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Abstract: Aim: We report here our experience in a larger series of differentiated thyroid cancer (DTC) patients who had been treated by 99mTc-sestamibi radio-guided surgery (RGS) for 131Iodine (131I)-negative loco-regional recurrent disease. Methods: Fifty-eight patients with loco-regional 131I-negative recurrent disease from DTC were studied with 99mTc-sestamibi directed RGS using a hand-held 11-mm gamma probe as an intra-operative detector. Patients were selected for RGS on the basis of (a) progressive increase of serum thyroglobulin (Tg) levels after first treatment during follow-up, (b) negative high dose (100mCi, 3.7GBq) 131I whole-body scan, and (c) positive pre-operative 99mTc-sestamibi scintigraphy for the presence of loco-regional recurrent disease. There were 41 papillary (1 “tall” cell variant), 13 follicular and 4 Hürthle cells tumours. In 14 patients thyroid cancer recurred in the thyroid bed while cervical lymph node metastases were found in 37 patients, and 7 patients had recurrent disease both in the thyroid bed and in cervical lymph nodes. Results: At bilateral neck exploration, 147 metastastic foci ranging from 4mm to 51mm in largest diameter (mean tumour diameter=17.3±9.5mm) were removed. Eighty-five of them (58%) had been pre-operatively identified at 99mTc-sestamibi scintigraphy. After RGS, serum Tg levels normalised in 43 of 58 patients (serum Tg<2ng/ml – they were considered disease-free), serum Tg remained slightly increased in 12 patients without evidence of metastatic disease at scintigraphic and radiologic imaging (serum Tg<10ng/mg – they were considered living with microscopic disease), while serum Tg significantly increased up to values>900ng/ml in 3 patients who developed lung metastases. The mean lesion to background 99mTc-sestamibi uptake ratios decreased in all 58 patients (p <0.0001). Post-surgical follow-up ranged 6–72 months (mean±SD=29.6±13.5 months). The operating surgeon assessed RGS as very useful in 14 patients in whom metastatic foci were embedded in fibrotic tissues or located behind blood vessels, useful in 22 patients, moderately useful 17 patients and not useful in 5 patients. Conclusion: Our data suggest that a 99mTc-sestamibi intra-operative gamma probe can be used to identify and guide resection of recurrent loco-regional tumour in DTC patients with 131I-negative loco-regional metastatic foci. [Copyright &y& Elsevier]

Abstract Background Although sentinel node biopsy (SNB) is becoming the standard approach for axillary staging in patients with small breast cancer, criteria for patient selection and some technical aspects of the procedure have yet to be clearly defined. The aim of the present survey was therefore to investigate the way in which SNB is used by general surgeons working in the Veneto region, Italy. Methods A 29-item questionnaire regarding various aspects of SNB practice was mailed to surgeons in charge of breast surgery in all the 56 surgical centres of the region. Results The rate of response to the questionnaire was 82.1% (n = 46); 69.6% (n = 32) of the respondents routinely perform SNB in their clinical practice. Most of the interviewed surgeons (93.5%) expressed the belief that the acceptable false negative rate should be ≤5%. However, among the surgeons who perform SNB, only 34.4% performed more than 20 SNB during the learning phase. Indications are limited to tumours of ≤1 cm by 31.2% (n = 10) of respondents, ≤2 cm by 46.9% (n = 15) and ≤3 cm by 21.9% (n = 7). Almost all respondents (93.7%) agreed that a clinically positive axilla is a contraindication to SNB, while opinions differed widely concerning other potential contraindications. In most of the centres considered, SN identification is undertaken on the day before surgery using a subdermal injection of 30–50 MBq of 99mTc-albumin-nanocolloid followed by lymphoscintigraphy. Conclusions SNB is currently performed in the majority of hospitals in the Veneto region. However, the training phase and criteria used for patient selection differ from centre to centre. Certified training courses and shared guidelines are therefore highly desirable.

Background: Although widely used for the management of patients with cutaneous melanoma, the sentinel lymph node (SLN) biopsy (SNB) procedure raises several issues. This study was designed to investigate: the predictive factors of SLN status, the false-negative (FN) rate, and patients' prognosis after SNB., Patients and Methods: This is an observational, prospective study conducted on a large series of consecutive patients (n = 1,313) enrolled by 23 Italian centers from 2000 through 2002. A commonly shared protocol was adopted for the SNB surgical procedure and the SLN pathological examination., Results: The SLN positive and false-negative (FN) rates were 16.9% and 14.4%, respectively (median follow-up, 4.5 years). At multivariable logistic regression analysis, the frequency of positive SLN increased with increasing Breslow thickness (p < 0.0001) and decreased in patients with melanoma regression (p = 0.024). At the multivariable Cox regression analysis, SLN status was the most important prognostic factor (hazards ratio (HR) = 3.08) for overall survival; the other statistically significant factors were sex, age, Breslow thickness, and Clark's level. Considering SLN and NSLN status, including FN cases, we identified four groups of patients with different prognoses. The 5-year overall survival of patients with positive SLNs was 71.3% in those with negative nonsentinel lymph nodes (NSLNs) and 50.4% if NSLNs were positive., Conclusions: Regression in the primary melanoma seems to be a protective factor from metastasis in the SLN. When correctly calculated, the SNB FN rate is 15-20%. Furthermore, the SNB is important to more precisely assess the prognosis of patients with melanoma.

Background: Sentinel Node Biopsy is an established staging technique in many adult malignancies. However, only few reports describe this procedure for the evaluation of regional lymph nodes in childhood and adolescents. Our experience with sentinel node biopsy in soft tissue sarcomas of extremities in children is reported., Methods: Seventeen children were evaluated with sentinel node biopsy between 2002 and 2007: 11 at initial surgery, 5 at primary re-excision, 1 at local relapse. The diagnosis was rhabdomyosarcoma in 5 and other soft tissue sarcomas in 12: Ewing/PNET sarcoma 6, epithelioid sarcoma 1, malignant peripheral-nerve-sheath tumor 1, undifferentiated sarcoma 1, myxoid liposarcoma 2, adult-type fibrosarcoma 1. Primary sites included lower limbs (8), upper limbs (9). Mapping of nodes was performed with lymphoscintigraphy plus intra-operative injections with blue-dye in 14 cases, with lymphoscintigraphy and intra-operative injections alone in 2 and 1, respectively., Results: Of the 17 lymphatic regions (9 axilla, 8 inguinal), 16 were identified with lymphoscintigraphy, 15 by intra-operative injections. Thirty-five lymph nodes were removed. Nodes were positive for metastasis in two patients with alveolar rhabdomyosarcoma and undifferentiated sarcoma. There were no complications. No further lymph node metastases were recognized either at diagnosis or during the follow-up (6-78 months)., Conclusions: Sentinel node biopsy was technically feasible, reliable, and free of complications. It could be an alternative to aggressive or random biopsies for extremity rhabdomyosarcoma and it can contribute to define those non-rhabdomyosarcoma soft tissue sarcomas that spread to regional nodes.

Purpose: The purposes of this study were to investigate the efficacy of radiocolloid lymphoscintigraphy and of handheld gamma probe procedure for sentinel lymph node biopsy (SLNB) in papillary thyroid carcinoma (PTC) and to evaluate its results in clinical staging., Materials and Methods: Sixty-five PTC consecutive patients entered the study. Patients underwent radiocolloid lymphoscintigraphy before surgery. Intraoperative sentinel lymph node (SLN) localization was performed using a handheld gamma probe. They were followed up at 2, 6 months, and yearly., Results: SLN metastases were diagnosed in 52%. Fifty-one patients underwent ablative 131-I therapy. The mean Tireoglobulin level in N0 vs N1 cases was 2.2 ng/ml vs 4.73 (p = 0.03) and 0.68 vs 2.1 ng/ml (p = 0.005) before and after 131-I therapy, respectively., Conclusions: In patients classified N0 by SLNB, ablative 131-I therapy could be avoided.

Unlabelled: 99mTc(N)-DBODC5 is the lead compound of a new series of monocationic 99mTc(N)-based potential myocardial imaging agents that exhibit original biodistribution properties. This study was addressed to elucidate the mechanisms of distribution, retention, and elimination of this promising 99mTc(N)-agent., Methods: The sex-related in vitro and in vivo stability and the subcellular distribution of 99mTc(N)-DBODC5 were investigated. Studies were performed by considering binding to the serum proteins; stability in rat serum, human serum, and rat liver homogenates; and the chemical integrity of the complex after extraction from rat tissues such as heart, liver, and kidney, as well as from intestinal fluids and urine. The effect of cyclosporin A on the in vivo pharmacokinetic properties of 99mTc(N)-DBODC5 was also evaluated. Subcellular distribution of 99mTc(N)-DBODC5 in ex vivo rat heart was determined by standard differential centrifugation techniques., Results: No significant in vitro serum protein binding and no notable biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was evidenced. In vivo experiments showed that sex affects the pharmacokinetic profile of the 99mTc(N)-complexes including metabolism and excretion. Chromatographic profiles of 99mTc(N)-radioactivity extracted from tissues and fluids of female rats were always coincident with the control. Conversely, a small percentage of metabolized species was detected by high-performance liquid chromatography in liver extracts of male rats. Furthermore, administration of cyclosporin A caused a significant reduction of lung, liver, and kidney washout along with a considerable variation in activity distribution in the intestinal tract in both male and female rats, thus indicating a possible implication of Pgp transporters in determining the biologic behavior of 99mTc(N)-DBODC5. However, this phenomenon was more pronounced in females. Subcellular distribution studies showed that 86.3% +/- 7.4% of 99mTc(N)-DBODC5 was localized into mitochondrial fraction as a result of the interaction with the negative membrane potential., Conclusion: Evidence showing that the new 99mTc(N)-myocardial tracers behave as multidrug resistance-associated protein P-glycoprotein substrates, combined with their selective mitochondrial accumulation, strongly supports the possibility that diagnostic application of 99mTc(N)-DBODC5 can be extended to tumor imaging and noninvasive multidrug resistance studies.

Background: The prognosis of patients with papillary thyroid carcinoma (PTC) is usually favorable; however, a subset of patients can develop local recurrence or distant metastases. The aim of this study was to evaluate the prognostic factors influencing the recurrence and the survival rate in 950 PTC patients., Materials and Methods: From 1990 to 2005, 950 consecutive patients affected by PTC were operated on at our Department. We analyzed the prognostic role of the following parameters: gender, age at initial treatment, extent of thyroid surgery, node dissection, tumor size, node metastases, distant metastases, stage, and 131-I therapy., Results: Seventy-nine patients (8.3%) developed locoregional or distant metastases after an average follow-up of 7.8 years (range 2-17 years); in particular local recurrence was observed in 25 cases and distant metastases in 54 cases. The global 10- and 15-year survival rates were 91.38% and 88.69%, respectively. At univariate analysis, all variables were significantly correlated with recurrence (P = .001) except gender (P = .3); moreover, gender (P = .2), node dissection (P = .5), and node metastases (P = .06) were not significant on 10- and 15-year survival. At multivariate analysis the age at first treatment, T4, M+, stage IV, the extent of thyroid surgery, and the 131-I therapy resulted to be significant and independent prognostic factors (P < .001)., Conclusion: Our data, in disagreement with other staging systems, suggest that gender does not play a significant role both in recurrence and survival. Moreover, the 131-I therapy was a statistically significant prognostic factor at univariate and multivariate analyses.

Objective: Papillary thyroid cancers (PTCs) with no iodine uptake have an aggressive behaviour and a poor prognosis. The aim of our study was to characterize, at molecular level, a subset of PTC with no 131 iodine ((131)I) uptake., Design and Methods: Forty-eight cancer tissues were divided into three groups: Group 1, 28 primary cancers; Group 2, 7 recurrences capable of trapping (131)I; and Group 3, 13 recurrences incapable of trapping (131)I. mRNA levels of thyroid genes (sodium/iodide symporter NIS, thyroglobulin, thyroperoxidase and pendrin) and glycolytic metabolism genes (GLUT-1, hexokinase I and II) and BRAF mutations were evaluated in the different groups., Results: Cancers with no (131)I uptake had slightly reduced NIS, significantly reduced thyroglobulin (P < 0.01), thyroperoxidase (P = 0.01) and pendrin (P = 0.03) and significantly increased GLUT-1 (P = 0.01) gene expression levels; and a high frequency of BRAF mutations (77%). BRAF(V600E) mutation, in both primary and metastatic thyroid cancers, is associated with a marked drop in thyroperoxidase (29-fold) and pendrin (20-fold) expression and a considerable increase (five-fold) in GLUT-1 expression., Conclusions: (1) The loss of (131)I uptake in recurrences depends not only on a decrease in NIS gene, but possibly on a reduction in the molecules regulating its intracellular metabolism; (2) the high GLUT-1 gene expression supports the use of positron emission tomography with specific tracers in clinical management of such cancers; and (3) BRAF(V600E) point mutations may lead to less differentiated phenotypes, suggesting a worse prognosis.

Aim: Papillary thyroid microcarcinoma (PTMC), a tumor measuring =or<1 cm according to the World Health Organization (WHO) histologic classification, is the most common histologic variant of thyroid cancer. The aim of this study was to evaluate the long-term outcome of surgical treatment for PTMC at a single institution with a view to differentiate therapy options based on risk of progression of disease by comparing our results with those reported in the literature., Methods: The study sample was a total of 587 cases of PTMC treated surgically at our institution between 1990 and 2006. PTMC was an incidental finding (PTMC-I) in 325 (55.4%) cases, diagnosed preoperatively (PTMC-D) at echography and needle-aspiration biopsy in 229 (39%), and occult with metastasis (PTMC-O) in 33 (5.6%). Patients were grouped into two classes (PTMC diameter =or>5 mm or <5 mm) and compared against prognostic factors: sex, age, type of PTMC (PTMC-I, PTMC-D, PTMC-O), extent of surgery, lymph node dissection, lymph node metastasis, iodine-131 (131-I) therapy, state of disease, relapses. These parameters were then compared against tumor size (PTMC diameter =or>5 mm or <5 mm), excluding cases of PTMC-O with metastasis., Results: Comparison of the two groups divided by tumor size, across the entire sample and after PTMC-O cases were excluded, revealed significant differences in the type of PTMC, frequency of partial thyroidectomy, presence of lymph node metastasis, iodine-131 therapy, life status and recurrence rate., Conclusion: Published PTMC studies were analyzed for definition of the disease, incidence, therapy, prognosis, and follow-up results and compared with our data. The results of our analysis argue against use of the term ''microcarcinoma'' in the wider sense since the three PTMC categories (PTMC-I, PTMC-D, PTMC-O) present different behaviour patterns. When cases of PTMC-O with clinically manifest metastasis were excluded, none of the patients with PTMC <5 mm in diameter were reoperated for tumor recurrence and all are currently free of disease. In conclusion In PTMC <5 mm in diameter, whether PTMC-I and PTMC-D, and without evidence of lymph node involvement, partial thyroidectomy may be a viable approach to treatment. By contrast, occult PTMC with metastasis is prognostically important and should therefore be treated like tumors =or>5 mm in diameter.

Purpose: It is a matter of controversy whether prophylactic lymph node dissection improves prognosis and survival in papillary thyroid carcinoma (PTC) patients without suspicion of lymph node metastases either clinically or on ultrasonography. It is possible that in such patients the use of lymphatic mapping and sentinel lymph node (SLN) biopsy, as are employed for other tumours, will be of assistance. The aim of this study was to evaluate the feasibility of preoperative 99mTc-nanocolloid lymphoscintigraphy and an intra-operative SLN procedure in the management of PTC patients., Methods: Twenty-five consecutive patients were entered in the study between April 2005 and October 2005. All had a preoperative diagnosis of malignancy obtained by fine-needle aspiration cytology (FNAC), without clinical or ultrasonographic evidence of loco-regional lymph node involvement. Patients underwent preoperative lymphoscintigraphy after the injection of 99mTc-nanocolloid [median 6 MBq (range 4-9 MBq) in 0.1-0.2 ml saline injected intratumorally under ultrasound guidance] and an intra-operative SLN procedure using a hand-held gamma probe. Surgery was performed by the same surgeon in all patients., Results: Preoperative lymphoscintigraphy identified at least one SLN in all patients. During surgery, using the gamma probe, the surgeon was able to find at least one SLN in all cases. A good correlation was found between preoperative imaging and probe results. Metastasis was found in at least one SLN in 12 (48%) patients. In seven (28%) patients the involved SLN was the most radioactive SLN, while in five (20%) patients a less radioactive SLN was involved by malignancy. Ten of these 12 patients had only micrometastases (<2 mm). Micrometastases were found in the most radioactive SLN in six cases and in less radioactive SLNs in four cases, while in two patients more lymph nodes visualised at lymphoscintigraphy ipsilateral to the primary tumour were sites of metastasis., Conclusion: The rate of nodal involvement was very high in our series: in 48% of patients at least one metastatic lymph node was found. From a technical point of view the intra-operative SLN procedure in PTC patients was easy to perform, without major intra-operative complications. Our promising preliminary experience needs to be confirmed in larger series of patients series with longer follow-up.