Antonio Ambrosi

Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology.

Cystic changes in metastatic cervical lymph nodes (CLN) from papillary thyroid cancer (PTC) may be a diagnostic pitfall in fine-needle aspiration biopsy (FNAB) cytology. We investigated in a series of CLN metastases from thyroid cancers (TC), including cystic PTC, and from a wide spectrum of extrathyroidal malignancies, the diagnostic role for metastatic TC of the rapid detection of thyroglobulin in eluates from FNAB (FNAB-Tg) of CLN. The study was carried out in a group of 79 subjects (22/57 M/F; median age, 56 years; range, 20-86 years) with enlarged CLN and thyroid nodules (TN), examined for potential metastatic TC, and harboring a large spectrum of incidentally diagnosed extrathyroidal malignancies (n = 24, mostly represented by lymphomas, lung, and breast cancers), CLN metastases from thyroid cancers (n = 28, including 6 cystic metastatic PTC), 6 specific lymphadenitis and 21 reactive lymphadenitis mostly detected (n = 16) during follow-up of patients with previously ablated TC. Markedly high FNAB thyroglobulin (Tg) values were found in all metastatic CLN TC. Two of the six cases with cystic metastatic CLN PTC were diagnosed by FNAB-Tg but not by cytology. In conclusion, FNAB-Tg has been confirmed as an easy modality and fast procedure to diagnose CLN metastasis from TC and high FNAB-Tg values with nondiagnostic cystic cytology strongly suggest cystic metastatic PTC.

TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells

TRAP1 is a component of a pro-survival mitochondrial pathway up-regulated in tumor cells. The evaluation of TRAP1 expression in 26 human colorectal carcinomas showed up-regulation in 17/26 tumors. Accordingly, TRAP1 levels were increased in HT-29 colorectal carcinoma cells resistant to 5-fluorouracil, oxaliplatin and irinotecan. Thus, we investigated the role of TRAP1 in multi-drug resistance in human colorectal cancer. Interestingly, TRAP1 overexpression leads to 5-fluorouracil-, oxaliplatin- and irinotecan-resistant phenotypes in different neoplastic cells. Conversely, the inhibition of TRAP1 activity by TRAP1 ATPase antagonist, shepherdin, increased the sensitivity to oxaliplatin and irinotecan in colorectal carcinoma cells resistant to the single agents. These results suggest that the increased expression of TRAP1 could be part of a pro-survival pathway responsible for multi-drug resistance.

Epidermal Growth Factor Receptor 1 Expression Is Upregulated in Undifferentiated Thyroid Carcinomas in Humans

BACKGROUND Epidermal growth factor receptor 1 (EGFR1) signaling is involved in human cancer cell progression and is responsible for aggressive biological behavior and poor clinical outcome in several human malignancies. Activation of the EGFR1 pathway has been proposed, among others, as being involved in the progression of thyroid cancer toward a thyroid-stimulating hormone (TSH)-independent phenotype. We have previously observed that undifferentiated thyroid carcinoma cells are hyper-sensitive to EGF signaling of downstream intracellular pathways, and this correlated both with the loss of TSH-dependency and increase in EGF-dependent proliferation and migration. Thus, we hypothesized that the upregulation of EGFR1 protein expression may be enhanced in parallel with transition toward a poorly differentiated phenotype in human thyroid carcinomas. METHODS The expression of EGFR1 was evaluated, by immunohistochemistry, in a series of 49 human thyroid carcinomas at different degrees of tumor differentiation. RESULTS The expression of EGFR1 protein was significantly upregulated in poorly differentiated and anaplastic thyroid carcinomas, whereas it was absent or faint in normal thyroid gland tissue and in differentiated thyroid papillary carcinomas. Of note, selected thyroid tumors characterized by a mixed population of differentiated and undifferentiated tumor cells, likely progressing from well to poorly differentiated and anaplastic phenotypes, exhibited EGFR1-negative differentiated fields together with EGFR1-positive poorly differentiated and anaplastic areas. CONCLUSIONS Upregulation of EGFR1 expression may be a molecular marker of dedifferentiation in thyroid epithelial carcinomas, likely being responsible for the activation of EGF signaling observed in tumor cells and favoring progression toward an angiogenic, poorly differentiated, TSH-independent phenotype.

Three cases of papillary carcinoma and three of adenoma in thyroglossal duct cysts: Clinical-diagnostic comparison with benign thyroglossal duct cysts

The clinical and diagnostic findings of 3 cases of papillary thyroid carcinoma in thyroglossal duct cyst (TDC) were compared to those of 3 cases of adenoma in TDC and 2 cases of benign TDC. The neck masses of the subjects with benign TDC grew slowly, whereas those of 2 patients with papillary carcinoma and 1 of the patients with adenoma grew rapidly (especially those with carcinoma). On the other hand, one case of carcinoma, and two cases of adenoma in TDC were diagnosed incidentally. Benign TDC had an anechoic pattern at US, whereas the cysts containing carcinoma and adenoma showed the presence of a mural nodule at US. Microcalcifications in the mural mass were present in one patient with carcinoma. The 3 patients with carcinoma in TDC underwent total thyroidectomy. The histology was negative in all 3 patients for thyroid cancer and thyroid nodules. However, in 2 of them it revealed the carcinoma invading the cyst wall and adjacent tissues, 1 of which also exhibited 2 metastatic lymph nodes in the central neck area. The cases reported illustrate the utility of enhancing one’s clinical suspicion of carcinoma in patients bearing TDC, even when incidentally discovered. In particular, rapid growth of the cystic mass, and the presence of a mural nodule on US, especially with calcifications, must raise the physician’s suspicion for a cancer arising in TDC.

High Frequency of Incidental Diagnosis of Extrathyroidal Neoplastic Diseases at the Fine-Needle Aspiration Biopsy of Laterocervical Lymph Nodes in Patients with Thyroid Nodules

This study was undertaken to evaluate the frequency of the incidental diagnosis of extrathyroidal lymph node diseases at ultrasound-guided fine-needle aspiration biopsy/cytology (FNAB/C) being done to check the presence of metastatic thyroid cancer in 30 subjects with thyroid nodule (TN) and enlarged cervical lymph nodes (CLN). The patients in whom cytology suggested the presence of malignancy in the TN or in the CLN underwent surgical removal for histologic diagnosis. The spectrum of diseases revealed by this survey included: (1) 10 benign diseases including 1 case of Piringer-Kuchinka lymphadenitis with benign TN; (2) 10 metastatic thyroid cancers (2 anaplastic and 8 papillary cancers); (3) 3 benign TN associated with metastatic invasion of cervical lymph nodes from lung (2 cases) and breast (1 case) cancer; (4) 1 Hodgkins lymphoma of the cervical lymph nodes with hyperplastic TN; (5) 3 nodal lymphomas with benign thyroid nodule and 2 cases of thyroid lymphoma with nodal invasion; and (6) 1 nodal sarcoidosis with benign TN. The results of this study demonstrate that important neoplastic and hematologic diseases affecting the cervical lymph nodes may frequently be incidentally detected using ultrasonography (US) and FNAB/C in the diagnostic procedure for thyroid nodule.

Laparoscopic treatment of biliary hepatic cysts: short- and medium-term results

BACKGROUND The aim of this study was to evaluate the postoperative morbidity and, in the medium-term results, the incidence of relapses in the laparoscopic treatment of non-parasitic hepatic cysts (NPHC) and polycystic liver disease (PCLD). PATIENTS AND METHODS From 1999 to 2003, 12 patients with NPHC and 3 patients with PCLD with few large cysts in the anterior hepatic segments underwent laparoscopic fenestration and deroofing. RESULTS There were no conversions and no mortality; the mean operative time was 55 min for NPHC and 120 min for PCLD. Postoperative morbidity comprised two patients with bronchopneumonic infiltrations and in one patient with PCLD ascites resolved spontaneously. All the patients experienced resolution of the symptomatology. Follow-up was carried out from 3 to 38 months (mean 18 months). There was no relapse of the disease. DISCUSSION The preoperative selection of patients is fundamental to program the surgical treatment. Laparoscopy can be considered a safe and efficacious treatment for NPHC and PCLD.

Propofol but not sevoflurane prevents mitochondrial dysfunction and oxidative stress by limiting HIF-1α activation in hepatic ischemia/reperfusion injury.

Mitochondrial dysfunction, reactive oxygen species (ROS) production and oxidative stress during reperfusion are determinant in hepatic ischemia/reperfusion (I/R) injury but may be impacted by different anesthetic agents. Thus, we aimed at comparing the effects of inhaled sevoflurane or intravenous propofol anesthesia on liver mitochondria in a rodent model of hepatic I/R injury. To this, male Wistar rats underwent I/R surgery using sevoflurane or propofol. In the I/R model, propofol limited the raise in serum aminotransferase levels as compared to sevoflurane. Mitochondrial oxygen uptake, respiratory activity, membrane potential and proton leak were altered in I/R; however, this impairment was significantly prevented by propofol but not sevoflurane. In addition, differently from sevoflurane, propofol limited hepatic I/R-induced mitochondria H2O2 production rate, free radical leak and hydroxynonenal-protein adducts levels. The I/R group anesthetized with propofol also showed a better recovery of hepatic ATP homeostasis and conserved integrity of mitochondrial PTP. Moreover, hypoxia-inducible factor 1 alpha (HIF-1α) expression was limited in such group. By using a cell model of desferoxamine-dependent HIF activation, we demonstrated that propofol was able to inhibit apoptosis and mitochondrial depolarization associated to HIF-1α action. In conclusion, hepatic I/R injury induces mitochondrial dysfunction that is not prevented by inhaled sevoflurane. On the contrary, propofol reduces liver damage and mitochondrial dysfunction by preserving respiratory activity, membrane potential and energy homeostasis, and limiting free radicals production as well as PTP opening. These hepatoprotective effects may involve the inhibition of HIF-1α.

Cell differentiation and iodine-131 uptake in poorly differentiated thyroid tumour in response to nevirapine.

On Feb 13, 2003, a 76-year-old woman was referred with a follicular variant of a thyroid papillary carcinoma and underwent a total thyroidectomy and debulking of the right laterocervical region, which showed several metastases in the right laterocervical lymph nodes, vessel infi ltration, and a neoplastic thrombosis of the internal jugular vein (pathological stage T4bN1aMx). During the next 2 years, apart from the persistence of the disease in the upper mediastinum and right laterocervical lymph nodes, the rapid and progressive appearance of multiple lung and bone metastases was noted during whole-body scans with recombinant thyroid-stimulating hormone (TSH)-stimulated iodine-131. She therefore underwent another surgical debulking of the right laterocervical region and upper mediastinum, and excision of the right internal jugular vein with the neoplastic thrombus on July 29, 2003, with external-beam radiotherapy (50 Gy in 28 fractions) of the laterocervical region and upper mediastinum in November, 2003, and three applications of recombinant TSH-stimulated I metabolic treatment (4834 MBq on June 6, 2003; 7400 MBq on Feb 23, 2004; and 5374 MBq on Nov 15, 2004). However, these treatments had little eff ect on disease progression, as shown by persistence of the disease in the upper mediastinum and right laterocervical lymph nodes in the fi rst I whole-body scan after treatment, followed rapidly by multiple bone and lung metastases seen in the second and third scans after treatment. On May 27, 2005, a whole-body scan with CT showed a region of contrast enhancement in the left retromandibular region, with multiple metastases in the right upper mediastinum (the region of the previous surgical excision of the neoplastic thrombus), both lungs, a dorsal vertebra, the right ilium, and the left femur. However, only the right upper mediastinal and retromandibular lesions showed any signs of radioiodine uptake, albeit low, during the I whole-body scan done before the CT scan (fi gure 1). These features were interpreted as probable signs of rapid and progressive dediff erentiation of the initial thyroid papillary carcinoma, which was confi rmed by the presence of cell anisokaryosis, nuclear pleiomorphism, and scanty colloid, and undetectable expression of thyroglobulin and sodium iodine symporter proteins in tumour cells (fi gure 2), which were obtained by an echo-guided fi ne-needle aspiration biopsy of a right laterocervical lymph node. Antibodies against thyroglobulin and the Na/I symporter were initially tested in primary cultures of human thyroid cells (positive control) and in anaplastic thyroid carcinoma ARO cells (negative control), and showed positive cytoplasmic staining in normal thyrocytes and a low signal in anaplastic thyroid tumour cells (fi gure 3). At that time, serum thyroblobulin was 795 μg/L, with a low serum thyroid peroxidase antibody titre. After consent from the ethics committee of the Riuniti Hospital (Foggia, Italy) was obtained, the patient started treatment with nevirapine (200 mg once a day for 14 days, then 200 mg twice a day for 7 months). A progressive increase in serum thyroglobulin was noted, which reached a peak concentration of 3925 μg/L 3 months after nevirapine treatment started. Moreover, 2 months after starting nevirapine, the retromandibular metastasis, which was metabolically silent before treatment with nevirapine, showed radioiodine uptake of 2·1 times higher than that seen before treatment, whereas the right upper mediastinal lesion showed 54% upregulation of radioiodine uptake (fi gure 1, table). The patient received a fourth dose of I metabolic treatment (9250 MBq on Aug 22, 2005), and 5 months later, the I whole-body scan Lancet Oncol 2006; 7: 877–79

A recurrent epidermoid cyst of the spleen: report of a case and literature review

BackgroundSplenic cysts are rare disease. Epidermoid cysts of the spleen belong to the primary nonparasitic splenic cysts group. They are an unusual event in surgical practice. Usually, epidermoid cysts occur in children and young female. Most often, they are asymptomatic, but they may present with abdominal discomfort.Case presentationWe are reporting a rare case of a 23-year-old female came to our attention with history of intermittent pain and previously undergone two times to laparoscopic decapsulation of the cyst in others institutions. During hospitalization, serum and intracystic levels of tumor marker CA19-9 increased. Enhanced CT of the abdomen showed recurrent large cyst in the upper pole of the spleen with satellite nodules. Laparotomic total splenectomy was performed. Histopathological and immunoreactive examinations were executed, and they revealed stratified squamous epithelium on the inner surface of cystic wall, which was positive for EMA, CEA, and CA19-9. The diagnosis of epidermoid cyst was confirmed.ConclusionsRecently, the surgical approach is changing towards conservative treatments in order to save the spleen in young patients for immunological reasons. Sometimes, this target is not achievable. In such circumstances, like recurrent large cyst, anomalous anatomical relationship to the surrounding tissues, total splenectomy is safe and necessary.

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

TRAP1 is a HSP90 molecular chaperone upregulated in colorectal carcinomas and involved in control of intracellular signaling, cell cycle, apoptosis and drug resistance, stemness and bioenergetics through co-traslational regulation of a network of client proteins. Thus, the clinical significance of TRAP1 protein network was analyzed in human colorectal cancers. TRAP1 and/or its client proteins were quantified, by immunoblot analysis, in 60 surgical specimens of colorectal carcinomas at different stages and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic colorectal tumors. TRAP1 is upregulated at the transition between low- and high-grade adenomas, in in situ carcinomas and in about 60% of human colorectal carcinomas, being downregulated only in a small cohort of tumors. The analysis of TCGA database showed that a subgroup of colorectal tumors is characterized by gain/loss of TRAP1 copy number, this correlating with its mRNA and protein expression. Interestingly, TRAP1 is co-expressed with the majority of its client proteins and hierarchical cluster analysis showed that the upregulation of TRAP1 and associated 6-protein signature (i.e., IF2α, eF1A, TBP7, MAD2, CDK1 and βCatenin) identifies a cohort of metastatic colorectal carcinomas with a significantly shorter overall survival (HR 5.4; 95% C.I. 1.1-26.6; p=0.037). Consistently, the prognostic relevance of TRAP1 was confirmed in a cohort of 55 metastatic colorectal tumors. Finally, TRAP1 positive expression and its prognostic value are more evident in left colon cancers. These data suggest that TRAP1 protein network may provide a prognostic signature in human metastatic colorectal carcinomas.