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Background The timing of parathyroidectomy in kidney transplant candidates suffering from secondary hyperparathyroidism before versus early or late after transplantation remains controversial. Methods The short-term follow-up cohort comprised 66 patients with 1-year post-transplant follow-up, while the long-term follow-up cohort contained 123 patients. Risk-adjusted identification of independent risk factors for compromised renal graft function (KDIGO stage ≥ IV) was performed using multivariable regression analysis adjusted for propensity score logits for parathyroidectomy before versus after renal transplantation. Intra-individual matched-pairs analyses were used to identify significant effects of post-transplant parathyroidectomy on graft function as assessed by estimated glomerular filtration rate (eGFR) and paired t tests. Results Donor kidney function KDIGO stage III (P = .030; OR = 5.191, 95% CI: 1.100–24.508), donor blood group 0 (P = .005; OR = 0.176, 95% CI: 0.048–0.642), and post-transplant parathyroidectomy (P = .032; OR = 17.849, 95% CI: 1.086–293.268) were revealed as independent significant risk factors for compromised renal graft function in the short-term follow-up cohort using propensity score risk adjustment while post-transplant parathyroidectomy had no independent influence in the long-term follow-up cohort (P = .651). Parathyroidectomy after renal transplantation compromised graft function early after parathyroidectomy and at last follow-up in all post-transplant parathyroidectomy cases (P ≤ .004). Parathyroidectomy within the first post-transplant year was associated with compromised renal graft function until last follow-up (P = .004), while parathyroidectomy late post-transplant was not. Conclusion Parathyroidectomy should be conducted before transplantation or, if this is not possible, preferably after the first post-transplant year.

Introduction Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort study is located at the interface of medical and surgical consideration of sHPT treatment options and identifies risk-factors for nodular hyperplasia of PG. Material and methods One-hundred-eight resected PG of 27 patients with a broad spectrum of sHPT severity were classified according to the degree of hyperplasia by histopathology. Twenty routinely gathered parameters from medical history, ultrasound findings of PG and laboratory results were analyzed for their influence on nodular hyperplasia of PG by risk-adjusted multivariable binary regression. A prognostic model for non-invasive assessment of PG was developed and used to weight the individual impact of identified risk-factors on the probability of nodular hyperplasia of single PG. Results Independent risk-factors for nodular hyperplasia of single PG were duration of dialysis in years, PG volume in mm3 determined by ultrasound and serum level of parathyroid hormone in pg/mL. Multivariable analyses computed a model with an Area Under the Receiver Operative Curve of 0.857 (95%-CI:0.773–0.941) when predicting nodular hyperplasia of PG. Theoretical assessment of risk-factor interaction revealed that the duration of dialysis had the strongest influence on the probability of nodular hyperplasia of single PG. Conclusions The three identified risk-factors (duration of dialysis, PG volume determined by ultrasound and serum level of parathyroid hormone) can be easily gathered in daily routine and could be used to non-invasively assess the probability of nodular hyperplasia of PG. This assessment would benefit from periodically collected data sets of PG changes during the course of sHPT, so that the choice of medical or surgical sHPT treatment could be adjusted more to the naturally changing type of histological PG lesion on an individually adopted basis in the future.

Parathyroid glands (PG) are rarely analyzed in renal transplant (RTX) patients. This study analyzes comparatively PG of RTX and end-stage renal disease (ESRD) patients. The clinical part of the study evaluates if total parathyroidectomy with autotransplantation (TPT+AT) treats appropriately hypercalcemic hyperparathyroidism in RTX patients.TPT+AT was performed in 15 of 23 RTX and 21 of 27 ESRD patients. Remaining patients underwent less-than-total PT. Volume and stage of hyperplasia were determined from 86 PG of RTX and 109 PG of ESRD patients. Patients were categorized according to the presence of small PG (volume100 mm(3)). Calcium homeostasis and hyperparathyroidism were evaluated 2 years after PT in RTX patients.PG of RTX patients were significantly smaller, but similar hyperplastic in comparison to PG of ESRD patients. Small PG were more frequent in RTX than in ESRD patients (19% vs 6%) and mainly graded normal or diffuse hyperplastic (94%). Forty-seven percent of RTX, but only 14% of ESRD, patients receiving a total PT possessed ≥1 small PG (P.05). Overall, PT treated successfully hypercalcemic hyperparathyroidism. However, TPT+AT caused permanent hypocalcemia in 50% of RTX patients without small PG and even in 83% of RTX patients with small PG. All RTX patients receiving less-than-total PT were normocalcemic at 2-year follow-up. Logistic regression revealed a 10.7 times greater risk of permanent hypocalcemia in RTX patients with small PG receiving TPT+AT compared with RTX patients without small PG receiving TPT+AT or RTX patients undergoing less-than-total PT.Surgeons performing PT should be aware of the high frequency of small and less diseased PG in RTX patients. In this context, TPT+AT might overtreat hypercalcemic hyperparathyroidism in RTX patients, especially when small PG are present.

ObjectiveThe objective of this study was to determine whether the use of recombinant human TSH (rhTSH) to stimulate radioiodine uptake after thyroidectomy is as efficacious as a period of withholding thyroid hormones, while at the same time avoiding hypothyroidism, reducing sick leave time and shortening the hospital stay.DesignOur aim was to compare the standard procedure of differentiated thyroid cancer treatment, which consists of thyroidectomy followed by 4 weeks of hypothyroidism and a conclusive ablative activity of 131iodine, with a new shortened treatment in which l-thyroxine (T4) medication is initiated a day after thyroidectomy, followed by application of rhTSH stimulation and subsequent ablation a few days after surgery. We presumed our treatment to represent the most sophisticated strategy for the reduction in sick leave days overall without any reduction in safety or the efficacy of ablative therapy.MethodsPatients (n=25) were randomized either for surgery and rhTSH stimulation or surgery and l-T4 abstinence before the first application of radioiodine. Ablation success was determined by neck ultrasound and serum thyroglobulin during follow-up. RhTSH receivers were monitored for an average of 635 days (s.d.±289) and patients in l-T4 abstinence for an average of 624 days (s.d.±205). Both groups were statistically compared for significant differences in treatment efficacy, safety and overall time of sick leave.Results and conclusionsOur shortened treatment proved to be equally efficacious and safe in comparison with the conventional therapy regimen. At the same time, it showed economic advantages through the reduction in average sick leave time from ∼29 days (l-T4 abstinence) down to ∼6 days (rhTSH stimulation) as well as sustaining the patient's quality of life by the complete avoidance of hypothyroidism.

A 35-year-old man reported persistent exertional dyspnoea and pressure sensation over the left chest for the last six weeks. On auscultation there were diminished breath sounds over the right base. Chest X-ray demonstrated a 10 cm large ventral paracardiac shadow on the right. Computed tomography suggested a hernia of the foramen of Morgagni; persisting symptoms indicated a laparotomy. This revealed an opening of about 1.5 cm in the right substernocostal triangle through which the entire greater omentum had herniated into the thorax. The omentum was repositioned and the hernial defect closed by direct suture. The postoperative course was without complication and the patient was discharged after seven days.

Zielsetzung. Bestimmung des Stellenwertes des arteriellen Stimulationstests mit venoser Blutentnahme (ASVS) zur praoperativen Lokalisation von Insulinomen. Methodik. Dreizehn Patienten mit endogenem Hyperinsulinismus wurden bei nichtkonklusiver externer Vordiagnostik praoperativ mittels transabdominellem Ultraschall (US), Spiral-CT (CT),MRT, endoskopischem Ultraschall (EUS), digitaler Subtraktionsangiographie (DSA) in Verbindung mit dem ASVS-Test untersucht. Die Resultate wurden mit intraoperativen Befunden und den histologischen Ergebnissen korreliert. Ergebnisse. Die Sensitivitaten betrugen fur US 8%,MRT 27%, CT 46%, EUS 50%,DAS 69% und ASVS 92%.Die intraoperative Palpation und Ultraschall (IOUS) erzielten eine Sensitvitat von 77%.Bei 3 Patienten war das Insulinom intraoperativ weder palpabel noch durch IOUS lokalisierbar, die Resektion erfolgte anhand der praoperativen Diagnostik. Der ASVS-Test als funktionelles Verfahren war in der Detektion den praoperativen bildgebenden Verfahren uberlegen. Schlussfolgerungen. Der ASVS-Test erwies sich als das zuverlassigste Verfahren fur die Lokalisationsdiagnostik.Vor dem Hintergrund gesundheitsokonomischer Uberlegungen sollte er bei negativer Schnittbilddiagnostik fruhzeitig eingesetzt werden.

Grundlagen: Als eine Alternative zur Steroidsubstitutionstherapie wurde die syngene Transplantation von adrenocorticalen Zellpopulationen unter die Nierenkapsel an LEWIS-Ratten untersucht.

The aim of this study was determination of the significance of the arterial stimulation test with venous sampling (ASVS) in the preoperative localization of insulinoma. Eleven patients with endogenous hyperinsulinism underwent preoperative transabdominal US, spiral computer tomography (spiral CT), MRI, endoscopic ultrasound (EUS) as well as angiography (DSA) combined with ASVS. The results were compared with intraoperative findings, intraoperative ultrasound (IOUS) and histopathology. There were no complications related to the ASVS test. In 11 patients the tumor could be localized with the various modalities as follows: US 1 of 11 (9%), MRI 3 of 10 (30%), spiral CT 4 of 11 (36%), EUS 5 of 10 (50%), DSA 8 of 11 (73%), and ASVS 10 of 11 (91%). In 2 patients the tumors were intraoperatively neither palpable nor detectable by IOUS, and consequently the intraoperative management was governed by information provided by DSA combined with the ASVS test. Ten patients had solitary benign insulinomas and 1 patient with multiple endocrine neoplasia I had two tumors adjacent to each other in the pancreatic tail. Arterial stimulation test with venous sampling was the most sensitive preoperative test for regionalizing the insulinoma in our set of patients. It can be performed safely in the course of a regular DSA examination and may affect intra-operative management in patients in whom the tumors are not detectable by palpation or IOUS.

Syngeneic transplantation of adrenocytes was investigated in Lewis rats in regard to differentiated hormone secretion and cortex regeneration after bilateral adrenalectomy as an alternative to steroid substitution. Methods Purified cell suspensions of glomerulosa (density 1.061 +/- 0.001 g/ml) and fasciculata (density 1.034 +/- 0.003 g/ml) cells were obtained by density gradient separation and were transplanted under the kidney capsule either immediately or after a 29-day culture period. Animals were killed after transplantation of cultured glomerulosa (CG-Tx) or cultured fasciculata cells (CF-Tx), noncultured glomerulosa cells (G-Tx) or non-cultured fasciculata cells (F-Tx), or both cell types (GF-Tx) for morphological studies after 30, 120, and 360 days. Plasma samples were drawn for measurement of corticosterone and aldosterone as well as 24 hr-urine for sodium and potassium levels at day 3, 30, 120, and 360 after transplantation. Results In primary culture fasciculata cell number remained stationary although glomerulosa cell number increased to almost 10-fold. Vital cortex cells were demonstrated in each explanted graft by histochemistry but only group G-Tx, CG-Tx, and GF-Tx (purified cell suspensions of zona glomerulosa and fasciculata) showed neocortex-like structures. We found plasma (urine) corticosterone to decrease from preoperatively 256-304 ng/ml (226-239 ng/day) in untreated animals to levels about half as high 3 days after transplantation, increasing to normal values in all study groups 30 days after treatment (data given as range). Plasma aldosterone concentrations, 150-180 pg/ml in untreated rats, decreased to nondetectable levels for 1 week after bilateral adrenalectomy. At day 30 group GF-Tx, G-Tx, and CG-Tx showed comparable aldosterone plasma concentrations (104-122 pg/ml); however, levels in F-Tx and CF-Tx were 19-49 pg/ml, and did not increase significantly within the observation period. Conclusions Cells derived from the zona glomerulosa maintain viability, produce both aldosterone and corticosterone, and regenerate a neocortex with cells that histologically resemble both zona glomerulosa and fasciculata cells. They are therefore suitable for adrenocortical transplantation. In contrast, cells derived from the zona fasciculata maintain viability, but do not regenerate zona glomerulosa and do not produce aldosterone. These results suggest that the cell migration model, in which zona glomerulosa cells can acquire the phenotype of zona fasciculata cells as they can migrate centripetally, is more likely the correct explanation of adrenocortical zonation.

Background. A new model of cellular adrenocortical transplantation after bilateral adrenalectomy in the mouse was established. This model was used to study the effects of the expression of the transgenic MHC class I molecule H-2K (K b ) on graft survival and morphologic features, corticosterone secretion, and the possibility of tolerance induction in the recipient. Method. A single cell suspension of purified adrenocortical cells was grafted under the kidney capsule of B10.Br (H-2 k ) mice having adrenalectomies. Syngeneic, fully MHC-mismatched, and MHC class I-incompatible K -transgenic mice served as donor strains. To analyze graft function, urinary excretion and serum levels of corticosterone were monitored over 100 days. Tolerance induction in the graft recipients of K b -transgenic and third party skin grafts was tested on day 50 after adrenocortical transplantation. Histological sections of the adrenocortical grafts were obtained on day 100. Results. Recipients of syngeneic and K b -transgenic grafts displayed pretransplant corticosterone levels on days 20, 50, and 100 and ACTH-stimulated serum corticosterone levels similar to those of controls on day 100 after adrenocortical transplantation. In contrast, in recipients of fully MHC-mismatched grafts, corticosterone excretion was significantly reduced. In this group, 4 of 7 mice did not survive. Syngeneic skin grafts survived indefinitely in recipients of syngeneic and K b -transgenic adrenocortical grafts, whereas K b -transgenic and fully MHC-mismatched skin grafts were acutely rejected. Tissue sections of the adrenocortical grafts revealed vascularized cell conglomerates in syngeneic and K b -transgenic grafts without infiltrations of mononuclear cells. Furthermore, a differentiation similar to adrenocortical organization was partly found. Conclusion. In conclusion, a model of cellular adrenocortical transplantation was established. The results show that syngeneic transplantation resulted in physiological corticosterone levels early after transplantation, whereas fully MHC-incompatible grafts were rejected. Recipients of K b -transgenic grafts showed unimpaired adrenocortical function, but did not tolerize toward K b -transgenic skin grafts. Possible mechanisms include a local immunomodulatory effect of glucocorticoids secreted by the graft and a low immunogenicity of the relatively small numbers of transplanted cells.

Background: Although differentiated carcinoma of the thyroid gland is a relatively benign tumor, up to 20% of patients are endangered by potentially fatal complications resulting from infiltrating tumor growth into the upper aerodigestive tract. Methods: This study included 33 patients who underwent 34 tracheal or laryngotracheal procedures for invasive differentiated thyroid carcinoma under the direction of a single surgeon (G.F.W.S.). From 1990 to 1994, radical tumor extirpation was performed by “window” resection, and from 1995 to 1998, radical surgery consisted of either circumferential sleeve resection or laryngotracheal “step” resection—a novel method of reconstruction in cases of unilateral tumor infiltration into the larynx and trachea. Resection was limited to laminar ablation in 17 cases. The mean follow-up of 16 patients who survived was 42.5 months (range, 2 months to 8.9 years). Results: Procedures resulting in primary end-to-end anastomosis of the upper airways were associated with lower perioperative morbidity and improved recurrence-free survival when compared with “window” resections with muscle flap reconstruction. In cases of superficial tracheal tumor infiltration, laminar ablations were sufficient for local tumor control. Conclusions: Radical eradication of differentiated thyroid carcinoma infiltrating the upper airways followed by radioiodine application should be considered the treatment of choice. Laryngotracheal “step” resection allows tumor extirpation with preservation of neural and muscular structures of the larynx. (Surgery 1999;126:1078-88.)

Background: Metastatic neuroendocrine pancreatic tumors have a poor prognosis. We have studied retrospectively the efficacy of liver transplantation as ultimate therapy of otherwise untreatable symptomatic neuroendocrine hepatic metastases originating in the pancreas. Methods: We reviewed our experience of liver transplantation (LTx) for hepatic metastases of neuroendocrine pancreatic tumors in ten patients. The indication for liver grafting was seen in cases of irresectable metastases and when patients were suffering from otherwise untreatable tumor-associated symptoms due to massive hormonal release or large intra-abdominal tumor bulk. Results: In four patients, the primary tumors had been removed before LTx, in five patients simultaneously with LTx and in one case 46 months after grafting. There was no operative mortality. After hepatectomy and LTx, all patients had complete relief of symptoms and all preoperatively increased hormonal levels returned to normal. In nine of ten patients, the transplant procedure had the potential for cure, whereas, in one patient, the primary tumor had remained in situ at LTx and was removed 46 months later by an R2-resection. At present, nine patients are alive with a median follow-up of 33 months (range 13.5 months to 117 months). The one patient in whom the primary tumor was removed after transplantation died due to massive intra-abdominal tumor spread 68 months after LTx. Currently, two patients are without evidence of disease, but one of them after re-operation because of lymph-node metastases 8 months after transplantation. The longest disease-free survival is now more than 7 years. In seven of nine patients, tumor recurred between 1.5 months and 48 months after transplantation. Conclusions: Patients with otherwise untreatable symptomatic neuroendocrine hepatic metastases of pancreatic origin may benefit from total hepatectomy and liver transplantation with regard to symptomatic relief and long-term survival, despite frequent recurrence of disease. In some patients, liver transplantation may even offer the chance for cure.

OBJECTIVE: This article describes the experience with liver transplantation in patients with irresectable neuroendocrine hepatic metastases. SUMMARY BACKGROUND DATA: Liver transplantation has become an established therapy in primary liver cancer. On contrast, there is little experience with liver transplantation in secondary hepatic tumors. So far, in the majority of patients being transplanted for irresectable liver metastases, long-term results have been disappointing because of early tumor recurrence. Because of their biologically less aggressive nature, the metastases of neuroendocrine tumors could represent a justified indication for liver grafting. METHODS: In a retrospective study, the data of 12 patients who underwent liver transplantation for irresectable neuroendocrine hepatic metastases were analyzed regarding survival, tumor recurrence, and symptomatic relief. RESULTS: Nine of 12 patients currently are alive with a median survival of 55 months (range, 11.0 days to 103.5 months). The operative mortality was 1 of 12, 2 patients died because of septic complications or tumor recurrences or both 6.5 months and 68.0 months after transplantation. all patients had good symptomatic relief after hepatectomy and transplantation. Four of the nine patients who are alive have no evidence of tumor with a follow-up of 2.0, 57.0, 58.0, and 103.5 months after transplantation. CONCLUSIONS: In selected patients, liver transplantation for irresectable neuroendocrine hepatic metastases may provide not only long-term palliation but even cure. Regarding the shortage of donor organs, liver grafting for neuroendocrine metastases should be considered solely in patients without evidence of extrahepatic tumor manifestation and in whom all other treatment methods are no longer effective.

Introduction. Differentiated thyroid cancer treatment usually consists of thyroidectomy and radio ablation in hypothyroidism 4-6 weeks after surgery. Replacing hypothyroidism by recombinant human thyroid stimulating hormone can facilitate radio ablation in euthyroidism within one week after surgery. The outcome of this approach was investigated.Methods. This is a prospective randomized trial to compare thyroidectomy and radio ablation within a few days after preconditioning with recombinant human thyroid stimulating hormone versus thyroidectomy and radio ablation separated by four weeks of L-T4withdrawal. Tumors were graded into very low-, low- , or high-risk tumors. Recurrence-free survival was confirmed at follow-up controls by neck ultrasound and serum thyroglobulin. Suspected tumor recurrence was treated by additional radio ablation or surgery. Quality-of-life questionnaires with additional evaluation of job performance and sick-leave time were used in all patients.Results. Radio ablation in euthyroidism in quick succession after thyroidectomy did not lead to higher tumor recurrence rates of differentiated thyroid cancers in any risk category and was significantly advantageous with respect to quality-of-life (P<0.001), sick-leave time (P<0.001), and job performance (P=0.002).Conclusion. Recombinant human thyroid stimulating hormone can be used safely and with good efficacy to allow radio ablation under sustained euthyroidism within one week after thyroidectomy.

Expression of thyrotropin receptor (TSHr) was analyzed in normal human thyroids and differentiated thyroid tumours by Northern blotting of total RNA and by Western blotting of detergent-solubilized membrane proteins with an antibody specific for the extracellular domain of TSHr. Under nonreducing conditions TSHr stained as a 90-kDa protein in normal thyroid tissue. Expression varied in differentiated carcinomas from normal to not detectable in parallel to steady state TSHr mRNA levels and TSH binding in a TSH binding assay. The negative expression of TSHr in some patients with differentiated carcinomas may have consequences for the TSH suppressive treatments of these patients.

Lymph node metastases have been proven to be the main prognostic factor in medullary thyroid carcinoma (MTC). This retrospective study was undertaken to evaluate the efficiency of two surgical techniques of regional lymph node dissection with regard to the normalization of pentagastrin-stimulated serum calcitonin level and patient survival: selective lymphadenectomy, i.e., the excision of macroscopically or microscopically involved lymph nodes, versus a systematic lymphadenectomy performed by the new technique of a compartment-oriented microdissection. From 1970 to 1990, 82 patients with sporadic (n = 57) and hereditary (n = 25) MTC underwent a total of 142 operations including 63 selective lymphadenectomies and, since 1986, 35 systematic lymphadenectomies. The study revealed that in node-positive MTC the rate of interventions with a postoperative normalization of pentagastrin-stimulated serum calcitonin was higher after systematic lymphadenectomy (29.2%) than after selective lymphadenectomy (8.5%) (P0.01). The rate of patients undergoing repeat surgery due to a recurrence of MTC was 48% after selective lymphadenectomy and 10% after systematic lymphadenectomy. Survival was significantly better for patients after systematic versus selective lymphadenectomy (P0.005). This study thus emphasizes that systematic lymphadenectomy, using the technique of a compartment-oriented microdissection of cervicomediastinal lymph nodes, represents the preferred surgical treatment as well as the optimum technique in primary as well as secondary node-positive MTC.

We studied the records of 342 patients with papillary thyroid carcinoma out of a total of 728 thyroid cancer patients treated at the Medical School of Hannover (MHH) from 1972 through 1992. The comprehensive data-abstracting forms were designed, and the acquired information was coded, stored, maintained, and evaluated by the Clinical Cancer Registry of the MHH. A total of 160 patients (46.8%) initially had lymph node metastases (N1 status). The N status significantly influenced recurrence (p0.00001) and survival (p0.00001). Excluding other risk factors developed by univariate and multivariate analysis, such as high age (age45 years, p0.001), tumor invasion (T4 tumor, p0.005), and distant metastases (M1, p0.001), lymph node metastases remained an independent, highly significant prognostic marker for more aggressive papillary thyroid cancer. N1 status did not influence survival of patients with T4 tumor but did influence those with T1-T3 status (p0.001). The influence of N1 status remained significant in patients older (p0.001) and younger (p0.05) than 45 years of age. Systematic compartment-oriented dissection of lymph node metastases improved survival (p0.005, T1-T3) and recurrence (p0.00001, T1-T3) especially in patients with T1-T3 tumors. In conclusion, lymph node metastases with a significant incidence at a young age and male sex had a substantial effect on survival and recurrence especially in those with tumor status T1-T3. Systematic compartment-oriented dissection of the lymph node metastases results in better survival and a lower recurrence rate.

Parathyroidectomy (PT) corrects tertiary hyperparathyroidism in patients who have received renal grafts but can result in deterioration of renal function.To compare different surgical procedures for their effect on renal function and efficacy to cure tertiary hyperparathyroidism.A retrospective cohort study.University clinic.Eighty-three patients with functioning renal grafts receiving PT for the first time.Group 1 received an incomplete PT, with at least 1 entire parathyroid gland (PG) remaining in situ (n = 12). Group 2 received an incomplete PT, with the most morphologically conserved PG partially resected (n = 22). Group 3 received a complete PT, with autotransplantation of PG tissue (n = 49).The primary end point was the postoperative change in glomerular filtration rate. Secondary end points were rates of redialysis, hypercalcemia, and hyperparathyroidism within 5 years.A decrease in glomerular filtration rate occurred postoperatively in 75 patients (90%) and correlated significantly with the extent of PG resection. Recovery of renal function at month 6 was observed in group 1, but not in groups 2 and 3 (P.001). Seven patients (8%) needed permanent dialysis (1 in group 2 and 6 in group 3). Hypercalcemia was abrogated in 78 patients (94%), without significant differences among the groups. Assessment of parathyroid hormone levels in accordance with target ranges from the Kidney Disease Outcomes Quality Initiative guidelines did not reveal significant differences in the rates of recurrent hyperparathyroidism.Incomplete PT preserving at least 1 entire PG does not cause deterioration of renal graft function and provides long-term correction of hypercalcemia and tertiary hyperparathyroidism.

Pleuropulmonary blastoma (PPB) is a rare dysontogenetic tumor that usually develops in the first decade of life and has been recognized as a distinct clinico-pathological entity different from the ordinary pulmonary blastoma of adulthood. Since the tumor grows aggressively and tends to metastasize early, physicians have to be aware of late onset of symptoms and uncommon manifestations. We report a case of PPB in a young adult and its recurrence in the pancreas after primary surgical treatment and adjuvant chemotherapy. Keeping in mind the moderate prognosis of PPB in children, accurate assessment and treatment of PPB require a team approach of oncology, radiology and surgery to establish new therapeutic guidelines in the future.

We present a case report on a 35-year-old patient in whom a malignant sympathetic paraganglioma of the organ of Zuckerkandl was the cause of severe hypertension with excessive perspiration at night. Since curative surgery was not possible medical treatment was initiated. Interferon alfa 2b (Intron A, Essex Pharma) and the somatostatin-analogue SMS 201–995 (Sandostatin, Sandoz) had no effect on catecholamine production and progression of the tumor. Treatment with alpha-methyl-para-tyrosin (MPT, [Metyrosin], Demser, MSD) turned out to be an effective and well tolerable therapy in this patient with peritoneal carcinosis. Clinical and hormonal progression of the paraganglioma resumed only after two years of therapy, which constitutes the longest documented period of time of successful MPT treatment. The superior efficacy of MPT in our patient should encourage postoperative medical treatment with MPT in malignant pheochromocytoma or malignant paraganglioma, particularly when the tumor turns out to be resistent to alpha blocking drugs.

A correlation is demonstrated between chronic hemodialysis using cuprophane membranes (mean duration: 13 years) and pathological fractures (n = 7 in 6 patients) after lytic bone deposits of beta 2-microglobulin amyloid (n = 13 patients). The characteristic symptom complex includes painful impingement syndrome of the shoulder, carpal tunnel syndrome, painful hip and recurrent knee effusions. The first steps of the clinical diagnostic procedure are to demonstrate lytic defects in skeletal radiographs and to verify the presence of beta 2m by biopsy or puncture. Due to reduced regeneration capacity in amyloid bone lesions the resulting surgical therapy should aim at total joint replacement or augmented osteo synthesis. Definitive operative treatment should be aspired even in the absence of manifest fractures, as the natural course of the disease is characterized by progression of the bone destruction and a continuous pain syndrome.

Background. The expression of RET/PTC chimeras was demonstrated in 10% to 20% of sporadic papillary thyroid carcinomas (PTCs), whereas rearrangements of NTRK1 were detected less frequently. Some investigators have hypothesized that RET/PTC activation is preferentially associated with slow-growing tumors of low malignancy in elderly patients; other studies support the contrary. Methods. Expression analysis of RET and NTRK1 was performed by duplex reverse transcription-polymerase chain reaction in tumor tissues from 119 patients with PTC. Samples with suspected rearrangements were further analyzed for the expression of the hybrid messenger RNAs RET/PTC 1 to RET/PTC 7 and for known NTRK1 chimeras, respectively. Results. Seventeen of 119 tumors (14.3%) revealed somatic rearrangements of RET; NTRK1-derived hybrids were demonstrated in 15 cases (12.6%). In patients with RET/PTC chimeras, a statistically not significant tendency towards younger age, lower recurrence rate, and improved survival was observed, despite increased incidence of lymph node metastasis. Cumulative survival analysis of NTRK1 rearrangement-positive individuals demonstrated a worse outcome when compared with patients with expression of RET hybrids (P =.055). Conclusions. The high incidence of yet uncharacterized NTRK1 hybrid mRNAs in our patient cohort leads to the speculation that activating chromosomal rearrangements of several tyrosine kinase receptors may be a common feature of PTCs and that the expression of distinct chimeras may potentially be of prognostic significance. (Surgery 2000;128:984-93.)

Hintergrund: Pathogene somatische Translokationen desRET Proto-Onkogenes bzw. Expressionen der verschiedenen RET/PTC Chimaren konnten in etwa 10-25% der sporadisch auftretenden papillaren Schilddrusenkarzinome (PTC) nachgewiesen werden. Die wenigen existierenden Studien mit Genotyp/Phanotyp-Korrelationen kommen zu divergierenden Ergebnissen bezuglich der Verwendbarkeit vonRET-Rearrangements als prognostische Marker fur das sporadische PTC.

Hintergrund: Bei der oralen Hormonsubstitution bei Nebennierenrinden-Insuffizienz kann die fehlende Kompensation von notwendigen Sekretionsspitzen wahrend psychischer und physischer Stressituationen zu vital bedrohlichen Addison Krisen fuhren. Eine allo-gene Nebennierenrinden-Transplantation (NNR-Tx) konnte eine wesentliche Verbesserung in der Behandlung der adrenocorticalen Insuffizienz darstellen.

Hintergrund: Nur wenige Faktoren erlauben pradiktive Aussagen uber die Prognose des C-Zell-Karzinomes (medullary thyroid carcinoma, MTC). Methode: Daten von 146 MTC-Patienten (63 Frauen und 83 Manner), welche im Zeitraum von 1971–1997 in unserer Klinik behandelt wurden, wurden dokumentiert und ausgewertet. Ergebnisse: Univariate sowie multivariate Analysen der Uberlebenszeit der Patienten sowie der rezidiv-freien Intervalle nach erfolgter Primaroperation bzw. Rezidivoperation wiesen Alter, Geschlecht, Tumorstadium sowie das Ausmas der chirurgischen Resektion als prognostische Faktoren aus. Totale Thyreoidektomie und systematische Lymphadenektomie verbesserten das Uberleben. Schlusfolgerung: Der lokoregionaren Lymphadenektomie und dem Zeitpunkt der Komplettierungsresektion nach subtotaler Thyreoidektomie kommen entscheidende Bedeutung zu.

C-Zell-Karzinome, auch medullare Schilddrusenkarzinome (medullary thyroid carcinoma, MTC) genannt, entstehen als maligne Transformation der parafollikularen, Calcitonin-produzierenden C-Zellen der Schilddruse und treten sporadisch (75%) sowie familiar gehauft (25%) auf. Keimbahnmutationen im Bereich des RET ProtoOnkogenes wurden als pradisponierende Faktoren zur Entwicklung eines hereditaren MTC identifiziert, d. h., eines sogenannten familiaren MTC (FMTC) bzw eines mit dem Multiple Endokrine Neoplasie Syndrom Typ 2 (MEN 2A und MEN2B) assoziierten C-Zell-Karzinomes. Aufgrund der nahezu 100% Penetranz der autosomal-dominanten pathogenen Punktmutationen ist bei Gentragern aus betroffenen Familien eine prophylaktische Thyreoidektomie bereits im Kindesalter indiziert.

Despite recent advances in the understanding of the role of the RET proto-oncogene in the development of familial and approximately 30% of sporadic medullary thyroid carcinomas (MTC), little is known about other genetic events that modify the course and outcome of the disease. We compared the expression of genes in intrathyroidal MTCs to autologous local lymph node metastases by means of mRNA differential display (DDRT-PCR). This is the first report of differential display using surgical specimens of a primary cancer and its metastases. Total RNA was extracted from tumor tissue of two patients with MTC associated with multiple endocrine neoplasia (MEN 2B) and sporadic MTC, respectively. Following reverse transcription (RT), the products were PCR-amplified and separated on a denaturating polyacrylamide gel. RT-PCR products demonstrating differential expression were reamplified and used as probes for Northern blot analysis. Six fragments for which differential expression was confirmed were cloned and sequenced. Resultant sequences were tested for homology to sequences in public data bases, and two novel MTC-derived fragments (MDF-1, MDF-2) were identified. Sensitivity of the method was confirmed by identification of a sequence encoding the calcitonin precursor flanking peptide which is expressed almost exclusively in MTC and normal thyroid C cells. Overexpression of the ribosomal genes S3a and P0 was found in the metastases. Recent reports suggest that components of the translational apparatus act as regulatory mediators of growth, proliferation, and neoplastic change. The altered expression of ribosomal proteins and gene products encoded by MDF-1 or MDF-2 may play an important role in the progression and metastatic spread of MTC.

While autoantibodies against thyroid peroxidase (TPO) are known to produce cytotoxicity in vitro, their in vivo effects are still obscure. In addition, the mechanism of TPO autoantibody creation needs to be disclosed because the localization of TPO on thyrocytes is considered to be restricted to the apical membrane, which is not in contact with immunocompetent cells. In order to study these crucial processes in the pathogenesis of thyroid autoimmunity, the ultrastructural localization of TPO and IgG was determined and quantified in thyrocytes of normal thyroid gland and thyroid tissue of patients suffering from Graves’ disease. This was done by using ultrathin frozen sections and the immunogold method. IgGs were detected in the follicular lumen, close to the apical membrane, in transport vesicles, the endoplasmic reticulum, and the Golgi apparatus of thyrocytes from patients with Graves’ disease. The labeling of TPO in the basolateral membrane was distinctly lower than that of the apical membrane, but was significant in comparison to the plasma membrane labeling of fibroblasts present in the same sections. These data indicate that thyroid autoantibodies may perform their cytotoxic function in intracellular compartments besides the plasma membrane. TPO molecules on the basolateral membrane of HLA class II antigen-positive thyrocytes may initiate antigen presentation of TPO as well as the formation and uptake of TPO autoantibodies.

The thyroid is affected by one of the most common organ-specific autoimmune diseases in humans. Three major autoantigens are involved in thyroid autoimmune disease: thyroglobulin (TG), thyroid peroxidase (TPO), and thyroid-stimulating hormone (TSH) receptor. Both hyperthyroidism and the development of goitre in Graves’ disease are caused by stimulating autoantibodies against TSH receptors. Autoantibodies against TG and TPO can be detected in Graves’ disease and Hashimoto’s thyroiditis.

There are several theories about the physiologic regeneration of adrenals and maintenance of physiologic steroid secretion after subtotal loss of adrenal cortical cells. According to the cell migration theory, adrenocytes from the zona glomerulosa migrate centripetally toward the medulla. This theory is opposed by the zonal theory according to which each zone resplenishes its cells independently. What these theories have in common is that they are based on data from the intact adrenal gland. We transplanted purified glomerulosa cells under the kidney's capsule of Lewis rats. The tissue was removed 30, 60, 90, and 150 days after transplantation to investigate the presence of two specific enzymes that are responsible for the secretion of aldosterone and corticosterone. Cytochrome p-450as is specific for glomerulosa cells producing aldosterone, and cytochrome p-45011beta is specific for fasciculata cells producing corticosterone. After sequencing the genetic code of these enzymes it became possible to demonstrate expression of the enzymes by in situ hybridization. The transplanted glomerulosa cells turned their enzymatic property to fasciculata cells expressing cytochrome p-45011beta. Our results suggest that glomerulosa cells are able to take over the physiologic function of a whole adrenal cortex in the absence of fasciculata cells, and that they are sufficient to maintain the function of the adrenal cortex.

Between 1982 and February 1996 11 patients underwent liver transplantation for irresectable neuroendocrine hepatic metastases. The operative mortality was one of 11, while two patients died due to sepsis respectively tumor recurrence 7 and 68 months after transplantation. Eight patients are alive with a median survival of 55 months (range from 10 days to 8.5 years). In three patients there is no evidence of tumor and the longest disease-free survival is 102 months after LTx.

Clinical data of 139 patients with hereditary medullary thyroid carcinoma (HMTC) from nine european centres surgically treated from 1980 to 1991 were reviewed retrospectively to analyse the value of systematic versus selective lymphadenectomy (LA). Biochemical cure rate was significantly higher in patients who underwent LA compared to patients who did not. In nodal-positive HMTC, systematic LA compared to selective LA improved biochemical cure in small but not large tumours. In nodal-negative HMTC, systematic LA compared to selective LA could not improve biochemical cure in either small or large primary tumours. To prevent local recurrences with the risk of increased surgical and tumour-related morbidity, systematic LA should be performed in all HMTC patients regardless of the primary tumour stage. However, an improvement of biochemical cure by systematic LA seems to be possible only in nodal-positive small primary tumours without distant metastases.

Using a human TSH receptor (TSH-R) cDNA probe, we investigated TSH-R transcript levels in 13 human thyroid fragments by Northern blot analysis; 7 Graves' disease, 2 Hashimoto's disease, 3 endemic goiter, and 1 healthy thyroid gland were studied. TSH-R expression levels were variable, but displayed a close correlation to the expression of thyroid peroxidase (r = 0.703; P < 0.05), thyroglobulin (r = 0.817; P < 0.01), and the nuclear oncogene c-fos (r = 0.935; P < 0.001), but not c-myc. Overall, TSH-R transcript levels were low or absent in those thyroids in which expression of the major histocompatibility complex class I or II (MHC I or II) was high, thus establishing an inverse relation (MHC I, r = -0.791; P < 0.01; MHC II, r = -0.784; P < 0.01). In situ hybridization showed that apart from lymphocytes, thyroid cells themselves were the source of MHC II transcripts. gamma-Interferon expression was only detectable in 1 Hashimoto's goiter. Our findings suggest that next to lymphocyte infiltration, active regulatory events in the thyrocyte are responsible for the inverse relation between functional parameters (TSH-R, thyroid peroxidase, thyroglobulin, and c-fos) and immunological markers (MHC I and II).

Der kunstliche Hormonersatz nach vollstandiger operativer Entfernung oder Funktionsverlust der Nebennierenrinden ist ein bislang nicht befriedigend gelostes Problem. Im Rahmen primarer und sekundarer adrenocorticaler Insuffizienzen konnte nachgewiesen werden, das auch bei mehrfach fraktionierter Substitution und individueller Anpassung der Steroiddosis Addisonkrisen, aber auch inadaquat hohe Steroidspiegel mit zum Teil manifesten Cushingsyndromen auftreten konnen [1].

Steady state mRNA transcript levels of thyroid differentiation markers such as TSH receptor (TSHR), thyroglobulin (Tg) and thyroid peroxidase (TPO) as well as a potential marker of dedifferentiation, c-myc, marker were investigated in patients with thyroid tumors and in normal controls using Northern blot analysis. Blots were normalized by acridine orange staining whereas analysis of beta-actin mRNA levels revealed highly variable levels already in normal tissue suggesting regulation of this "constitutively" expressed gene. Determination of c-myc mRNA revealed increased steady state mRNA levels in anaplastic carcinomas (ATC) as compared to normal tissues. However, in some patients c-myc transcript levels were lower in the tumor than in the adjacent normal tissue reducing the significance of c-myc as a marker of dedifferentiation. High levels of TSH mRNA were found in control thyroids, whereas in ATC no normal TSHR mRNA was detected. In PTC and follicular thyroid carcinomas (FTC) the transcripts varied from increased to markedly reduced levels. In one patient with FTC 2 independent preparations of the tumor revealed different results, undetectable and clearly detectable TSHR mRNA levels. Xenotransplantation of this tissue on nude rats showed a variable expression pattern in the individual xenotransplantations suggesting heterogeneity of the tumor tissue. Tg and TPO mRNA were strongly expressed in normal tissues and completely lost in all ATC. In differentiated thyroid tumors the transcript levels of Tg and TPO varied from normal to complete loss of expression of either Tg or TPO, or both.(ABSTRACT TRUNCATED AT 250 WORDS)

The multiple endocrine neoplasia (MEN) syndromes are genetically transmitted endocrinopathies. In both types of MEN syndrome, usually one organ predominantly is affected; however, the individual manifestation of the disease with regard to time and extent of organ involvement varies considerably. Unlike in MEN 1, in MEN 2 surgical treatment represents the therapy of choice for each part of the disease.

Bei chronisch dialysierten Patienten werden im Verlauf eines typischen Symptomenkomplexes aus multifokalen Gelenkbeschwerden mit zunehmender Haufigkeit pathologische Frakturen beobachtet: im Laufe von bis zu 15 Jahren Hamodialyse tritt ein chronisches Beschwerdebild auf aus Karpaltunnelsyndromen, Impingement der Schulter, Kniegelenksergussen, HWS- und Huftgelenksbeschwerden [1, 8], Im Skelettrontgenbild werden an typischen gelenknahen Pradilektionsstellen zystiforme osteolytische Knochendefekte gefunden. Das Serumprotein β 2-Mikroglobulin (β 2m) ist ein den Immunglobulinen strukturell ahnelndes Leichtkettenprotein mit einem Molekulargewicht von ca. 12000 Dalton. Als Bestandteil des MHC-I-Rezeptors an der Oberflache aller kerntragender Zellen ist es ein ubiquitares physiologisches Endprodukt von Zellzerfall und -umsatz und wird unverandert renal ausgeschieden. Die normalen Serumspiegel von 0,2 bis 0,4 mg/1 werden uberschritten bei vermehrter Produktion durch erhohten Zellumsatz bei Entzundung und bei eingeschrankter Nierenausscheidungsleistung. Beim noch kompensiert Niereninsuffi-zienten ist der erhohte β 2-Serumspiegel schon fruhzeitig nachweisbar und gilt als Parameter der Niereninsuffizienz [9]. Die ab dieser Phase beginnende Einlagerung von β 2m als atypisches Amyloid in Knochen, Synovial- und Sehnenstrukturen erklart sich durch seine Affinitat zu Kollagen und kann immunhistologisch nachgewiesen werden [2, 3]. Im jahrelangen Prodromalstadium stellen die schon nach nahezu gesetzmasigen Mustern auftretenden multifokalen Arthralgien eine Einschrankung von Mobilitat und Wohlbefinden dar, welche die betroffene multimorbide Patientengruppe besonders hart trifft.

Background The genetic background of papillary thyroid carcinoma (PTC) has been elucidated by the identification of somatic translocations of the tyrosine kinases RET and NTRK1. Expression of RET/PTC chimeras has been demonstrated in 10–25 per cent of sporadic PTCs while rearrangements of NTRK1 were detected less frequently. Based upon the limited data available, some investigators have hypothesized that RET/PTC activation is preferentially associated with slow growing tumours of low malignancy in elderly patients, while other studies support the contrary. Methods Tumour tissues from 115 patients with sporadic PTC were harvested at operation and snap frozen. Following RNA extraction, expression analysis of the RET proto-oncogene as well as the NTRK1 gene was performed by multiplex reverse transcriptase–polymerase chain reaction. Samples with suspected rearrangements of the genes were further analysed for expression of the hybrid messenger RNAs RET/PTC1 to RET/PTC4, and for known NTRK1 chimeras. Clinical data of all patients were documented in an extensive database of thyroid carcinomas maintained by this research group. Results Twenty-one (18 per cent) of 115 tumour samples revealed somatic rearrangements of RET while translocations of the NTRK1 gene were demonstrated in 2 per cent of all samples analysed to date. The mean age of all patients was 52 (range 14–86, median 54) years and that of patients positive for RET rearrangements was 49 (range 14–82, median 49) years. Nine of 21 RET-rearranged tumours showed aggressive behaviour with locally invasive tumour growth and infiltration of adjacent structures such as muscles, vessels and trachea. Tumour samples without detectable RET translocations were associated with organ-exceeding tumour growth in only 20 per cent of cases. Conclusion These data represent one of the most comprehensive studies on gene translocations and their clinical significance in PTC. In accordance with international publications, an incidence of 2 per cent of NTRK1 rearrangements and 18 per cent of RET translocations is reported, which is in contrast to other national reports of low rearrangement rates. Somatic translocations were associated with tumours demonstrating aggressive behaviour in almost half of patients with PTC in all age groups, indicating a prognostic role of oncogenic RET/PTC activation.

Background Hormone substitution for the treatment of adrenocortical insufficiency (Addison's disease) does not adequately substitute the physiological circadian secretion of corticosteroids leading to long-term sequelae and reduced quality of life. Moreover, oral administration of corticosteroids cannot mimic the hormone peaks required in stress situations. This lack of adaptation to physical and psychological stress may lead to life-threatening Addisonian crises. Allogeneic transplantation of adrenal cortex may offer an alternative. Methods Major histocompatibility complex (MHC) class I transgenic mice (H-2Kb) were used for the implementation of an animal model of adrenocortical transplantation. Tissue fragments or selectively isolated cell suspensions of the adrenal cortex were transplanted underneath the kidney capsule of adrenalectomized mice. Kb-transgenic murine cells as well as allogeneic adrenal cortex cells were cocultured in mixed lymphocyte cultures (MLC) in order to examine the alloimmune response. Lymphocytes from T-cell receptor transgenic mice and normal allogeneic mice respectively served as responder cells. The immune response, i.e. lymphocyte proliferation, was quantified by measuring the [3H]thymidine uptake of responder cells. The effect of corticosteroids secreted by adrenocortical cells was antagonized by the steroid receptor antagonist Mifepristone (RU 486). Results Without need for immunosuppressive drugs, adrenocortical grafts were demonstrated to proliferate and produce corticosteroids at physiological concentrations 20 days after transplantation. Coculture of adrenal cortical cells in MLC markedly suppressed lymphocyte proliferation. This inhibited immune response was not completely antagonized by RU 486. Conclusion In vitro, the presence of adrenocortical cells potently suppressed allogeneic immune responses. This effect was not only due to the secretion of corticosteroids, pointing to a additional immunomodulatory property of adrenocortical cells. Successful allogeneic transplantation of MHC-II-matched adrenal cortex grafts in a murine model raises the possibility of applying these methods in humans.

Human thyrotropin (TSH) receptor steady-state transcript levels were analyzed by Northern blot analysis in thyroids of patients with thyroid carcinoma, with hyperfunctioning adenoma and in normal controls. In control tissue and benign tumors expression levels of TSH receptor mRNA were high whereas in anaplastic carcinomas no normal TSH receptor mRNA was detected. In papillary and follicular tumors it varied from normal to markedly reduced levels. Thyroid peroxidase (TPO) and thyroglobulin (Tg) mRNA were strongly expressed in normal tissue and in hyperfunctioning adenomas but were completely lost in all anaplastic tumors. In papillary tumors expression of TPO and Tg mRNA varied from normal to a complete loss of expression of either TPO, Tg or both. Tg and TPO steady-state expression did not correlate to TSH receptor transcript levels. C-myc mRNA was highly expressed in anaplastic carcinomas, very variable in normal controls and in differentiated thyroid tumors and low in hyperfunctioning adenomas. In summary, TSH receptor mRNA is persistently expressed in all differentiated thyroid tissues and tumors but lost in undifferentiated carcinomas. Its persistence far along the transformation pathway further supports the concept that this gene which inserts the thyrocytes in the physiological regulatory network is almost constitutively expressed in this cell.

The fibrolamellar karzinoma of the liver (FLC) as an uncommon variant of the hepatocellular karzinoma (HCC) is an indolent growing tumor. In its prior manifestation the FLC occurs at the adolescence and young adult stage. Early stage diagnosis and aggressive surgical treatment achieve better long-term results than usual resection of the HCC. Usually the FLC is, caused by its inconspicuous clinical appearance, diagnosed at a stage too advanced for effective surgical treatment. Especially the young patient's age and the remaining therapeutic options for palliative or curative treatment postulate a difficult decision for the surgeon. When a subtotal hepatectomy cannot be performed, total hepatectomy with liver transplantation is a valuable option. Palliative treatment protocols include systemic chemotherapy, ethanol instillation and chemoembolisation. We report the case of a 21-year-old male patient who presented with a recurrent intrahepatic FLC, peritoneal karzinomatosis confined to the right lower abdomen including gastric, splenic, diaphragmatic and colon transversum metastasis 14 months after primary surgery. We selected this patient as a reasonable candidate for an extended resection in trying to offer the optimal therapeutic modality. Thus we performed a right hemihepatectomy, near complete resection of the right diaphragm, total gastrectomy with lymphadenectomy including en bloc resection of spleen, colon transversum, omentum majus and peritonectomy of the paravesical region. Furthermore hyperthermic intraperitoneal chemotherapy was carried out the next day. The patient's postoperative course remained uncomplicated with fast recovery. Presently, 6 months after surgery, the patient has no evidence of recurrence.

Drei Nahttechniken zur Reinsertion des vorderen Kreuzbandes (ACL), die Naht nach Muller, nach Marshall und die „lateral trap“-Technik wurden an frischen Kreuzbandpraparaten vom Schaf ausgefuhrt und hinsichtlich Bruchkraft, Steifigkeit, Bruchdehnung, Bruchenergie und Versagensmodus beurteilt. Allein die „lateral trap“-Technik erreichte eine primare Maximalbelastbarkeit (µ = 191,1 N) die sich hinreichend mit dem Belastungsspektrum des ACL (Chen, Black) uberschneidet und damit eine fruhfunktionelle Behandlung ermoglicht. Die geringen Werte der Muller- (µ = 33,7 N) bzw. Marshall-Technik (µ = 82,8 N) lassen ohne Augmentation keine befriedigenden Ergebnisse erwarten.