Simultaneous mitral valve replacement and liver transplantation.

We report the case of a 57-year-old man who underwent successful simultaneous surgery involving mitral valve replacement for acute endocarditis and orthotopic liver transplantation for end-stage liver disease.

Immunohistochemical detection of E-cadherin in differentiated thyroid carcinomas correlates with clinical outcome.

A retrospective immunohistochemical analysis of the adhesion molecule E-cadherin (E-CD) was performed in 112 differentiated thyroid carcinomas and 38 synchronous and 20 relapse metastases primarily from operations performed at the Medical School Hanover between 1982 and 1992. E-CD-specific antibody 5H9 was applied to paraffin-embedded tissues. All patients were clinically followed for a maximal period of 12 years. Lack of E-CD expression i.e., <5% of tumor cells positive) occurred in 18 of 112 (16.1%) cases, whereas the majority showed either low (24.1%), medium (35.7%), or high (24.1%) positivity. No difference was found between papillary (n = 88) and follicular (n = 24) carcinomas. Univariate statistical analysis for survival (Kaplan-Meier) showed that lack of E-CD expression (P < 0.024) is an adverse prognostic factor for differentiated thyroid carcinomas. The highest significance was seen among patients without lymph node involvement at first presentation (pN(0); P = 0.0068) and among females (P = 0.0033). Multivariate analysis (Cox model) indicated that E-CD staining is an independent prognostic factor (corrected risk factor, 3.7; P < 0.03) in addition to distant metastasis (pM1) and tumor size. A comparison of E-CD stainings between primary tumors and their metastatic lesions showed similar results in both synchronous and relapse metastases after therapy. In conclusion, E-CD immunostaining is an independent prognostic indicator for differentiated thyroid carcinomas. It may help to uncover the small group of patients with differentiated thyroid carcinomas carrying a high risk of suffering an unfavorable clinical outcome.

Expression levels of the thyrotropin receptor gene in autoimmune thyroid disease: coregulation with parameters of thyroid function and inverse relation to major histocompatibility complex classes I and II.

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).

Differentiated corticosteroid production and regeneration after selective transplantation of cultured and noncultured adrenocortical cells in the adrenalectomized rat.

UNLABELLED: 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.

Transplantation of H-2Kb-transgenic adrenocortical cells in the mouse having undergone an adrenalectomy: functional and morphological aspects.

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(b) (Kb) 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-2k) mice having adrenalectomies. Syngeneic, fully MHC-mismatched, and MHC class I-incompatible Kb-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 Kb-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 Kb-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 Kb-transgenic adrenocortical grafts, whereas Kb-transgenic and fully MHC-mismatched skin grafts were acutely rejected. Tissue sections of the adrenocortical grafts revealed vascularized cell conglomerates in syngeneic and Kb-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 Kb-transgenic grafts showed unimpaired adrenocortical function, but did not tolerize toward Kb-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.

Thyrotropin receptor and leukocyte adhesion molecules in autoimmune thyroid disease: a study of their gene expression by northern blot analysis and in situ hybridization.

In order to characterize the role of leukocyte-activating antigens and other immunological parameters in autoimmune thyroid disease, mRNA levels of intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1, E-selectin), invariant chain (Ii) and the thymic hormone thymosin beta (T beta 4) were investigated in 18 human thyroid glands, including eight Graves' thyroids, two Hashimoto's thyroids, two endemic goiters and six healthy controls. Northern blot analysis showed that in autoimmune thyroid disease, expression of ICAM-1 and T beta 4 was correlated to transcript levels of Ii, whereas in the healthy controls, expression of T beta 4, ICAM-1 and ELAM-1 was low or nearly absent. ELAM-1 and TSH receptor (TSH-R) expression, the latter serving as a thyroid specific marker, was increased in some diseased gland but showed no relation to the immunological parameters mentioned above. Localization of the specific mRNAs by in situ hybridization demonstrated a cell-specific expression of TSH-R (thyrocytes), ELAM-1 (vascular endothelial cells) and T beta 4 (cells of hematopoietic origin). In contrast, transcripts of Ii and ICAM-1 were found in thyrocytes, leukocytes and endothelial cells. Our results implicate a coordinate expression of ICAM-1, T beta 4 and Ii in autoimmune thyroid disease, yielding distinct cellular expression patterns. Differential expression of ICAM-1, Ii and the TSH-R in thyroid epithelial cells indicates active regulatory events within the thyrocyte.

Cystic enlargement of extrahepatic bile ducts.

BACKGROUND: Cystic enlargement of the extrahepatic bile duct system is a rare abnormal finding. A congenital origin is usually supposed; however, the pathogenesis is unknown. We report on our experience with extrahepatic bile duct cysts with special regard to cause, treatment, and recurrent disease. METHODS: From 1976 to 1991, 13 patients, 35 to 74 years of age, were treated for extrahepatic bile duct cysts. Seven patients had previously undergone cholecystectomy. Two patients were admitted because of recurrent disease; neither had undergone curative resection. RESULTS: In 11 patients a biliojejunal anastomosis with a Roux-en-Y was created after cyst resection; one patient underwent a diverticular stalk resection with end-to-end anastomosis of the choledochal duct. After a mean follow-up of 68 months eight of 10 patients were alive, two of whom complained about cholangitis. Recurrent diffuse dilatation of the remaining choledochus developed in one patient; one other patient died of cholangiocellular carcinoma 2 years after operation. CONCLUSIONS: In patients who had undergone previous cholecystectomy or with recurrent disease an acquired malformation cannot be excluded. Surgical treatment is always indicated because of imminent complications and should aim at complete resection of cystic tissue. Periodic postoperative evaluation is necessary to detect recurrent disease and malignant transformation.

Invasive differentiated thyroid carcinoma: tracheal resection and reconstruction procedures in the hands of the endocrine surgeon.

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.

Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma.

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.

A murine model of allogeneic adrenocortical cell transplantation: perspectives for the treatment of Addison's disease in humans.

BACKGROUND: Hormone substitution for the treatment of adrenocortical insufficiency (Addison's disease) does not adequately substitute the hormone peaks required in stress situations. Therefore, allogeneic transplantation of adrenal cortex could offer an intriguing alternative. METHODS: Major histocompatibility complex (MHC) class I transgenic mice were used for the implementation of an animal model of adrenocortical cell transplantation in adrenalectomized mice. K(b)-transgenic cells and allogeneic adrenocortical cells were cocultured in mixed lymphocyte cultures to examine the alloimmune response. Lymphocytes from T-cell receptor transgenic mice and normal allogeneic mice served as responder cells. The effect of corticosteroids secreted by adrenocortical cells was antagonized by the steroid receptor antagonist mifepristone (RU486). RESULTS: In vitro coculture experiments showed that MHC class I disparate adrenocortical cells failed to activate B10.BR and T-cell receptor transgenic lymph node cells. In the presence of mifepristone this inhibitory effect was antagonized, resulting in strong lymphocyte proliferation. Activation of B10.BR lymphocytes by K(b)-disparate spleen cells was also abolished in the presence of adrenocortical cells. This effect, however, could not be reversed by mifepristone. CONCLUSIONS: In vitro, the presence of adrenocortical cells potently suppressed allogeneic immune responses. This effect was only in part due to the secretion of corticosteroids, pointing to an additional immunomodulatory property of adrenocortical cells.

Follow-up in 103 patients with catecholamine-secreting tumours.

103 patients from a group of 115 patients with catecholamine secreting tumours were reinvestigated 7.0 +/- 4.9 years following surgery. Throughout the follow-up period 15 patients had died. In four of them death was definitively, in seven subjects possibly associated to the primary endocrine disorder. Following surgery improvement of general well-being was documented in 85% of the patients. Hypertension was corrected in 61 %, but 26% of the patients remained hypertensive and symptoms of hypotension like orthostasis developed in 24%. A significant increase in weight (> 5 kg) was observed in 26% of the subjects throughout the follow-up period, but did not result in a higher prevalence of diabetes mellitus which had to be treated in 16% of the patients before and only 14% following surgery. However, palpitations, increased sweating and headache persisted in 16%, 17% and 12% of the patients, respectively. Symptoms of cardiac insufficiency developed in 32%. Persistent discomfort related to the scar was reported by 55% of the patients following lumbar surgery and by 30% of the subjects that were operated on via a transabdominal approach. Hence we conclude that surgery of catecholamine-secreting tumours results in an improvement of health and well-being in most subjects according to objective criteria as well as to the judgement of the patients themselves.

[Radical surgical intervention with conventional radiation versus multimodality therapy protocol in undifferentiated thyroid cancer]. / Radikale chirurgische Intervention mit konventioneller Radiatio versus multimodalem Therapieschema beim undifferenzierten Schilddrüsenkarzinom.

Out of a total of 550 patients with thyroid cancer diagnosed over the 16-year period 1972-June 1989, 44 showed undifferentiated carcinoma and were treated by thyreoidectomy and early postoperative external irradiation. In order to analyse the outcome in patients treated by primary surgery in contrast to patients treated by means of a multimodal therapy concept we compared our surgical procedures with regard to primary surgical approach, early postoperative course, operative complications and survival to the data on the multimodal therapy concept of the Karolinska Hospital reported by E. Tallroth et al. 1987. A significantly better survival was correlated with radical (n = 20) versus palliative tumour resection (n = 24) (p less than 0.001), and total thyroidectomy (n = 25) versus subtotal thyroidectomy (n = 19) (p less than 0.006). Radical surgery with early postoperative external irradiation revealed no postoperative mortality and no symptomatic cervical tumour recurrence. By contrast, palliative surgery, particularly in the case of synchronous tracheotomy, was attended by a relatively high mortality (29%) and symptomatic local recurrences. The results of this study suggest that in undifferentiated thyroid carcinoma an attempt at radical tumour resection should be undertaken, since multimodal therapy procedures revealed a significantly highly complication rate (up to 36%) and, in comparison with a radical surgical treatment policy, showed a higher rate of local recurrences (0% vs. 48%) and a lower survival (mean survival 42 vs. 15 months).

[Diagnosis and surgical treatment of extra-adrenal pheochromocytoma]. / Diagnostik und operative Behandlung des extraadrenalen Phäochromocytoms.

From 1980 until 1991 10 patients were operated upon a paraganglioma: 5 patients with an encapsulated solitary tumor, two with infiltrating tumors and 3 with metastatic disease. The diagnosis of a catecholamine-producing tumor was most reliably made by norepinephrine analysis in urine and serum. The localization of the tumor was diagnosed in 9 of 10 cases by sonography and CT-scan. In 9 patients the tumor was excised completely, 4 times by extended resections. Whereas 4 out of 5 patients with an encapsulated solitary paraganglioma live to date without recurrence, all 3 patients suffering from metastatic disease had recurrent disease within one year postoperatively. A differentiated operative therapy of paragangliomas based on a clinical characterization is proposed: Encapsulated paragangliomas should always be excised. For solitary infiltrating tumors an extended resection may be necessary. This seems not to be justified for multiple infiltrating or metastasizing paragangliomas. Thus, only a reduction in size may be adequate for these tumors.

[Cervical interventions on the airway and esophagus in infiltrating thyroid cancer]. / Cervicale Eingriffe an der Luft- und Speiseröhre beim organüberschreitenden Schilddrüsencarcinom.

In 1989 und 1990 a resection within the region of the cervical airways and/or oesophagus was performed for an infiltrating tumor in 9 out of 95 patients (9.5%) suffering from thyroid carcinoma and in one patient with lymph node metastases from a carcinoma of the uterine cervix. There was no operative mortality. One patient died six weeks after resecting the anterior wall of the trachea of an intratracheal arterial bleeding due to radiation therapy. In one case the reconstruction of the trachea was performed with autologous material, in three patients alloplastic material was used. The oesophagus was reconstructed preferably by means of free microvascular jejunum autografts (n = 4), using a colon interposition in another two patients. In locally advanced differentiated and medullary thyroid carcinoma curative operations of the cervical hollow organs using microsurgical techniques can be performed with an acceptable operative risk and good functional results. They may markedly improve the otherwise limited prognosis of the disease.

Review: recent developments in adrenal surgery.

The improvements of biochemical methods and imaging techniques in the diagnosis of adrenal disorders have changed the surgical management with regard to indication for operation, surgical approach to the adrenals and the extent of resection. This study reviews recent developments in surgical strategy of adrenal disorders based on surgical treatment of 246 patients from 1975 to 1993 at the Medical School of Hannover. Today extraperitoneal incisions are used with increasing frequency in small benign tumours to minimize the surgical trauma. The indication for operation of adrenal incidentalomas should be considered in all patients with hyperfunctional lesions and suspected malignancy. Bilateral total adrenalectomy is attended with the need for life-long adrenocortical supplementation resulting in an impaired quality of life. In this respect MEN 2 patients with bilateral adrenomedullary disease benefit from unilateral or bilateral subtotal resections with preservation of adrenocortical function. In conclusion, adrenal surgery today aims at the reduction of surgical trauma, early diagnosis and treatment of adrenal malignancies, and the preservation of adrenocortical function.

Multivisceral resection and intraperitoneal chemotherapy in recurrent intra-and extrahepatic HCC.

Full text is available as a scanned copy of the original print version.

Surgical approach of synchronous medullary thyroid carcinoma and pheochromocytoma in MEN 2 syndrome.

In cases with concurrent medullary thyroid carcinoma (MTC) and pheochromocytoma, discussion regarding a one-stage versus two-stage treatment strategy approach remains open. From 1975 to 1990, 11 of 25 multiple endocrine neoplasia type 2 (MEN 2) patients presented with biendocrinopathies or triendocrinopathies synchronously. All patients were treated surgically and followed subsequently in our hospital. Of the group of nine patients with concurrent MTC and pheochromocytoma, five were treated in one-stage and four in two-stage procedures. No patient had major complications intraoperatively. For the two-stage group, the total hospital stay (preoperatively and postoperatively) averaged 35 days. For the one-stage group, the total hospital stay averaged 25 days. In patients with increased operative risks (patients with higher age and impaired physical condition or if neck surgery includes transsternal cervicomediastinal lymphadenectomy), two-stage procedures should be selected. However, in young patients with the MEN 2 syndrome or syndromes with small tumors detected by family screening, thyroidectomy, cervical lymphadenectomy, and adrenalectomy may be performed in a one-stage procedure without increasing surgically related morbidity.

[Multiorgan resection in combination with intraoperative, hyperthermic chemotherapy in recurrent fibrolamellar hepatocellular carcinoma. An individual therapeutic concept for a 21-year-old patient]. / Multiviszerale Resektion in Kombination mit intraoperativer, hyperthermer Chemotherapie beim Rezidiv des fibrolamellären, hepatozellulären Karzinoms. Ein individuelles, therapeutisches Konzept bei einem 21jährigen Patienten.

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.