[Endocarditis and ischemic stroke of rare cause]. / Endokarditis und ischämischer Apoplex mit seltener Ursache.

A 60-year-old male patient presented with ischemic-embolic stroke. Transesophageal echocardiography revealed the cause to be aortic valve endocarditis with highly eccentric aortic valve regurgitation. The blood cultures taken several times remained sterile. The indication for surgical aortic valve replacement was made. Conventional microbiological work-up of the heart valve did not reveal any pathogens. The additional molecular genetic testing using eubacterial PCR ("polymerase chain reaction" [PCR]) finally demonstrated the presence of Tropheryma whipplei. A number of therapeutic options were available. The authors decided on intravenous antibiotic therapy with ceftriaxone for 14 days and follow-up therapy with oral trimethoprim/sulfamethoxazole for 1 year. The case illustrates the importance of additional molecular diagnostics beyond the conventional methods in blood culture-negative endocarditis to identify the pathogen and initiate appropriate therapy.

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.

Regulatory T cells in peripheral blood, lymph node, and thyroid tissue in patients with medullary thyroid carcinoma.

BACKGROUND: Immunological response of the human body is controlled by the suppressive characteristics of regulatory T cells (Tregs). In various diseases a change in the number of Tregs is evident. For example, whereas Tregs are reduced in auto-immunological processes, an increase of Tregs is found with various malignant tumors. Regarding medullary thyroid carcinoma (MTC) no such studies have been performed to date. METHODS: Expression of CD4 and CD25 in CD45+ leukocytes from blood and lymph nodes was studied by flow cytometry in patients with MTC and patients with benign goiter. We also examined the marker forkhead box P3 (FoxP3), an intracellular transcription factor, which is supposed to be the most specific marker for Tregs. Immunohistochemical staining for FoxP3 was performed on lymph node and thyroid tissue. RESULTS: The number of FoxP3+ lymphocytes in peripheral blood was significantly higher in patients with MTC than in controls (p = 0.02). This result was confirmed immunohistochemically in lymph node and thyroid tissue, as well as in carcinoma tissue. No difference in CD4+CD25+ lymphocytes was observed between the two groups. After clinical staging (International Union against Cancer-UICC-stages) of MTC patients, triplication of FoxP3+ lymphocytes could be observed from MTC < UICC II to MTC > UICC II. CONCLUSIONS: An increase of FoxP3+ lymphocytes could be shown in peripheral blood of patients with MTC but not in patients with benign goiter; this increase also correlates with findings in lymph nodes and thyroid gland. The number of FoxP3+ cells correlated with the patients' prognosis. Therefore, FoxP3+ lymphocytes are a good diagnostic criterion for malignancy in patients with medullary thyroid carcinoma, and their presence at staging may influence therapeutic decisions.

New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour.

UNLABELLED: Clinical studies are needed to classify rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC) into one of the clinical risk groups. Here we describe two new RET mutations/variants, R770Q and L881V, in patients with MTC and analyzed genotype-phenotype correlations associated with these RET mutations in the gene carriers. FAMILY 1: Calcitonin screening in a 42-year-old female patient with multinodular goiter showed elevated levels. RET mutation analysis revealed a new variant in exon 13 R770Q (CGA>CAA) in the patient. A thyroidectomy with central and lateral node dissection was done. Histology showed MTC in a mixed variance with follicular cancer of 2 cm diameter (T2N0M0). Postoperatively there was no increase of calcitonin after pentagastrin stimulation. The patient is biochemically cured concerning MTC and FTC after radioiodine therapy. In the sister of the index patient surprisingly another, previously not described amino-acid substitution Y791N (TAT><) in the RET protooncogene was found. In the parents the R770Q variant was detected in the mother, the Y791N mutation in the father. Another sister carries the R770Q variant. In all other gene carriers (aged 44-70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed. FAMILY 2: In a 46-year-old female patient with nodular goiter thyroidectomy, central and left lateral lymph node dissection was done because of elevated calcitonin levels. Histology revealed a microcarcinoma with one lymph node metastasis (T1N1(1/8)Mx). RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). The L881V mutation was detected in five other family members. In the first generation stimulated calcitonin levels were in the normal range, therefore thyroidectomy had not yet been performed. In the sons of the index case thyroidectomy revealed CCH in the older one, no MTC in both. In a cousin thyroidectomy is intended because of elevated basal and stimulated calcitonin. CONCLUSION: Our clinical findings indicate that the L881V mutation may be associated with late-onset nonaggressive disease. If the germline RET R770Q variant has a causative role in the pathogenesis of the mixed medullar/follicular derived histology of the thyroid tumour in the index patient of family 1 has to be proven. The recommendations for prophylactic thyroidectomy in these mutations should be individualized depending on basal and stimulated calcitonin levels until more data are available.

Pre-operative localisation of hyperfunctional parathyroid tissue with 11C-methionine PET.

PURPOSE: Previous studies have shown high sensitivity of positron emission tomography (PET) with 11C-methionine in the pre-operative localisation of parathyroid adenoma and hyperplasia. Nonetheless, in secondary and tertiary hyperparathyroidism (HPT) and in patients with recurrent disease, pre-operative localisation of adenomatous (PTA) or hyperplastic tissue is still a problem with all available methods. The aim of this study was to define the optimal imaging protocol and to compare the diagnostic value of 11C-methionine PET and 99mTc-methoxyisobutylisonitrile (MIBI) single-photon emission computed tomography (SPECT): in particular, we wished to define the benefit of 11C-methionine in those patients with inconclusive or negative conventional imaging. METHODS: Thirty highly pre-selected patients with HPT were enrolled. Sixteen patients had primary HPT, 12 patients had secondary HPT, and two patients had recurrences of parathyroid carcinomas. All patients had ultrasound of the neck, dual-phase scintigraphy with 99mTc-MIBI and PET with 11C-methionine. SUV(parathyroid)/SUV(cervical soft tissue) (target-to-background) and SUV(parathyroid tissue)/SUV(thyroid tissue) (target-to-non-target) ratios were calculated. After surgery, histology of specimens was obtained in all patients but one. RESULTS: In 12 patients with secondary or tertiary HPT, 36 hyperplastic parathyroid glands were histologically verified. Twenty-five of 36 lesions (69%) were detected with 11C-methionine PET and 17 (47%) with 99mTc-MIBI scintigraphy. PET studies were positive in 17/18 (94%) cases in which HPT was related to adenomas or carcinomas. 99mTc-MIBI scintigraphy/SPECT yielded pathological lesions in 9/18 cases (50%). All eight atypical localisations of parathyroid glands were detected with PET but only six of the eight were detected with 99mTc-MIBI scintigraphy/SPECT. In 10/11 patients with recurrent HPT and non-diagnostic scintigraphy/SPECT, hyperfunctional parathyroid tissue was identified with 11C-methionine PET. The highest SUV(parathyroid)/SUV(cervical soft tissue) ratio was found 10 min, and the highest SUV(parathyroid tissue)/SUV(thyroid tissue) ratio 40 min post injection. In three patients clear delineation of hyperfunctional tissue was only achieved after 40 min post injection. CONCLUSION: 11C-methionine PET is a clinically useful method in highly pre-selected patients with recurrent primary HPT as well as in secondary and tertiary HPT if ultrasound and 99mTc-MIBI SPECT are inconclusive or negative. PET imaging of atypical PTA localisations is more accurate than conventional scintigraphy. In order to achieve optimal contrast of parathyroid glands versus thyroid tissue and adjacent soft tissue, imaging at both 10 min and 40 min is recommended.

[Intraarterial calcium stimulation (ASVS) for pancreatic insulinoma: comparison of preoperative localization procedures]. / Der Kalziumstimulationstest (ASVS) bei Insulinomen des Pankreas: Vergleich mit der bildgebenden Lokalisationsdiagnostik.

PURPOSE: Evaluation of clinical relevance of the arterial stimulation procedure with venous sampling (ASVS) in the preoperative localization of insulinoma. METHODS: Thirteen patients with endogenous hyperinsulinism underwent preoperative transabdominal ultrasound (US), helical CT (CT), MRI, endoscopic ultrasound (EUS), and angiography (DSA) in conjunction with the ASVS-test for the detection of insulinoma. The results were compared with intraoperative findings, intraoperative ultrasound (IOUS) and histology. RESULTS: Sensitivity was as follows: US 8%, MRI 27%, CT 46%, EUS 50%,DSA 69%,and ASVS 92%. Intraoperative palpation and IOUS yielded a sensitivity of 77%. In 3 patients the tumors were neither palpable nor detectable by IOUS, the mode of resection was based on preoperative diagnostics. The ASVS procedure as a functional test was superior to all other modalities for the preoperative tumor detection. CONCLUSION: The ASVS was the most sensitive diagnostic modality. It should especially be considered in terms of health economical aspects when CT or MRI do not yield conclusive results.

[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.

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.

Role of the intra-arterial calcium stimulation test in the preoperative localization of insulinomas.

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.

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.

Pancreatic metastasis of a pleuropulmonary blastoma in an adult.

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.

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.

Total hepatectomy and liver transplantation for metastatic neuroendocrine tumors of the pancreas - a single center experience with ten patients.

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.

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

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

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.

[Association of deletions of the RET proto-oncogene wtih aggressive course of sporatic C-cell carcinoma]. / Assoziation von Deletionen des RET Proto-Onkogenes mit einer aggressiven Verlaufsform des sporadischen C-Zell-Karzinomes.

A growing number of reports describing the association of certain deletions within exon 11 of the RET proto-oncogene with aggressive courses of medullary thyroid carcinoma, point to a potential prognostic relevance of molecular features in the sporadic tumor, analogous to the hereditary variant.

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.

Differential display in primary and metastatic medullary thyroid carcinoma.

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.