H. D. Röher

Lysophosphatidic acid, a novel lipid growth factor for human thyroid cells: over-expression of the high-affinity receptor edg4 in differentiated thyroid cancer.

Lysophosphatidic acid (LPA) is a small lipid mediator with pleiotropic biological activities, e.g., the regulation of cellular proliferation and various aspects of cellular physiology. Signal transduction is achieved by binding to 2 high‐affinity receptors, EDG2 and EDG4, and a group of low‐affinity receptors, EDG1–7, all belonging to the superfamily of G protein–coupled receptors. We examined the growth‐regulatory effects of LPA in primary cultures of 8 goiters and 1 papillary thyroid cancer. We further assessed mRNA expression of high‐affinity receptors EDG2 and EDG4 in 14 normal thyroids, 29 papillary thyroid cancers, 7 follicular thyroid cancers and 13 goiters by quantitative RT‐PCR. We also identified mRNA expression of phospholipase A2 and LPA acyltransferase in fresh thyroid tissues derived from various sources. At concentrations of 10, 50 and 150 μM, LPA induced a 2‐fold rise of proliferation (p < 0.001) and acted as strongly as thyrotropin. The combination of LPA and TSH produced significant synergistic effects compared with each substance alone (p < 0.05). Normal thyroid, goiter and papillary or follicular thyroid cancer expressed 2 high‐affinity cognate LPA receptors, EDG2 and EDG4. EDG4 receptor mRNA expression was increased 3‐fold in differentiated thyroid cancer (p < 0.01), both papillary (p < 0.01) and follicular (p < 0.05), compared to normal thyroid or goiter. Overall expression of EDG2 receptor was unchanged in malignancy; however, increased EDG2 expression in individual samples correlated with lymphonodular metastasis (p = 0.01). Thus, lipid mediators are a novel class of factors involved in the control of proliferation in the human thyroid. Altered mRNA expression of the high‐affinity LPA receptor EDG4 suggests a role in the pathogenesis of differentiated thyroid cancer.

Ultrasonography for Diagnosis of Acute Appendicitis: Results of a Prospective Multicenter Trial

A prospective multicenter observational trial was performed to assess the performance and clinical benefit of ultrasonography of the appendix in the routine clinical examination. Included in the study were 2280 patients with acute abdominal pain from 11 surgical departments in Germany and Austria. Ultrasonography of the appendix was performed in 870 (38%) of the patients (range 16-85%). The overall sensitivity of ultrasonography of the appendix was 55% (13-90%), the specificity 95% (range 82-100%), positive predictive value 81% (50-100%), and negative predictive value 85% (68-96%). With respect to single ultrasound scan findings, adequate sensitivity (44%) was achieved only with the target phenomen, not with the other criteria. There were no correlations between the ultrasound findings of the appendix and the diagnostic accuracy of the clinician, the negative appendectomy rate, or the perforated appendix rate. From the study it can be concluded that there is no proven clinical benefit of ultrasound scanning of the appendix in the routine clinical diagnosis.

Trends in Peptic Ulcer Bleeding and Surgical Treatment

An evidence-based approach is followed, with grading of evidence by study design, to evaluate surgical treatment of a bleeding peptic ulcer. In contrast to endoscopic treatment, reports of surgical treatment are rare, with only five randomized trials having been identified. Epidemiologic studies have demonstrated that the incidence of emergency surgery has not changed despite major improvements with endoscopic treatment. There are no proven alternatives to emergency operation for massive bleeding uncontrollable by endoscopic procedures. There is some debate about surgery for rebleeding, but no randomized trial has assessed whether a second endoscopic treatment alone is preferable to surgery with or without repeated endoscopic treatment. Concerning the type of operative procedure, the existing body of evidence, including two randomized studies, indicates that patients are best served by a relatively aggressive surgical approach. Today the value of these studies is limited owing to prevention of ulcer recurrence by eradication and technical improvements of local procedures (e.g., arterial ligation). Early elective surgery was tested in two randomized studies and several uncontrolled series, which demonstrated that it may be beneficial in high risk groups and harmful in others. Indications for early elective surgery should be refined taking into account updated prognostic information and more effective endoscopic treatment. Because of a new understanding of ulcer disease the role of surgery has changed markedly within the last years, no longer aiming to cure the disease but primarily to stop the hemorrhage. Evidence, however, is not derived from properly randomized controlled trials but is based on theoretic arguments and knowledge from studies not primarily dealing with operative treatment.

Therapy of suspected intrathoracic parathyroid adenomas

Background and aims: Ectopic mediastinal parathyroid adenoma as a cause of primary hyperparathyroidism (pHPT) can normally be resected from conventional collar incision. In rare cases with adenomas deeper in the chest, a transthoracic approach is necessary. Patients/methods: We report our experience of 19 patients with suspected mediastinal parathyroid adenomas from a total of 1035 patients with pHPT who were operated on between 1986 and 2000 using an open approach (sternotomy or thoracotomy) or video-assisted mediastinal or thoracoscopic surgery (VAMS/VATS). Results: Fourteen patients underwent an open approach with a success rate of 71% (10 of 14). Four patients remained hypercalcaemic. There were four complications in three patients: three permanent recurrent nerve palsies and one chylus fistula, requiring further surgery. VATS was successful in three of four patients with conversion to sternal splitting because of a false-negative frozen section in one patient. Another patient had parathyroid adenoma retrosternally which could not be resected by means of VAMS and had to be excised using a transsternal approach. There were no complications of minimal invasive procedures. All five patients were normocalcaemic after the operation. Conclusion: Ectopic parathyroid adenomas not resectable by means of a collar incision are rare causes of pHPT and comprise 1.25% of all patients with pHPT in our series. For these patients, VATS revealed an alternative to conventional open procedures. In questionable cases, however, the collar incision should precede the VATS procedure.

BEHANDLUNGSFEHLER BEI OPERATIONEN DER SCHILDDRUSE

Summary. The frequency of medico-legal issues after surgery is rising. Knowledge of the character and frequency of such problems following surgery of the thyroid gland is scant. Analysis of 21,515 cases of adverse effects after medical treatment from 1975 through 1998 identified 222 cases (1 %) of litigation following surgery for thyroid diseases. The frequency of litigation problems rose exponentially during this interval. Malpractice was confirmed in 36 cases (16 %). The litigation was directed against the surgeon in 95 % of cases, the anesthesiologist in 2 %, both of them in 3 % and the ear-nose-throat surgeon in one case. Eighty-nine percent of the 222 cases occurred after routine thyroid surgery. Typical complications such as recurrent nerve palsy (50 %), hypoparathyroidism (14 %), bleeding (3 %), and late goiter recurrence (1 %) accounted for 63 % of the presumed but for only 31 % of ascertained malpractice cases. Atypical complications such as other neurologic deficits (10 %), infections (5 %), residual nodules (4 %), scar problems (5 %) accounted for 37 % of the suspected but for 70 % of confirmed malpractice cases. Deficiencies in obtaining informed consent were present in only 11 %. Malpractice was more frequently judged to be present, if a second operation was necessary (P < 0.001), if the goal of the operation had been missed (P < 0.001), or if any kind of complication was followed by a fault in postoperative care (P < 0.001).Zusammenfassung: Trotz steigender Häufigkeit medikolegaler Probleme ist die Kenntnis über Art und Häufigkeit von Behandlungsfehlern nach Operationen der Schilddrüse gering. Die Analyse eines Kollektivs von 21.515 Beschwerdefällen aus der Zeit von 1975–1998 im Raum der Ärztekammern Nordrhein und Baden-Württemberg ergab 222 Beschwerden (1 %) nach Operation der Schilddrüse. Die Zahl der Beschwerden stieg im Beobachtungszeitraum exponentiell an. In 36 Fällen (16 %) stellten die Gutachterkommissionen Behandlungsfehler fest. Die Beschwerde betraf in 95 % den Chirurgen, in 2 % den Anaesthesisten, in 3 % beide Disziplinen und einmal einen HNO-Arzt. Von den Beschwerden bezogen sich 90 % auf Komplikationen nach Routine-Eingriffen an der Schilddrüse. Operationstypische Komplikationen wie Recurrensparesen (50 %), Hypoparathyreoidismus (14 %), Nachblutung (3 %) und Spätrezidiv (1 %) machten zusammen 63 % der Behandlungsfehlervorwürfe, aber nur 31 % der bestätigten Behandlungsfehler aus. Atypische Komplikationen wie neurologische Defizite (10 %), Infektionen (5 %), belassene Knoten (4 %), Narbenprobleme (5 %) machten 37 % der Vorwürfe, aber 70 % der Behandlungsfehler aus. Aufklärungsmängel lagen bei nur 11 % der festgestellten Behandlungsfehler vor. Die Feststellung eines Behandlungsfehlers war besonders häufig gegeben, wenn eine erneute Operation erforderlich wurde (p < 0.001), wenn das Operationsziel nicht erreicht wurde (p < 0.001) oder wenn einer Komplikation ein Fehler in der Nachbehandlung folgte (p < 0.001).

Activin A and Activin Receptors in Thyroid Cancer

Proliferation is controlled by a network of mitogenic and growth inhibitory factors. Transforming growth factor-beta1 (TGF-beta1) and activin A are the most important growth inhibitors of benign follicular epithelial cells of the human thyroid. The effects of these substances on malignant primary thyrocytes are not known. We have examined the growth regulatory effects of activin A and TGF-beta1 in primary cultures derived from four papillary cancers, two follicular thyroid cancers, and three benign thyroid tissues. Malignant cells demonstrated resistance to activin and TGF-beta1 or reversal to a weak but significant mitogenic effect (p < 0.001). We also evaluated the activin receptor transcription pattern. Isoforms alk4-1, 4-2, and 4-3 were found in benign (n = 12) and malignant (n = 22) tissues. Two subtypes of type I and type II activin receptors were demonstrated. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated a significant threefold downregulation of alk4-1 receptors in papillary (n = 25) and follicular (n = 18) thyroid cancers as compared to normal thyroids (n = 12) (p < 0.001). To our knowledge these are the first data to demonstrate reversal of activin and TGF-beta1 effects in thyroid malignancy and to demonstrate changes of the type Ib activin receptor expression in thyroid malignancy.

Genetic and Biochemical Screening for Endocrine Disease

AbstractThe development of biochemical and genetic screening tests for inherited endocrine diseases has dramatically changed our approach to surgical patients with endocrine tumors. Among more than 1800 patients with endocrine tumors and a possible inherited disease operated on between 1986 and 1997, there were 6.1% to 7.3% who were found to have a familial disease associated with familial medullary thyroid cancer, (MTC), multiple endocrine neoplasia type IIa (MEN-IIa), MEN-IIb, or MEN-I. Genetic testing for the RET proto-oncogene is therefore recommended for all patients with MTC, and testing for the MEN-I gene is recommended in patients with suspected MEN-I and in specific clinical subgroups with an increased probability of endocrine tumor heredity. Early treatment based on early diagnosis by genetic testing appears to improve survival and to decrease morbidity in these patients.

A Left Nonrecurrent Inferior Laryngeal Nerve in a Patient with Right-Sided Aorta, Truncus Arteriosus Communis, and an Aberrant Left Innominate Artery

The identification and prevention of injury to the inferior laryngeal nerve is one of the main issues in thyroid surgery. Sound knowledge of anatomic variants of the nerve is of major importance. In rare cases the nerve does not run the recurrent way and it is therefore difficult to identify the nerve. Abnormal developments of the aortic arch during embryogenesis include malformation of the great vessels and can be the reason for anatomic abnormalities. A cause for a nonrecurrent nerve on the right side is the so-called lusorian artery, a right retroesophageal subclavian artery. Left-sided nonrecurrent nerves are seldom if ever documented. Only two cases have been published so far of patients with situs inversus viscerum, where left nonrecurrent nerves were associated with inverse, left-sided lusorian arteries.

Incidentally Found Medullary Thyroid Cancer: Treatment Rationale for Small Tumors

The object of this study was to assess the extent of surgery required for small sporadic medullary thyroid cancers (sMTCs). We retrospectively studied 261 patients with MTCs treated in our institution between 1986 and 2002 and identified 15 patients with small pT1 or pT2 sMTCs. The tumors were diagnosed incidentally, so surgical therapy was less than total thyroidectomy. Total thyroidectomy with or without neck dissection was applied to all other patients as standard surgical treatment of care. Patients were systematically followed up by postoperative ultrasonography, calcitonin, carcinoembryonic antigen levels, and pentagastrin stimulation tests. On long-term follow-up over a period of 4.6 years, the rate of biochemical cure in these patients who underwent less than total thyroidectomy for a sporadic incidentally diagnosed tumor was 100%. We concluded that completion thyroidectomy and neck dissection are not mandatory in patients in whom a solitary small sMTC is incidentally discovered by histologic diagnosis following operation so long as a genetic background is excluded. Nevertheless, such patients require systematic careful long-term follow-up.

Growth Regulation of Thyroid and Thyroid Tumors in Humans

In a study of growth regulation of the human thyroid gland and thyroid tumors we investigated the impact of iodine and that of the thyroid-specific growth-stimulating hormone TSH. Further studies included locally active growth factors such as the epidermal growth factor, insulin-like growth factor, and tissue transforming growth factors alpha and beta. In addition to studies of growth regulation by the various growth factors in mostly normal thyrocytes, the impact of tumor-specific mutations in oncogenes and tumor-suppressor genes was investigated. The results demonstrated distinct changes in tissue specificity and sensitivity to external stimuli. This rather complex view on thyrocyte growth regulation may be confusing, but it describes the biologic reality more precisely. Increased knowledge of the regulatory processes may lead to the development of new tumor- and patient-specific therapeutic approaches, especially for preventing benign goiter recurrence and for treating follicular and papillary thyroid cancers.