25% of the 890 vitiligo patients and in 21.1% of their first degree relatives. Then, clinical observation enabled to discover that 3 of 15,126 patients had undergone exeresis for a thyroid carcinoma and in the 890 vitiligo patients, who had undergone particular investigations, we found a thyroid carcinoma in 3 subjects. In one case lymphnodal involvement and bone metastases in the maxillary district were found. The purpose of this work is to evaluate the incidence of thyrosis and of thyroid carcinoma in vitiligo patients observed for 20 years.

[Guidelines for the routine assessment of respiratory surgical risk: thoracic radiography]. / Linee guida per la valutazione routinaria del rischio chirurgico respiratorio: la radiografia del torace.

Through the three years between June 1995 and June 1998 the authors applied an evaluation schedule for the respiratory surgical risk to all the patients undergoing general surgery. Chest X-ray was included in this schedule as a first-level test and it was performed systematically on all the patients. The purpose of the study was to verify the effectiveness of chest X-ray as a routine examination of the respiratory performance, evaluating its predictive value on 1715 cases. The routine employment of this preoperative test on patients resulting risk-free at an accurate clinical anamnestic examination doesn't seem to be justified, basing on the preliminary results achieved. Therefore, chest X-ray should be considered a second-level test, to be performed on the basis of a precise clinical query only. This way a significant health-care cost reduction could be achieved, without affecting the quality of patient's management.

Fine needle aspiration biopsy in the preoperative management of patients with thyroid nodules.

The aim of this study was to evaluate the role of Fine Needle Aspiration Biopsy (FNAB) in the preoperative diagnostic management of patients with solitary or dominant thyroid nodules. This study was performed on 1054 patients followed for various thyroid disorders during a three year period (1992-1995). One hundred thirty eight patients were surgically treated, 61 after cytological indication and 77 after clinical indication, of these, 67 were cytologically negative and 10 were not conclusive. The cytological diagnosis was compared to the final histological result. Among the 138 cases, 27 were malignant, 39 were adenomas and 72 were benign lesions. Of the 67 cytologically negative cases, 63 (94%) were histologically benign, three were papillary carcinomas and one was an oxyphilic adenoma. Of the 45 cytologically suspicious aspirates, four were malignant neoplasias, 38 were follicular adenomas, two were hyperplastic goiters and one was an Hashimoto thyroiditis. All the 16 cytologically positive cases, were confirmed histologically. The limits of FNAB, which emerge from our and other studies, were based mainly in the difficulty of discriminating follicular adenomas from well differentiated follicular carcinomas. Nevertheless, FNAB with ultrasonographic support, has been unanimously accepted as a guide test in the selection of patients with thyroidal pathology who need surgery.