Angiotensin converting enzymes ACE and ACE2 in thyroid cancer progression.

Angiotensin-converting enzymes, ACE and ACE2, play not only a pivotal role in the regulation of blood pressure, but are involved in the processes of pathophysiology, including thyroid dysfunction or progression of several neoplasia such as cancers of skin, lungs, pancreas and leukemia. However, their role in the thyroid carcinogenesis remains unknown. We examined in this study the expression of ACE and ACE2 in thyroid tissues and their possible employment as biomarkers for thyroid cancer progression. Thyroid tissues, including 14 goiters (G), 12 follicular adenomas (FA), 10 follicular thyroid carcinomas (FTC), 14 papillary thyroid carcinomas (PTC) and 11 undifferentiated thyroid carcinomas (UTC), were subjected to RT-PCR and protein analyses with primers or antibodies specific for ACE and ACE2, respectively. FA revealed significantly increased ACE compared to other groups and FTC was significantly higher than UTC. ACE2 was significantly increased in PTC in comparison to G, FA and UTC, and in FTC as compared to G. The ratio ACE/ACE2 decreased, while ACE2/ACE increased with the differentiation grade of thyroid carcinoma. ACE was significantly diminished in individuals older than 50. Both ACEs were significantly diminished in M1 patients, ACE2 additionally in higher tumor masses. ACE and ACE2 are regulated within thyroid benign and malignant tissues. As the transcript ratio between both enzymes correlate proportional with the differentiation status of thyroid cancer, ACE and ACE2 may serve as new markers for thyroid carcinoma.

[Surgical treatment options for cervical paragangliomas]. / Chirurgische Therapieoptionen bei zervikalen Paragangliomen.

The therapies available for the rare tumor entity of cervical paraganglioma (PG) are currently undergoing a paradigm shift. The treatment of choice for small carotid body tumors, malignant and active endocrine tumors is surgical resection; however, for locally advanced carotid body tumors and vagal PG, surgical therapy should be critically evaluated. Due to the immediate proximity of these hypervascularized tumors to the caudal cranial nerves, there is a risk of severe nerve damage with a significant impairment of quality of life after resection, particularly for locally advanced cervical PG, emphasizing further the importance of a restrictive surgical strategy. External radiotherapy can provide an equivalent primary therapeutic option with respect to the rate of recurrence and is accompanied by a lower morbidity. The slow rate of tumor progression and the multifocality of the familial variant of cervical PG or significant comorbidities in older, asymptomatic patients warrant a less aggressive treatment strategy for these tumors. When a wait and scan approach is implemented, a closely monitored radiological and clinical re-evaluation is of upmost importance. In a multidisciplinary approach the following critical points require consideration before a therapy is implemented,: size and location of the tumor, progression rate, genetic background, patient age and general condition, relevant comorbidities, the presence of synchronous PG and/or vasoactive catecholamine-producing tumors. Although best practice algorithms for the treatment of cervical PG have already been devised, recent innovative developments have led to more patient-tailored, individualized treatment approaches.

Correlating the length of internal carotid artery stenosis to the technique of endarterectomy and anesthesia used.

A consensus correlating the length of the internal carotid artery stenosis (short vs. long) to the preferred Endarterectomy (Conventional Vs. Eversion) and type of anesthesia (General Vs. cervical blockade) implemented has not yet been met. In a collaboration study between two hospitals in Germany and Georgia, 215 patients were analyzed and stratified into 3 groups according to length of stenosis, surgical technique and type of anesthesia used. In this series, for eversion endarterectomy with cervical blockade, non-neurological complications commenced at 1,78%. For conventional endarterectomy performed under general anesthesia, patients with a short stenosis had no postoperative complications whatsoever, whereas the incidence rate for various neurological deficits was 2,7% for long stenosis. In case of short stenosis of the internal carotid artery, eversion endarterectomy with cervical block, seems to be an optimal choice. Whereas for long stenosis, conventional endarterectomy under general anesthesia is a more suitable option.

[Perforation of carotid artery causing cervical hematoma]. / Perforation der A. carotis communis als Ursache eines Halsgefäßscheidenhämatoms.

BACKGROUND: Perforation of the carotid artery is a rare, life-threatening emergency. This entity is usually caused by failed puncture of jugular veins, external trauma, or infection of the vascular wall. The existence of spontaneous rupture as a cause of vessel rupture is discussed in the literature. CASE REPORT: The case of a 57-year-old woman who suffered painful cervical swelling on the left side for 2 days is described. Six weeks prior to this, she had received transjugular intrahepatic shunt implantation (TIPS) via the jugular vein because of liver cirrhosis. Further signs were vocal cord dysfunction and Horners' syndrome on the left side. Computed tomography (CT) with contrast agent revealed a huge mass surrounding the common carotid artery. Differentiation between a solid tumor and carotid dissection was primarily not possible. Radiological considerations also comprised an abscess or even a paraganglioma. Only color duplex sonography revealed a pendular blood flow slightly caudal of the carotid bifurcation. In agreement with the CT findings, a calcified plaque appeared directly downstream of the presumed vessel injury. Operative revision was performed in collaboration with the vascular surgeon. Transluminal endarteriectomy and vessel reconstruction with patch plasty was performed. CONCLUSION: Cervical hematoma caused by carotid injury of unknown origin is a rare differential diagnosis of sudden cervical swelling. In this case, failed venous puncture in conjunction with pre-existing arterial plaque and therewith inflammation of the vessel wall could have caused the injury and delayed carotid rupture.

[Endocrine surgery for neck paraganglioma: operation, radiation therapy or wait and scan?]. / Endokrine Chirurgie zervikaler Paragangliome: Operation, Strahlentherapie oder "wait and scan"?

BACKGROUND: Head and neck paraganglioma (HNP) represent rare endocrine tumors. Therapy is decided on genetic findings, tumor characteristics (e.g. tumor size, localization and dignity), age of patient and symptoms. In terms of local control radiation therapy is as equally effective as surgery but surgical morbidity rates secondary to cranial nerve injuries remain high. PATIENTS: Based on 6 patients with 11 solitary (4 patients) and multiple (2 patients) HNP (8 carotid body tumors, 1 vagal, 1 jugular and 1 jugulotympanic paraganglioma) the specific characteristics of the need for surgery as well as correct choice of treatment in cases of sporadic succinate dehydrogenase (SDH) negative and hereditary SDH positive HNP will be exemplarily demonstrated. RESULTS: A total of 6 carotid body tumors (four sporadic, two hereditary) were resected in 4 patients, five as primary surgery and one as a revision procedure. In one case a preoperative embolization was performed 24 h before surgery. Malignancy could not be proven in any patient. The 30-day mortality was zero. In the patient with bilateral hereditary carotid body tumors, unilateral local recurrent disease occurred. After resection of the recurrent tumor permanent unilateral paralysis of the laryngeal nerve, glossopharyngeal nerve and hypoglossal nerve occurred. All patients were followed-up postoperatively for a mean of 64 months (range 23-78 months) with a local tumor control rate of 100%. The overall survival rate after 5 years was 100%. CONCLUSIONS: Given a very strict indication with awareness of surgical risks selective surgery has a key position with low postoperative morbidity in the treatment of HNPs. We prefer surgery for small unilateral paraganglioma, malignant or functioning tumors.

Advances in the management of hereditary medullary thyroid cancer.

This work draws on recent advances during the era of codon-oriented prophylactic surgery for hereditary medullary thyroid cancer (MTC). Milestones included identification of RET (REarranged during Transfection) as the susceptibility gene, introduction of prophylactic surgery on evidence of a RET germline mutation, revelation of genotype-phenotype correlations within the MEN 2 spectrum and demonstration of age-related progression of MTC. Novel surgical techniques, notably systemic microdissection and compartment-oriented surgery, have greatly enhanced surgical cure. Uncovering molecular pathways from RET genotype to MEN 2 phenotype should provide treatment options for RET mutation carriers whose MTC currently is too advanced for cure.

Medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is subdivided into sporadic (75 %) and hereditary (25 %) forms. Several germline mutations in the RET proto-oncogene are the source of distinct clinical phenotypes in hereditary MTC including familial MTC (FMTC) and multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B). The higher the penetrance of the MEN 2 phenotype the earlier the progression of MTC which forms the basis for the currently recommended codon-related concept of prophylactic thyroidectomy. In patients with sporadic MTC, routine calcitonin (CT) measurement in nodular goiter patients has been shown to reduce the frequency of advanced tumor stages. Patients with CT levels over 100 pg/ml after pentagastrin stimulation are recommended for total thyroidectomy. In patients with unexpected sporadic MTC after histological examination, completion thyroidectomy is currently only recommended when CT levels remain elevated. The extent of lymph node dissection in patients with MTC is controversial. However, with respect to lymphonodal micrometastases, systematic compartment-oriented microdissection has been shown to reduce the frequency of lymphonodal recurrence. On the other hand, to avoid unnecessary lymph node dissection, a more individualized concept is required in the future. New chemotherapeutic agents (tyrosine kinase inhibitors), therapeutic nuclids (90Yttrium-labeled octreotide), and chemoembolization of liver metastases are currently the most promising therapeutical concepts in patients with distant metastases.

[Therapeutic results after papilloduodenal injuries following ERCP]. / Behandlungsergebnisse nach papilloduodenalen ERCP-Verletzungen.

INTRODUCTION: Our goal was to compare operative vs. conservative therapeutic strategies after injuries following ERCP. METHODS: Eight patients with ERCP-induced injuries were surveyed retrospectively. Four of them were treated operatively, four conservatively. Criteria for an operative therapy were clinical and radiological findings and laboratory data. RESULTS: The four patients that were treated conservatively had an uncomplicated course whereas three of four patients treated operatively had long and complicated stays. In these patients the operation was performed more than 24 hours after injury. All of them showed advanced biliary peritonitis. One patient was operated on within 24 hours. He was discharged after a short stay without complications. All injuries were located in the retroperitoneum. Five patients showed anatomical abnormality of either duodenum, papilla or common bile duct. In five cases the duodenum was involved in the injury. CONCLUSIONS: The course of disease of the operated patients was longer and more complicated compared to those treated conservatively. According to our data the timing of the operation seems to be an important criterion with respect to the prognosis. Due to the small number of patients, whether conservative therapy should be preferred cannot be determined. The role of the location of injury is also not clarified.

Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma.

INTRODUCTION: Calcitonin is a sensitive marker for medullary thyroid carcinoma. Normalisation of calcitonin levels following resection of medullary thyroid carcinoma has been described after a few hours; however, it may be observed more than 4 weeks after surgery. The aim of this study was to correlate the postoperative calcitonin kinetics with preoperative calcitonin levels and tumour stage. Furthermore, we wanted to test the prognostic impact of the calcitonin kinetics. Therefore, only patients with postoperative normalisation of calcitonin levels (biochemical cure) were included in this study. METHODS: Fourteen biochemically cured patients were analysed, including measurement of postoperative basal and pentagastrin-stimulated calcitonin concentration. With respect to the time of postoperative basal calcitonin normalisation, patients were classified into two groups: (A) patients with normalisation of basal calcitonin levels within 24 h and (B) patients with normalisation of basal calcitonin levels later than 24 h postoperatively. RESULTS: Eight patients were found to have normalisation of basal calcitonin levels within 24 h (group A). In the remaining six patients (group B), the period to normalisation of basal calcitonin levels varied from 6 days to 14 days and longer. There were no differences between the two groups with regard to tumour size, number and pattern of lymph node metastases and tumour stage. However, preoperative basal calcitonin levels were significantly different (258 ng/ml vs 955 ng/ml, P<0.01). In the group with slow-decreasing calcitonin levels, no strong correlation between the preoperative level and the postoperative time to normalisation of basal calcitonin levels could be established, which may be due to the small number of patients. After a median follow-up of 21 months, no patient developed tumour recurrence. However, an increased basal calcitonin level was observed in one patient from group B. All other patients had normal basal and peak calcitonin levels. CONCLUSION: Using a highly sensitive calcitonin assay, we demonstrated that normalisation of basal calcitonin levels may be delayed in patients suffering from medullary thyroid carcinoma. The lack of correlation of preoperative levels and the time to normalisation of the basal calcitonin levels, as well as the positive pentagastrin test in some of the patients, argues that this phenomenon is not simply due to prolonged biochemical calcitonin elimination. Nevertheless, a prognostic influence could not be shown in this study due to the short follow up-period. Further investigations and a longer follow-up are necessary to determine the nature and the prognostic impact of delayed normalisation of calcitonin levels.

[Quality assurance study of benign and malignant goiter. Prospective multicenter data collection regarding 7,617 patients]. / Qualitätssicherungsstudie benigne und maligne Struma. Prospektive multizentrische Erhebungsstudie mit 7,617 Patienten.

A quality control study was undertaken on 7,265 patients with benign goitre and 352 patients with malignant goitre who were surgically treated between 1.1.98 and 31.12.98. 3 hospital groups were defined according to surgical workload: Group 1: < 50 operations/yr; Group 2: 50-150 operations/yr; Group 3: > 150 operations/yr. The temporary rate of recurrent laryngeal nerve (RLN) palsies for benign goitre was 3.9% and the permanent 1.1%. For malignant goitre the rates were 12.8% and 6.8% respectively. The rate of temporary (p < 0.040) and permanent (0.003) palsies after surgery for benign goitre was lower in group 3 compared to group 1 and 2. There were too few cases for statistical analysis of the malignant goitres. After benign goitre surgery a transient hypocalcaemia rate of 6.3% and a permanent of 1.1% were observed. For malignant goitre the incidence was 23.8% and 7.1%, respectively. A significantly increased rate of permanent hypocalcaemia (p < 0.003) was demonstrated in group 3 after surgery for multinodular goitre. Centres in group 3 made more extended (smaller thyroid remnants) resections (p < 0.01) with the equivalent rate of general complications. The average inpatient stay for malignant goitres was 13.1 days and for benign goitres 8.7 days. On average, patients with bilateral resections for benign goitre stayed 0.4 days longer in hospital than those with unilateral procedures. Prophylactic antibiotics were administered to 2.1% of patients and 94.6% received thrombosis prophylaxis.

Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers.

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and > or = 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (> or = 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r = 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.

[Vascular complications in thoracic outlet syndrome: combined transaxillary revascularization and rib resection]. / Vasculäre Komplikationen bei Thoracic-outlet-Syndrom: kombinierte transaxilläre Revascularisation und Rippenresektion.

Based on two patients with vascular complications in thoracic outlet-syndrome, the anatomic and pathophysiologic principles prior to surgery are discussed. Causative therapy including rib resection and elimination of the embolic source in the subclavian artery is often supplemented by peripheral revascularization with bypass, lysis and/or sympathectomy. The transaxillary approach seems to be optimal, combining minimally invasive principles with a long exposure of the subclavian artery from segment 3 to the proximal axillary artery.

Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: prospective multicenter study in Germany.

Risk factors for postoperative complications of benign goiter surgery have not been investigated systematically. To this end, a prospective multicenter study (January 1 through December 31, 1998) was conducted involving 7266 patients with surgery for benign goiter from 45 East German hospitals. High-volume providers (>150 operations per year) performed 69% (5042/7266), intermediate-volume providers 27% (50-150), and low-volume providers 4% (258/7266) of operations. Among the hospital groups, the pattern of thyroid disease did not vary significantly, but there was a trend that small-volume providers tended to perform more operations for uninodular goiter and high-volume providers treated more patients with Graves' disease and recurrent goiter. Extent of resection (p < 0.0001) and remnant size (multinodular goiter and recurrent goiter, p < 0.001), differed significantly, with total thyroidectomy being performed more often in hospitals with more than 150 operations compared to hospitals with an operative volume of less than 150 procedures per year. Despite the larger extent of resection and smaller remnant size, rates of recurrent laryngeal nerve (RLN) palsy or hypoparathyroidism were not increased. When the logistic regression analyses were fitted to evaluate the impact of risk factors on transient and permanent RLN palsy and hypoparathyroidism, larger extent of resection [relative risk (RR) 1.5-2.1] and recurrent goiter (RR 1.8-3.4) consistently evolved as independent risk factors. With hypoparathyroidism, additional significant factors included patient gender (RR 2.1-2.4), hospital operative volume (RR 0.8-1.5), and Graves' disease (RR 2.8). Unlike parathyroid gland identification during hypoparathyroidism, RLN identification (RR 1.6) significantly (p = 0.01) reduced permanent RLN palsy rates. The multivariate analyses clearly confirmed the pivotal role of routine RLN identification, independent of the extent of the thyroid resection. These findings might help hospitals with lower operative volumes to identify patients at increased risk whom they might consider for specialist care.

Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis.

BACKGROUND: The aim of this study was to identify better prognostic parameters for normalization of serum calcitonin in medullary thyroid carcinoma (MTC) patients. METHODS: In 73 patients who had undergone systematic lymph node dissection for MTC between September 1995 and November 1998, preoperative (n = 29) and postoperative (n = 65) basal and stimulated serum calcitonin were correlated with the pTNM classification and the number of positive regional lymph nodes and compartments. RESULTS: In contrast to pT and M, there was a significant correlation between postoperative calcitonin and the pN category. With rising numbers of positive lymph nodes (0, 1-9, 10-19, and > or = 20), postoperative basal and stimulated calcitonin increased exponentially, and gross distant metastases (M1) occurred more frequently (0%, 4%, 13%, and 50%; P = 0.013). Conversely, serum calcitonin was less often normalized (65%, 31%, 0%, and 0%; P = 0. 003). There was a close correlation between the number of positive lymph nodes and the number of affected compartments (P < 0.001; r = 0.93). Irrespective of location, involvement of 10 or more lymph nodes and more than 2 compartments precluded normalization of serum calcitonin. CONCLUSIONS: Quantitative lymph node analysis of MTC improves prediction of calcitonin normalization. When more than two compartments are involved, normalization of serum calcitonin cannot be attained. Surgery should then be less extensive and more directed at preventing local complications.

Repeat mediastinal lymph-node dissection for palliation in advanced medullary thyroid carcinoma.

BACKGROUND: In medullary thyroid carcinoma (MTC), the effectiveness of repeat mediastinal lymph-node dissection for palliation of specific symptoms caused by discrete mediastinal lesions is unclear in non-bulky tumor disease. METHODS: Between November 1994 and August 1998, five symptomatic MTC patients with radiologic evidence of mediastinal tumor and elevated calcitonin levels were subjected to repeat mediastinal lymph-node dissection. RESULTS: At reoperation, an average of 7 of 25 (28%) removed cervical and 5 of 9 (56%) dissected mediastinal lymph-nodes were positive on histopathology. A substantial fraction of these were excised from anatomical regions inaccessible through a purely cervical or partial sternotomy approach. Clinical symptoms were effectively palliated in all five patients. Basal serum calcitonin levels fell only moderately, suggesting distant micrometastases. Mortality was nil. Morbidity encompassed two cases of hypoparathyroidism and a lymphatic fistula that closed spontaneously on total parenteral nutrition. One patient later required cervical reoperation deferred at secondary surgery. All five patients have since remained free of cervical and mediastinal tumor at a mean follow-up of 15 months. CONCLUSIONS: In mediastinal lymph-node metastases, repeat lymph-node dissection is warranted for palliation of discrete anatomic lesions inaccessible through a cervical approach.

Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma.

Normalization of calcitonin levels after surgery has been regarded as the most powerful prognostic factor for medullary thyroid carcinoma (MTC). Although the prognosis of patients with persistent hypercalcitoninemia may be acceptable, the biochemical cure rate can be improved by new microdissection techniques. This raises certain questions: Can extension of locoregional lymphadenectomy (LA) further improve biochemical cure and survival after primary or reoperative MTC surgery? Which factors concerning TNM categories are associated with the possibility of postoperative normalization of calcitonin levels? This study included 64 patients with sporadic MTC operated on from 1986 to 1997. Altogether 27 patients underwent primary surgery, and 37 patients were reoperated, performing a microdissection of all four locoregional compartments (four-compartment lymphadenectomy, or 4CLA). For primary MTC the biochemical cure rate was 100% in node-negative patients and 33% in node-positive patients; the latter could be improved to 45% after 4CLA. In contrast to reoperative MTC, the rate of lymph node metastases (LNMs) with primary MTC correlated with the pT category (pT1 33%, pT2 53%, pT3 100%, pT4 100%) but not with age or sex. Again in contrast to reoperative MTC, mediastinal LNMs in primary MTC were present only in patients with a pT4 tumor. At reoperation, 4CLA was able to cure 22% of node-positive patients, 28% without proved distant metastases. No patient with extrathyroidal tumor involvement or distant metastases was biochemically cured after either primary or reoperative surgery. For all node-positive MTC patients, in addition to cervicocentral LA at least a bilateral cervicolateral LA is recommended. Transsternal mediastinal lymph node dissection is indicated in patients with LNMs in the cervicomediastinal transition, facilitating biochemical cure in up to 45% after the first operation and 22% after reoperative surgery of sporadic MTC.