[Pancreatic hyperinsulinism--changes of the clinical picture and importance of differences in sporadic disease course (experience with 144 patients operated in the period 1986-2009)]. / Pankreatischer Hyperinsulinismus--Wandel des Krankheitsbildes mit spezifischen Unterschieden auch bei sporadischen Erkrankungsformen (Eigene Erfahrung an 144 operierten Patienten von 1986-2009).

The diagnoses of pancreatogenic hyperinsulinism and insulinoma (benign or malignant) were almost synonomously used during the last decades. Only familial forms of hyperinsulinism, i. e., in patients with multiple endocrine neoplasia type 1 were separately discussed. The surgical literature concentrated on technical questions, comparing open and minimal invasive techniques. The clinical diagnosis of patients with pancreatogenic hypo-glycaemia syndrome (NIPHS) and the pathological diagnosis of insulinomatosis has now opened up new questions in the diagnosis and therapy of pancreatogenic hyperinsulinism. On the basis of our experience from 144 patients operated on for pancreatogenic hyperinsulinism during the last 22 years with 16 NIPHS patients and with the help of the relevant literature, we explain the prerequisites that surgical therapy has to fulfil in the treatment of patients with pancreatogenic hyperinsulinism today.

Poor late prognosis of bleeding peptic ulcer.

BACKGROUND AND AIMS: Long-term course of peptic ulcer bleeding is unclear. Because of a more aged and more diseased ulcer population, the long-term prognosis may be expected as poor. MATERIALS AND METHODS: In a prospective study, all patients with peptic ulcer bleeding treated at the Department of Surgery of the Heinrich-Heine-University in Düsseldorf were included between 1986 and 1995. Follow-up covered hospital mortality, 1-month mortality, 1-year mortality, and 5-years mortality. Significant prognostic parameters for death were investigated in univariate and multivariate analysis. RESULTS: One hundred and seventy-one out of 192 patients with peptic ulcer bleeding could be followed up. One-month mortality was similar to hospital mortality with 12.3%, 1-year mortality was 28.7%, and the 5-years mortality was 46.8%! In univariate analysis, statistically significant prognostic factors for death were ages beyond 70 years, concomitant diseases, risk-related drugs, postinterventional complications, and recurrent bleeding. In multivariate analysis, age, postinterventional complications, and type of admission were statistically significant parameters for death. CONCLUSION: Long-term prognosis of peptic ulcer bleeding is poor! The majority of deaths after hospital stay is probably not because of ulcer bleeding, but because of more aged patients with severe concomitant diseases.

Mutation of the p53 gene in a differentiated human thyroid carcinoma cell line, but not in primary thyroid tumours.

The p53 gene has been implicated as a tumour suppressor, with mutations occurring in many carcinomas, such as colon, breast and lung. We have sequenced exons 5, 7 and 8 containing conserved gene regions in the only available differentiated thyroid follicular carcinoma cell line and found a mutation at position 273, Arg----His, with no normal allele present. The same mutation was also present in DNA from the tumour of origin. However immunohistochemical analysis of 129 human thyroid tumours using a panel of p53 antibodies was unequivocally negative. Southern blotting in 20 cases failed to demonstrate any deletion or rearrangement, and direct genomic sequencing of 20 carcinomas showed normal DNA sequence for exons 5, 7 and 8. Thus p53 abnormalities may not be important in human thyroid carcinogenesis, in contrast to colon, breast and lung. However, the FTC 133 cell line was only established after 132 unsuccessful attempts with other differentiated thyroid follicular tumours. Since this line and the corresponding tumour of origin have a p53 mutation, we propose that p53 mutation may confer on thyroid follicular tumour cells the ability to grow in culture. This has potential applications for the future development of thyroid carcinoma cell lines.

Mutation and methylation analysis of TP53 in adrenal carcinogenesis.

AIM: To investigate the role of coding region mutation and promoter hypermethylation of TP53 in adrenocortical cancer formation. METHODS: Twenty sporadic adrenocortical cancers (ACCs) and five normal adrenal tissue samples were available for analysis. Coding region mutation of TP53 in 20 ACCs was examined by polymerase chain amplification using intronic primers for exons 2-11 and direct sequencing of the product. In 10 ACCs and five normal adrenal tissue specimens, methylation of the 16 CpG sites within the TP53 promoter was examined using bisulphite methylation sequencing. RESULTS: Coding region mutation in TP53 was demonstrated in 5 of 20 ACCs. There were four mis-sense mutations and one frameshift mutation. Four of 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter and 3 of 4 died of disease within 12 months of surgical resection. No methylation was seen in the TP53 promoter in 10 ACC and the five normal adrenal tissues examined. CONCLUSION: Coding region mutation in TP53 occurs in 25% of ACCs with a trend toward a poorer prognosis. Promoter methylation of TP53 is not present in ACC as a mechanism for tumour suppressor gene (TSG) inactivation and, therefore, other genes in the 17p13 region are implicated in adrenal carcinogenesis.

[Mild head injury]. / Leichtes Schädel-Hirn-Trauma. Wann zu Hause, wann in der Klinik uberwachen?

Mild injuries to the head are a common everyday occurrence. Only one out of 30,000 patients suffering mild traumatization of the brain subsequently goes on to develop a complication that requires treatment. Such patients can be identified on the basis of the Glasgow Coma Scale and the determination of risk factors, and these data also serve as an aid for deciding whether surveillance at home or hospitalization is indicated.

Complete sequencing and messenger ribonucleic acid expression analysis of the MEN I gene in adrenal cancer.

Adrenal cancer is a rare sporadic disease that has also been observed in the context of multiple endocrine neoplasia type I (MEN I). Adrenal lesions occur in up to 40% of MEN I patients. Loss of heterozygosity of the 11q13 band harboring the menin gene has been reported in more than 50% of patients with adrenal cancer. Despite this high index of suspicion, former screening studies did not reveal mutations of the MEN I gene in 28 patients. We identified loss of heterozygosity of 11q13 microsatellites in five of five patients (100%). In 40%, heterozygosity was retained in codon 418 of the MEN I gene. Complete direct DNA sequencing data of the entire coding region and adjacent splice sites of the MEN I gene were obtained in 14 patients with sporadic adrenal cancer. In only one of them a heterozygous missense mutation, R176Q (exon 3), was identified. Due to the heterozygous pattern and unknown biological effect of this mutation, it is not clear whether there is a causal relationship with adrenal cancer. The total mutation frequency in sporadic adrenal cancer is 1 of 14 (7%). Menin messenger RNA expression was identified in 14 of 14 patients (100%). Transcriptional inactivation of the menin gene is, hence, unlikely to cause loss of its tumor suppressor function in adrenal cancer. Furthermore, we examined three patients who presented adrenal cancer in the context of sporadic multiglandular endocrine tumor disease previously diagnosed on clinical grounds to be MEN I syndrome. An opal stop codon mutation was identified in codon 126 (exon 2) in the adrenal cancer of one of these patients. Formation of the adrenal cancer in this patient may be rather coincidental because the mutation was present in a heterozygous pattern. There was no mutation of the menin gene in the two other patients. This may mean that formation of adrenal cancer in the context of multiglandular endocrine disease denotes an entity different from MEN I in some patients.

A method to perfuse liver metastases with heated blood (45 degrees C, 45 min).

To heat the livers in ten pigs (20-30 kg) a system of two pumps, both connected to the cannulated A.femoralis and to two radio-wave heating devices, was used. With pump I the arterial vascular system of the liver was perfused for 45 min via the A.gastroduodenalis with a constant volume of 150-200 ml blood/min, heated to 44-45 degrees C. With pump II 50-700 ml/min heated blood was pumped into the portal vein to raise the temperature and oxygen content of the portal flow. During the heating period the A.hepatica was clamped. A temperature of 45 degrees C is a highly toxic for the differentiated liver tissue, but the more simply structured wall of the arteries tolerates this temperature. This difference in heat resistance allows the perfusion of the arterial vascular system of the liver with blood heated to a temperature that is fatal to liver tissues. On the way from the A.gastroduodenalis to the liver periphery the heated blood becomes cooled by the surrounding cooler liver tissues. Finally the supply to the lobules is a mixture of arterial and venous blood, i.e. the highly toxic agent, heat, becomes "detoxified" by cooling before reaching the heat-sensitive liver lobules. Changing flow and temperature in the portal vein allows the temperature of the liver lobules to be kept within a safe range, i.e. below 43 degrees C. The raised oxygen content in the portal flow allows the arterial perfusion to be stopped for 10 min (to subject a heated metastasis to a period of hypoxia). Liver enzymes reached their maximal level 2 days after heating and returned to normal within 1 week. It is supposed that this method allows the temperature in a liver metastasis to be raised to a tumoricidal level.

Overexpression of Gs alpha subunit in thyroid tumors bearing a mutated Gs alpha gene.

Point mutations occurring at codon 201 of the gene coding for the alpha subunit of the stimulatory G protein impair intrinsic GTPase activity and lead to a constitutive activation of adenylate cyclase. We have examined thyroid follicular and papillary carcinomas and follicular adenomas and found samples that bear this mutation at codon 201 of the Gs alpha gene. Both mutation-positive and mutation-negative tissue samples were investigated for the level of Gs alpha expression relative to a pool of normal thyroid tissue, using immunoblotting against two (mid-region-specific and C-end-specific) antipeptide antibodies. Using 8000 g and 100,000 g membrane fractions of homogenized tissues we have demonstrated that the Gs alpha proteins in normal ad neoplastic thyroid tissues are represented by three isoforms: 43 kDa, 45 kDa and 52 kDa. We have quantified and compared the amount of Gs alpha protein and find it is overexpressed in mutation-bearing tissue samples.

Distribution of Gs-alpha activating mutations in human thyroid tumors measured by subcloning.

In the search for the prevalence and distribution pattern of Gs-alpha gene mutations in differentiated thyroid tumors we examined 66 tumor tissue samples for the presence of mutations at "hot-spot" codons 201 and 227 using methods based on the polymerase chain reaction, subcloning and sequencing. The prevailing type of single-base substitution at codon 201 (71.4%) corresponded to the replacement of the wild-type sequence CGT (Arg) with TGT (Cys). The fragments of the Gs-alpha gene, including codon 201 or 227 from five follicular carcinomas and one follicular adenoma, were subcloned in Escherichia coli and it was found that the proportion of alleles with mutated codon 201 varied from 3.2% to 43%. Sequencing of the corresponding region has confirmed preliminary data indicating that the single-base changes CGT (Arg) to TGT (Cys) or CGT to CAT (His) occurred. There was only a weak correlation between the prevalence of cells bearing a mutation in the Gs-alpha gene and the level of Gs-alpha protein expression in the corresponding thyroid tumors.

Expense and benefit of neoadjuvant treatment in squamous cell carcinoma of the esophagus.

BACKGROUND: The effectiveness of neoadjuvant treatment (NT) prior to resection of squamous cell carcinoma of the esophagus (SCCE) in terms of prolonged survival has not been proven by randomized trials. Facing considerable financial expenses and with concerns regarding the consumption of the patient's remaining survival time, this study aims to provide rationales for pretreating resection candidates. METHODS: From March 1986 to March 1999, patients undergoing resection for SCCE were documented prospectively. Since 1989, NT was offered to patients with mainly upper and middle third T3 or T4 tumors or T2 N1 stage who were fit for esophagectomy. Until 1993, NT consisted of chemotherapy. Since that time chemoradiation has also been applied. The parameters for expense and benefit of NT are costs, pretreatment time required, postoperative morbidity and mortality, clinical and histopathological response, and actuarial survival. RESULTS: Two hundred and three patients were treated, 170 by surgery alone and 33 by NT + surgery. Postoperative morbidity and mortality were 52% to 30% and 12% to 6%, respectively (p = n.s.). The response to NT was detected in 23 patients (70%). In 11 instances (33%), the primary tumor lesion was histopathologically eradicated. Survival following NT + surgery was significantly prolonged in node-positive patients with a median survival of 12 months to 19 months (p = 0.0193). The average pretreatment time was 113 +/- 43 days, and reimbursement for NT to the hospital amounted to Euro 9.834. CONCLUSIONS: NT did not increase morbidity and mortality. Expenses for pretreatment, particularly time and costs, are considerable. However, taking into account that the results are derived from a non-randomized study, patients with regionally advanced tumor stages seem to benefit, as seen by their prolonged survival.

Persistent hypertension after successful adrenal operation.

BACKGROUND: Up to 80% of patients with adrenocortical tumors comprising Conn's or Cushing's syndrome and patients with pheochromocytomas suffer from hypertension. Its implications in cardiovascular disease and its impact on quality of life make it the most important aim in therapeutic efforts. The aim of our study was to assess the long-term results in postoperative blood pressure after adrenalectomy and to evaluate potential risk factors for persistent hypertension. METHODS: Forty four patients with adrenal hypertension operated on between April 1986 and April 1991 underwent follow-up consisting of exact history, hormonal analysis, and adrenal imaging. RESULTS: Forty three patients were reexamined, which showed 11 patients (26%) with hypertension at dismissal from hospital and 17 patients (40%) with hypertension after a median of 2 years. Except for two recurrent tumors in adrenocortical carcinoma all patients were surgically cured. Antihypertensive medication could be reduced in 13 of 17 patients with persistent hypertension. Persistent hypertension did not correlate with the degree of preoperative blood pressure elevation, age, and gender, but it did correlate strongly with history of hypertension. Patients with normal blood pressure level after operation had a mean history of 5.7 years versus 11.5 years in patients with persistent hypertension (p < 0.03). CONCLUSIONS: The success of surgical treatment for adrenal hypertension strongly depends on early diagnosis and surgical intervention.

Malignant endocrine tumors in patients with MEN 1 disease.

BACKGROUND: In contrast with multiple endocrine neoplasia type 2, malignancies are of minor importance in multiple endocrine neoplasia type 1 (MEN 1) syndrome. METHODS: The data for 42 patients with MEN 1 syndrome were evaluated. Twelve patients (29%) had 1 or more associated malignancies: malignant gastrinoma (1 patient), neuroendocrine tumors of the thymus (2 patients), neuroendocrine tumors of the lung (3 patients), neuroendocrine tumor of the ileum (1 patient), adrenocortical carcinomas (2 patients), and a combination of neuroendocrine tumors of thymus, lung or pancreas (3 patients). RESULTS: Despite suspected MEN 1 syndrome in 7 patients, malignancies were detected late in 4 patients and could not be resected curatively. The survival rates for 5 years and 10 years after operation of the malignant tumor were 66% +/- 14% (SE) and 33% +/- 15% (SE), respectively. CONCLUSIONS: In patients at risk for the MEN 1 syndrome, genetic screening is indispensable. Gene carriers have to be followed up closely with hormone analysis and routine examination of the thorax, pancreas, and adrenal glands to detect malignancies as early as possible.

The effect of thyrotropin and cAMP on DNA synthesis and cell growth of human thyrocytes in monolayer culture.

Monolayer cultures of human thyrocytes from normal tissue (n = 10), and adenomas (n = 7), differentiated (n = 4), poorly differentiated (n = 2), and undifferentiated (n = 3) thyroid cancers were established to assess the significance of thyrotropin (TSH) and cAMP (adenosine 3',5'-cyclic monophosphate) on cell growth and DNA (deoxyribonucleic acid) synthesis. Cell growth of thyrocytes from normal and adenomatous tissues increased more rapidly (p less than 0.01) after TSH (0.1 IU/ml) was added but was unaffected by cAMP (10(-4) mol/L). In these cells, TSH also enhanced DNA synthesis twofold to twelvefold (p less than 0.01). The adenylate cyclase (AC) inhibitor, 2',3' dideoxyadenosine (ddA), increased DNA synthesis 1.3 to 6 times at a concentration of 2 X 10(-4) mol, whereas the membrane/passable cAMP analogue, dibutyryl-cAMP, and the AC stimulator, forskolin, failed to show any effect on DNA synthesis up to a concentration of 10(-5) mol/L (p less than NS). When administered simultaneously, TSH (1/2 maximum) and ddA (20 mumol) had no cumulative effect on DNA synthesis (p = NS). TSH stimulation in cancerous thyroid tissue (n = 11) demonstrated a lack of TSH response in seven of 11 monolayer cultures with no apparent correlation to cancer differentiation, patient age, or sex. Thus TSH was demonstrated to stimulate DNA synthesis and cell growth of human thyrocytes in monolayer cultures independent of the AC system. However, the TSH effect on cell growth and DNA synthesis was unpredictable in thyrocytes from cancerous tissues.

Safety of a low-dosage Filgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with an inflammatory process.

OBJECTIVE: To evaluate the effect and safety of a low dose Filgrastim treatment in surgical intensive care patients. DESIGN: Prospective, clinical study. SETTING: Surgical intensive care unit (ICU) in a university hospital. PATIENTS: Ten patients with the systemic inflammatory response syndrome (SIRS) and ten patients with sepsis were included in the study. INTERVENTIONS: Filgrastim was given intravenously at 1.0 microgram/kg for 3 days, followed by 0.5 microgram/kg for 4 days. MEASUREMENTS AND RESULTS: Filgrastim treatment increased leukocyte counts and plasma levels of G-CSF. Cytokine levels (IL-6 and IL-8) decreased in the first 3 days of treatment. None of the SIRS patients developed sepsis or multiple organ failure and none of the patients died. In the sepsis group four patients died. No adverse side effects were observed, especially no attenuation of lung injury. CONCLUSIONS: Low-dosage Filgrastim treatment in ICU patients is safe. Whether the observed changes of the inflammatory response can be attributed to Filgrastim has to be clarified in further randomized trials.

Fine structure of three major grades of malignancy of human pancreatic adenocarcinoma.

Fine structural analysis of a series of 51 adenocarcinoma in the human pancreas revealed their composition of one major cell type, a mucoprotein secreting cell which has a number of structural features resembling the cells of the larger interlobular ducts in the normal pancreas. In addition to mucus secretion, the tumor cells released large quantities of membrane material, both as vesicles pinched off from microvilli and as blebs sequestered from the plasma membrane. At the ultrastructural level the subdivision of tumors into three major grades of malignancy was manifested by a progressive loss in cell polarity and a reduction in the association of tumor cells with elements of the extracellular matrix (basal lamina). The highest grade of differentiation grew as tubular structures with a common luminal space, while with progressive dedifferentiation and loss of cell polarity secretion occurred into both luminal and interstitial spaces. This release pattern of tumor cell products, which constitute a complex mixture of exportable and constitutive proteins, will lead to their appearance in both pancreatic juice and blood circulation. Tumor cell spreading occurred along perineural sheaths and was combined with nerve fiber destruction. Primary tumors and lymph node or liver metastases did not differ significantly in their respective grading.

Activin A and activin receptors in thyroid cancer.

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

Gastric cancer: which patients benefit from systematic lymphadenectomy?

AIMS: The purpose of this study was to evaluate the value of systematic lymphadenectomy (SLA) in curative resected gastric cancer patients with respect to long-term survival, peri-operative morbidity and mortality. METHODS: We reviewed our prospectively gathered database of 309 resected gastric cancer patients and analysed the outcome of 185 R0-resected patients (60%) with respect to peri-operative morbidity, mortality and long-term survival by comparing 81 patients resected with SLA (D2-group) versus 104 patients resected without SLA (D1-group). RESULTS: Overall 5-year survival rates of R0-resected patients (n = 173; exclusion of peri-operative mortality) amounted to 49% and did not differ significantly between D2- and D1-groups (53% vs 47%); P=0.344). Nevertheless, subgroups of patients taking a benefit from SLA could be defined. Gastric cancer patients without LN metastases (pTx pN0; n=78) and patients with LN metastases only in perigastric lymph nodes (pTx pN1; n=34) showed a significantly better long-term prognosis when SLA was performed (84% vs 51%; P=0.001). Regarding peri-operative morbidity (38% vs 39%) and mortality (6% in each case) we could not find any differences between the D2- and D1-groups. CONCLUSIONS: We conclude that SLA is able to improve long-term survival for some tumour stages. Therefore SLA should be recommended as a standard procedure in all gastric cancer patients resected with curative intention.

Parathyroid carcinoma: problems in diagnosis and the need for radical surgery even in recurrent disease.

INTRODUCTION: From 1986 to 1999 we operated on 963 patients with primary hyperparathyroidism (pHPT). METHODS AND RESULTS: Parathyroid carcinoma was diagnosed clinically and histologically in four patients (0.4%). In two of these patients diagnosis of parathyroid cancer was delayed by misinterpretation of the histopathology leading to an autotransplantation of malignant parathyroid tissue in one case. In two patients multivisceral surgery was performed: beside thyroidectomy, neck dissection, tracheal wall resection and resection of the muscular layer of the oesophagus one patient received oesophagectomy and gastric transposition and one patient a lung wedge resection. Both patients had a temporary palliation of tumour-associated symptoms after multivisceral surgery. The first patient died 2 years after oesophagectomy and 12 years after primary diagnosis from local tumour recurrence and cachexia. The second patient is living with tumour recurrence presenting a serum calcium level of 4.2 mmol/l (normal range 2.0 to 2.5 mol/l) and multiple brown tumours 2 years after lung resection and 6 years after the primary diagnosis. CONCLUSIONS: We conclude that parathyroid carcinomas, being difficult to diagnose, warrant radical surgery, including multivisceral resection to prolong survival and reduce tumour and hypercalcaemia associated symptoms.

Surgery for Graves disease in childhood and adolescence.

Children and adolescents with thyroid disorders are predominantly treated by pediatricians and pediatric endocrinologists. Surgery for thyroid disorders still represents the third frequent operation in adults in Germany, but is seldomly indicated in children. Thus children and adolescents make up for 1.3% of all our patients and of these 89 patients only 21 (23.6%) suffered from Graves disease. Nevertheless surgery for Graves disease in children and adolescence is recommended because medical therapy has proven a high rate of recurrences in children and because radioiodine is only reluctantly applied to children, at least in Germany.

Molecular analysis of mutations in thyroid tumors with TGGE.

Immunohistochemical demonstration of overexpression of the p53 protein indicates a mutational alteration of the gene. Our own investigations of 59 differentiated thyroid carcinomas revealed an overexpression in 15% of the tumors. A correlation to unfavourable tumor prognosis was found (stage I and II: 0/11 (0%); stage III: 4/26 (14%); stage IV: 5/22 (23%)). For screening of one out of more than 300 possible mutations temperature gradient gel electrophoresis was employed. Analysis of the highly-conserved regions of the p53 gene (exon 5 to 8) could demonstrate a mutation in only 1 out of 31 differentiated thyroid carcinomas. The question arises whether accumulation of the protein is due to a mutational event or rather other molecular mechanisms.