S. Walgenbach

Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience

Abstract. When mutations of theRETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.

Outcome after surgery for primary hyperparathyroidism: ten-year prospective follow-up study.

Abstract. Clinical outcome after surgery for primary hyperparathyroidism was evaluated in a prospective long-term, follow-up study. From August 1, 1987 to August 31, 1998 a total of 360 patients were prospectively investigated and included in a follow-up study. All patients underwent follow-up examinations at regular surveillance intervals. The postoperative course is known for 94.5% of all patients. Follow-up was 1 month to 10 years (median 24 months; mean 34.5 ± 29.8 months). Asymptomatic primary hyperparathyroidism was rare (6%), and its true frequency could be confirmed only postoperatively because some of the patients were unaware of mild symptoms of hypercalcemic syndrome prior to surgery. Surgical cure was obtained in 97.7% of patients after initial cervical exploration; and successful parathyroidectomy provided long-term relief of symptoms. Within 2 years postoperatively, 84% of the patients recovered fully from hypercalcemic syndrome; in 58% of these patients recovery occurred within the first month after surgery. Skeletal symptoms persisted in 24% of patients 2 years postoperatively. To date no patient has developed recurrence of primary hyperparathyroidism. During follow-up in our study population mortality was significantly higher than the expected mortality risk for the German population as a whole (p= 0.00024). The present prospective follow-up study yielded conclusive outcome research data after operative therapy for primary hyperparathyroidism. The high cure rate and low morbidity, as well as the increased mortality, in our study population during follow-up after successful operative therapy for the disease emphasize the importance of early diagnosis and early surgical treatment for primary hyperparathyroidism, even in the absence of manifest symptoms.

Effects of Cytokines on the Expression of Cell Adhesion Molecules by Cultured Human Omental Mesothelial Cells

Cultured mesothelial cells (HOMES) are very responsive to the proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha). E-selectin, ICAM-1 and VCAM-1 are known to play an important role, because they are presented by diverse cell types, for example endothelial cells (ECs), and interact with co-responding ligands on white blood cell membranes. In this study, the expression of ICAM-1, VCAM-1, E-selectin as well as PECAM-1 on cultured HOMES was studied over 5, 24, 48 and 72 h exposure to IL-1 beta, interferon-gamma and TNF-alpha. In previous studies we have shown that IL-1 beta and TNF-alpha increase the expression of ICAM-1, E-selectin and VCAM-1 on the cytoplasmatic membranes of HUVECs, HSVECs and HAFECs (ECs from human umbilical vein, saphenous vein and femoral artery, respectively). Using a comparative quantitative cell enzyme immunoassay, we found that expression of the adhesion molecules ICAM-1 and VCAM-1 was significantly increased on HOMES in a dose- and time-dependent manner, compared to nonstimulated cells. Thus, ICAM-1 increased dramatically after 5 h incubation with TNF-alpha. Values of about 450% of the control level were measured. VCAM-1 was similarly stimulated after 24 h incubation with the same cytokine, although its level of expression was significantly lower than that of ICAM-1. In contrast to findings in the literature, VCAM-1 was not found to be expressed constitutively. E-selectin was neither constitutively expressed nor markedly inducible on HOMES. Only weak expression was found after 24 h incubation with high-dose IL-1 beta. PECAM-1 was expressed constitutively, as became evident in antibody dilution studies. These data indicate that HOMES respond to inflammatory stimuli, in some ways in a similar fashion to vascular endothelial cells, but also show a specific pattern of antigen presentation. The results are important for a better understanding of inflammatory processes in serous cavities. The data are also relevant for the improvement of antithrombogenous surfaces of the lumina of vascular prostheses by cell seeding.

Differential expression of cell adhesion molecules in inflamed appendix: correlation with clinical stage

The diagnosis of ‘early inflamed’, ‘recurrent’ or ‘sub‐acute’ appendicitis is often difficult and accompanied by controversies between clinical data, histological findings, and their interpretation. The expression of the intercellular cell adhesion molecule‐1 (ICAM‐1), the vascular cell adhesion molecule‐1 (VCAM‐1), and E‐selectin has been studied in 61 appendicectomy specimens for possible use as a diagnostic tool. This study demonstrates a different expression of CAM by endothelial (EC) and mesothelial cells (MC) in the various stages of appendicitis, with early E‐selectin and ICAM‐1 expression in EC, followed by VCAM‐1 in EC and MC. Appendices from patients with prolonged clinical symptoms defined by clinicians as ‘chronic’ appendicitis showed VCAM‐1 expression and occasionally weak expression of E‐selectin in EC. In several cases, discrepancies were found between the pre‐operative ‘clinical’ diagnosis, the histomorphological findings, and the immunohistological results. In this context, the expression of E‐selectin and VCAM‐1 in comparison with the histological features has potential significance in the diagnosis of ‘early acute’, ‘sub‐acute’ or ‘recurrent’ appendicitis. In addition, a correlation was demonstrated between the histological stages of appendicitis and the kinetics of CAM expression. The study also indicates that the time course of E‐selectin expression in vivo is longer than is suggested from in vitro data. Copyright

Prospective Evaluation of Parathyroid Graft Function after Total Parathyroidectomy and Heterotopic Autotransplantation in Renal Hyperparathyroidism by Bilateral Determination of Intact Parathormone in Cubital Venous Blood

Abstract. The value of gradients for intact parathyroid hormone (PTH) in the assessment of graft function after total parathyroidectomy/autotransplantation for renal hyperparathyroidism was evaluated in a prospective follow-up study. Altogether 99 patients who underwent operation from August 1, 1987 to December 31, 1996 were prospectively investigated and reexamined postoperatively, including analyses of serum calcium, alkaline phosphatase, and intact PTH in the antecubital venous blood of both arms. The postoperative course is known for all patients. Of the 99 patients included in the study, 95 underwent one to nine reexaminations (median three) over follow-up periods of 1 month to 5 years (median 24 months). Reproducible PTH gradients were established during follow-up. Ninety percent of the calculated gradients were ≤ 20. Intermittent postoperative hypocalcemia, due to calcium deficiency of the skeleton in renal osteopathy, led to an increase in PTH secretion and gradients. Increasing gradients > 20 during follow-up make graft-dependent recurrence probable. The presence of a gradient of approximately 1 in bilaterally elevated PTH levels may be an indication of hyperfunctioning parathyroid tissue in the neck or mediastinum. The combined assessment of the course of gradients for intact PTH, hormone levels in both arms, and serum calcium permits an objective evaluation of parathyroid graft function.

PECAM-1 Expression in Human Mesothelial Cells: An in vitro Study

Mesothelial cells are actively involved in inflammatory processes by expressing a set of cell adhesion molecules (CAMs). Transmigration of leukocytes into inflamed tissues requires a chemotactic stimulus and engagement of platelet-endothelial cell adhesion molecule-1 (PECAM-1). To investigate the kinetics involved in peritonitis, pure cultures of mesothelial cells are necessary. In previous studies, we have found that human mesothelial cells (HOMES) show a weak constitutive expression of PECAM-1, which cannot be further stimulated by cytokines. It is known that all serous cavities and body fluids contain numerous macrophages which strongly express this adhesion molecule. To identify the cells responsible for the expression of PECAM-1, mesothelial cells freshly obtained from omental tissue were isolated using PECAM-1-conjugated magnetic beads by cell sorting. For these studies, the negative as well as the positive fraction of isolated cells were used. As a control, freshly isolated monocytes were studied. Cell cultures were characterized by light and electron microscopy, as well as immunocytochemistry. The negative cell fraction was cultivated and stimulated for different times with tumor necrosis factor-alpha (30 and 300 U/ml), interleukin-1 beta (10 and 100 U/ml) and interferon-gamma (500 U/ml) and PECAM-1 expression was analyzed by a comparative quantitative cell enzyme immunoassay (EIA). The positive cell fraction was treated in the same manner. Both fractions of isolated cells showed strong positivity for cytokeratins 8, 18, 7 and 19, as well as vimentin. CD68, a monocyte marker, was not detected on mesothelial cells. In addition, EIA analysis confirmed the constitutive expression of PECAM-1 obtained from previous studies. This expression on HOMES was not inducible, irrespective of the type and concentration of cytokine studied. These data confirm PECAM-1 expression on mesothelial cells obtained from human omental tissue and suggest a critical role in transmigration of leukocytes during peritoneal inflammation.

Prospective Study of Parathyroid Graft Function in Patients with Renal Hyperparathyroidism After Total Parathyroidectomy and Heterotopic Autotransplantation by Measurement of the Intact Parathyroid Hormone Concentrations in Both Antecubital Veins

OBJECTIVE Evaluation of the value of gradients for intact parathyroid hormone after total parathyroidectomy and heterotopic autotransplantation for renal hyperparathyroidism. DESIGN Prospective long-term follow-up study. SETTING Teaching hospital, Germany. SUBJECTS A total of 115 patients operated on for renal hyperparathyroidism between 1 August 1987 to 15 August 1997. INTERVENTIONS 100/115 had total parathyroidectomy with autotransplantation. MAIN OUTCOME MEASURES Analyses of serum calcium, alkaline phosphatase, and intact parathormone in serum 1, 4, 8, 12, 18 and 24 months postoperatively and annually thereafter. Parathormone gradients were calculated as the ratio of the parathormone concentrations in the antecubital venous blood of the grafted and the non-grafted arm. RESULTS During follow-up (mean 32 months, range 1 month to 9 years), 111 of the 115 patients had one to 10 re-examinations (mean: 4) and in the patients who had had total parathyroidectomy with autotransplantation a total of 437 gradients could be calculated, 91% of which were < or =20. Postoperative hypocalcaemia caused by calcium deficiency of the skeleton led to an increase in parathormone secretion and gradients. Increasing parathormone gradients during follow-up as a result of excessive parathormone secretion in the grafted-arm indicated graft-dependent recurrence. In 6 of the 9 patients with graft-dependent recurrences the gradients exceeded 20. CONCLUSION The combined sequential assessment of gradients for intact parathyroid hormone and of serum calcium concentrations permits objective evaluation of parathyroid graft function.

PROGNOSTISCHE BEDEUTUNG DES E-CADHERIN BEIM PAPILLAREN SCHILDDRUSENCARCINOM

Summary. The prognostic significance of e-cadherin in papillary thyroid carcinoma was evaluated in a retrospective study. From September 1985 to December 1996, 113 patients underwent surgery for papillary thyroid carcinoma. Seventy-eight formalin-fixed, paraffin-embedded tissue samples were available for immunohistochemical analysis of e-cadherin expression. In 74 of these 78 patients the postoperative course is known for 2 months to 35.2 years (median 3.6 years, mean: 4.9 ± 4.8 years). Reduced or negative e-cadherin expression (≤ 20 %) was associated with advanced T categories of the primary tumours and higher rates of synchronous lymph node involvement and distant metastasis. During follow-up in this group of patients locoregional tumour recurrence occurred more frequently and survival was shorter than in patients with tumours which exhibited e-cadherin expression of > 20 %. Statistical analysis revealed e-cadherin expression (≤ 20 %/ > 20 %), synchronous distant metastasis (M0/pM1, cM1) and radicality of resection (R0/R1, 2) as significant risk factors for survival. Our findings provide evidence that e-cadherin is a prognostic factor in papillary thyroid carcinoma.Zusammenfassung. In einer retrospektiven Untersuchung wurde die prognostische Relevanz von e-Cadherin beim papillären Schilddrüsencarcinom analysiert. Von 78 von 113 Patienten, die zwischen dem 1. 9. 1985 und 31. 12. 1996 wegen eines papillären Schilddrüsencarcinoms operiert wurden, waren formalinfixierte, paraffineingebettete Präparate ihrer Schilddrüsencarcinome zur immunhistochemischen e-Cadherin-Analyse verfügbar. Von 74 dieser 78 Patienten ist der postoperative Verlauf über 2 Monate bis 35,2 Jahre bekannt (Median 3,6 Jahre; Mittel 4,9 ± 4,8 Jahre). Eine schwache bzw. negative e-Cadherin-Expression (≤ 20 %) fand sich bei höheren T-Stadien, es bestanden vermehrt synchrone Lymphknoten- und Fernmetastasen. Diese Patienten entwickelten häufiger locoregionäre Tumorrezidive und hatten eine ungünstigere Prognose. In der statistischen Analyse erwiesen sich die e-Cadherin-Expression (≤ 20 %/ > 20 %), eine synchrone Fernmetastasierung (M0/pM1, cM1) sowie die Radikalität des Eingriffs (R0/R1, 2) als prognostisch relevant. Unsere Daten sprechen für eine prognostische Bedeutung der e-Cadherin-Expression beim papillären Schilddrüsencarcinom.

Maschineller und manueller Bronchusverschluß —ergebnisse einer konsekutiven untersuchungsserie

SummaryAfter lobectomy and pneumonectomy in experimental evaluations stapled bronchial closures showed the lowest incidence of inflammatory reaction and the highest strength determined by leakage pressure compared with other suture material. A total of 233 lung resections - performed at Surgical University Clinic Köln-Lindenthal and the Clinic for General and Abdominal Surgery of the Johannes-Gutenberg-Universität Mainz — were reviewed. Mechanical stapling reduced the rate of bronchopleural fistulas to 2.0% compared with 7.1 % after manual suturing. In parallel, mortality related to bronchial stump leakage decreased to 0.7%. Main advantages of bronchial closure with staplers are the simplicity of their use, the speed and the uniformity of the closure. Thereby stapling devices are valuable completions in pulmonary surgery.ZusammenfassungExperimentelle Untersuchungen haben für den maschinellen Bronchusverschluß nach Lobektomie und Pneumonektomie im Vergleich zu anderen Nahtmaterialien die geringste Entzündungsrate und die höchste Zugfestigkeit ergeben. In einer konsekutiven Serie von 233 Lungenresektionen der Chirurgischen Kliniken Köln-Lindenthal und der Klinik für Allgemein- und Abdominalchirurgie der Johannes Gutenberg-Universität Mainz ging die Häufigkeit einer Bronchus-stumpfinsuffizienz von 7,1% nach manuellem Bronchusverschluß auf 2,0% und die insuffizienzbedingte Letalität auf 0,7% bei Anwendung des Klammergeräts zurück. Die wesentlichen Vorteile des maschinellen Bronchusverschlusses sind die Einfachheit der Anwendung, die Schnelligkeit und die Gleichmäßigkeit des Verschlusses. Damit stellen die Klammernahtgeräte bei Lungenresektionen eine wertvolle Ergänzung der Operationstechnik dar.After lobectomy and pneumonectomy in experimental evaluations stapled bronchial closures showed the lowest incidence of inflammatory reaction and the highest strength determined by leakage pressure compared with other suture material. A total of 233 lung resections-performed at Surgical University Clinic Köln-Lindenthal and the Clinic for General and Abdominal Surgery of the Johannes-Gutenberg-Universität Mainz--were reviewed. Mechanical stapling reduced the rate of bronchopleural fistulas to 2.0% compared with 7.1% after manual suturing. In parallel, mortality related to bronchial stump leakage decreased to 0.7%. Main advantages of bronchial closure with staplers are the simplicity of their use, the speed and the uniformity of the closure. Thereby stapling devices are valuable completions in pulmonary surgery.

Modified cryopreservation and xenotransplantation of human parathyroid tissue.

Introduction: A modified cryopreservation technique for human parathyroid tissue was compared with the standard method using a programmed freezer. Methods: Total parathyroidectomy was performed in three groups of 6-week-old Rowett nude rats. Group I (control) underwent no transplantation of parathyroid tissue (n=9). After 10 days, the rats of groups II (n=15) and III (n=15) underwent xenotransplantation of 20 mg cryopreserved human parathyroid tissue, which had been stored in liquid nitrogen at –196°C for 1–22 months prior to xenotransplantation. The parathyroid tissue was derived from 15 parathyroidectomized patients with renal hyperparathyroidism. Two tissue samples were obtained from every patient. One sample from every patient was cryopreserved by means of the technique of programmed cryopreservation: programmed freezing of human parathyroid tissue at a controlled rate of –1°C/min to –80°C prior to transfer to liquid nitrogen (group II). The second sample from every patient was cryopreserved by means of a modified cryopreservation technique: immediate placement of human parathyroid tissue in a freezer at –20°C and transfer to liquid nitrogen after 2 h (group III). Calcium and intact parathyroid hormone concentrations in serum were determined over a period of 60 days. Furthermore, individual differences in the calcium concentrations were assessed for each rat on the basis of the calcium levels recorded preoperatively and at day 60. Results: All animals in the control group developed hypocalcemia. Serum calcium concentrations returned to normal levels 60 days after xenotransplantation of parathyroid tissue, which had been cryopreserved using the modified technique (group III) in 12 of 15 rats (80%). At day 60, serum calcium had normalized in 10 of 15 rats (67%) after xenotransplantation of parathyroid tissue cryopreserved using programmed freezing (group II). After modified cryopreservation (group III), the median individual difference in the calcium concentrations was –0.16 mmol/l after programmed freezing (group II). At the end of the study, a median level of human intact parathyroid hormone of 3.5 pg/ml and 2.4 pg/ml was estimated for groups II and III, respectively. There was no statistical significant difference of the individual differences in the calcium concentrations or of the levels of human intact parathyroid hormone between groups II and III. Conclusion: Human parathyroid tissue was successfully xenografted in the present experimental study. The results obtained after cryopreservation using the described modified technique were equivalent to those recorded after controlled freezing in a programmed freezer. The simplified cryopreservation technique therefore appears to be suitable for human parathyroid tissue.