Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS: Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS: During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION: Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

The advantages and disadvantages of nerve monitoring during thyroid surgery in childhood.

BACKGROUND: Intraoperative damage of the recurrent laryngeal nerve (RLN) and the external branch of the superior laryngeal nerve (EBSLN) are common and cause complications in thyroid surgery. The method of intraoperative electrophysiological neuromonitoring (IONM) of the RLN and the EBSLN has been used in adults for several years. The question is whether IONM can be used in paediatric surgery for the identification and functional control of the RLN and the EBSLN, and what the advantages and disadvantages of using it are. METHODS: Surgical treatment of benign (n = 9) and malign (n = 2) thyroid diseases was carried out in eleven children (median age: 13 years) with a total of 18 nerves at risk (NAR). The function of the vocal cord was monitored in all children before and after surgery. Intraoperative identification and functional control of RLN and EBSLN was performed using the Neurosign 100. All results before and after resection of the thyroid gland were documented. RESULTS: A clear and reliable identification of the RLN and the EBSLN was possible in all cases. All NAR showed a constant physiological nerve signal before and after surgical resection of the thyroid gland. However, in one young patient the postoperative examination of the vocal cord revealed a partial paralysis on the left side after thyroidectomy, despite the constant intraoperative signal of the RLN. After a period of six months, normal functioning had resumed. CONCLUSION: The IONM of both RLN and EBSLN in adult surgery could be used successfully in paediatric surgery. In this study a clear and positive identification of both nerves was possible in all patients. Therefore the IONM of the RLN and EBSLN could develop into a successful and easy method for the prevention of intraoperative nerve damage during thyroid surgery in childhood and young adolescence. Assuming that a constant IONM signal represents a normal vocal cord, our evaluation showed that there is a small percentage of false negative and positive results.

[New concepts in treatment of gastric carcinoma]. / Neue Konzepte in der Behandlung des Magenkarzinoms.

Despite interdisciplinary approach to gastric cancer the outcome of patients remains poor. Even after curative resection most patients suffer from progression of disease and metastasizing course. Adjuvant treatment like chemotherapy or radiation can not improve survival substantialy. This is discussed to be due to dissemination of tumor cells, which are not affected by most treatment options. The new concept of tumor specific antibody therapy with a monoclonal antibody is discussed as an effective treatment especially to fight disseminated tumor cells and thus might help to improve the outcome in stomach cancer.

Tolerance of rat liver allografts induced by short-term selective immunosuppression combining monoclonal antibodies directed against CD25 and CD54 with subtherapeutic cyclosporine.

BACKGROUND: Our purpose was to develop and evaluate protocols for selective immunosuppression after liver transplantation using the monoclonal antibodies (mAbs) NDS-61, directed against the interleukin-2 receptor (CD25), and 1A29, directed against the intercellular adhesion molecule-1 (CD54), in combination with subtherapeutic cyclosporine (CsA). METHODS: Orthotopic rat liver transplantation (ORLT) was performed in a DA-to-LEW strain combination. Immunosuppression was administered from day 0 to +13. Functional parameters such as survival time, body weight, and serum bilirubin levels were measured and the liver grafts were evaluated histologically. RESULTS: A stepwise tapering of CsA from 3 to 0.25 mg/kg/day reduced the long-term survival rate. All animals died at a CsA dosage of 0.25 mg/kg/day, which was therefore defined as subtherapeutic. Monotherapy with the anti-CD25 mAb was performed at dosages of 600 and 1800 microg/kg/day. The lower mAb dosage resulted in a long-term survival rate of 12% and was defined as subtherapeutic. The combination therapy of CsA (0.25 mg/kg/day) and anti-CD25 mAb (600 microg/kg/day) produced a synergistic effect and led to a long-term survival rate of 84%. This survival rate was significantly higher than those after either CsA (P<0.005) or anti-CD25 mAb (P<0.001) monotherapy. Both dosages (10 and 30 microg/kg/day) of anti-CD54 mAb monotherapy as well as anti-CD54 mAb combined with a subtherapeutic dosage of CsA were ineffective in preventing acute allograft rejection. The addition of anti-CD54 mAb (30 microg/kg/day) to combined CsA plus anti-CD25 mAb therapy (triple therapy), however, increased the long-term survival rate to 100%. In the triple therapy group there was no rejection process in the liver allografts at any time, and donor-specific tolerance could be shown by donor-specific and third-party heterotopic heart transplantation. CONCLUSIONS: The synergistic action of subtherapeutic CsA plus anti-CD25 mAb NDS-60 could be demonstrated, whereas anti-CD54 mAb only had a positive effect in a triple therapy group. Triple therapy prevented both acute and chronic rejection and induced donor-specific tolerance.

Apoptosis of T lymphocytes in liver and/or small bowel allografts during tolerance induction.

BACKGROUND: Apoptosis of parenchymal cells has been described during allograft rejection. Immunologically privileged tissue in the mouse has been found to prevent rejection by initiating apoptosis of infiltrating lymphocytes. The aim of this study was to investigate whether apoptosis may play a role in T-cell regulation during rejection and subsequent tolerance induction after liver transplantation (LTx) and combined liver/small bowel transplantation (LSBTx). METHODS: LTx and LSBTx (Brown Norway-->Lewis) were performed without immunosuppression. Cell migration, activation, and apoptosis were investigated by means of sequential histology, immunohistochemistry, and the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling assay. Donor (Brown Norway) and third-party (Dark Agouti) cardiac allografts were transplanted into LSBTx recipients to determine specific tolerance. RESULTS: Transient acute cellular rejection occurred after LTx and LSBTx and was followed by specific tolerance. The kinetics of apoptosis were similar in liver allografts after LTx and LSBTx, but differed from the processes in small bowel allografts after LSBTx. Apoptosis of parenchymal cells in the grafted livers correlated directly with interleukin-2 receptor expression of the infiltrating T cells. During the late phase of rejection, a peak of apoptosis in the lymphocyte infiltrate was demonstrated, characterized as predominantly apoptotic CD8+ T lymphocytes. CONCLUSIONS: These results demonstrate that specific tolerance is achieved in both LTx and LSBTx after a transient rejection crisis. Apoptosis is involved in graft rejection and tolerance induction. Activation of T lymphocytes correlates with parenchymal cell apoptosis in the allograft. T-cell inactivation seems to result in apoptosis of cytotoxic T cells and tolerance, which appears to be unique to the liver allograft.

Persistence of stable intragraft cell chimerism in rat liver allografts after drug-induced tolerance.

BACKGROUND: Drug-induced tolerance of rat liver allografts is well documented. We analyzed cellular events during immunosuppressive therapy on day (d) 10 and in the late phase (d 100) after transplantation to assess for characteristics in the intrahepatic leukocyte (IHL) population in the phase of tolerance. METHODS: Lewis rats served as recipients of Dark Agouti rat livers. Temporary immunosuppression with either cyclosporine (CsA) monotherapy (3 mg/kg/d) or triple therapy that consisted of a subtherapeutic CsA dosage (0.25 mg/kg/d) and monoclonal antibodies directed against the interleukin-2 receptor (IL-2R, CD25) and the intercellular adhesion molecule-1 (ICAM-1, CD54) was administered from postoperative d 0 to d 13. Cell migration and cell activation within liver grafts was assessed by standard histology and flow cytometry. IHL apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL). RESULTS: Both CsA monotherapy and triple therapy prolonged liver allograft survival to more than 100 d and led to the induction of donor-specific tolerance. Untreated recipients rejected their allografts within 14 d. In both groups, donor-specific IHLs initially dropped to 18% to 25% on d 10, but they rebounded to as much as 40% on d 100 as a common characteristic of both groups. Within this population, donor-specific T cells were dominant. In both groups, increased numbers of activated (IL-2R+) CD8+ T lymphocytes were present on d 100. No accumulation of apoptotic IHL was observed on d 100. Their proportion was unchanged in the triple therapy group and slightly decreased in the CsA group compared to the syngeneic controls. CONCLUSIONS: The present study reveals that tolerant liver allografts are repopulated by donor-specific T lymphocytes. This phenomenon is independent of the type of applied immunosuppression. The persistence of activated CD8+ T cells in the phase of proven donor-specific tolerance on d 100 indicates that liver tolerance is associated with the state of a permanent intragraft immune activation. It seems that the coexistence of donor cells with infiltrating recipient cells within liver grafts, termed intrahepatic cell chimerism, is characteristic for tolerated liver allografts.

Videomicroscopic imaging of graft mucosa for monitoring immunosuppressive therapy after small intestinal transplantation in rats.

BACKGROUND: Early diagnosis of rejection and effective immunosuppressive treatment are essential after small intestinal transplantation. To date little is known about microscopic alterations of the intestinal mucosa of the graft during rejection. We attempted to determine whether videomicroscopic imaging of the graft mucosa is a suitable method for monitoring immunosuppressive therapy. METHODS: Real-time videomicroscopic imaging of an ileostoma was performed daily after allogeneic heterotopic small bowel transplantation in the rat (BN to LEW) with and without FK506 immunosuppression. Subsequently, the videomicroscopic findings were compared with the histologically determined grade of rejection. RESULTS: A semiquantitative staging system was established for the intravital mucosal changes during graft rejection. The earliest changes related to rejection appeared on POD 6 in the untreated allogeneic group. The mucosa developed patchy paleness and the mucosal architecture was interrupted in places. The crypts were slightly widened and their color turned dark red (stage I). These alterations spread progressively over the mucosa on POD 7 (stage II). On POD 9 the mucosa appeared pale, the villi were shortened, and the crypts appeared wide and rounded (stage III). In the animals treated with FK506 similar changes were observed, but with a delayed onset. When FK506 was administered as antirejection therapy at the onset of rejection, a temporary improvement of mucosal alterations was observed (stage II --> stage I). The video-microscopic stages correlated with the histological grade of rejection. CONCLUSIONS: The introduction of videomicroscopy has made computer-based high resolution imaging of mucosal microarchitecture possible. With videomi-croscopy beginning rejection can be detected, although it can still be reversed with antirejection therapy. This is a new noninvasive technique that might be of high clinical relevance.

Adjuvant therapy for gastric adenocarcinoma with the apoptosis-inducing human monoclonal antibody SC-1: first clinical and histopathological results.

In a first clinical trial with the apoptosis-inducing human antibody SC-1 eight patients with poorly differentiated stomach adenocarcinoma of diffuse-type received 20 or 30 mg of purified SC-1 antibody intravenously, followed 24 or 48 h later by gastrectomy and lymphadenectomy. In seven cases a significant induction of apoptotic activity was measured in primary tumors as compared with earlier biopsy material and in five patients a significant regression of tumor mass could be determined histopathologically. No toxic crossreactivity was observed with normal tissue or organs of patients.

Arterial reconstruction in diabetes and peripheral arterial occlusive disease: results in 192 patients.

OBJECTIVE: In the present study long-term patency and limb-salvage rates of femoro-distal bypasses were compared for patients with and without diabetes mellitus. METHODS: Between 1990 and 1994, some 192 femoro-crural bypass procedures were performed; 132 reconstructions were carried out on patients with peripheral arterial occlusive disease (PAOD), 60 bypasses on patients with PAOD and diabetes mellitus (DM). The two groups did not differ significantly regarding age, gender and risk pattern. RESULTS: The comparison of the two groups showed a significant advantage for the diabetic patients regarding the limb-salvage rate. In both groups there was also a significant difference regarding patency in favour of the diabetics. CONCLUSION: Patients suffering from diabetes and PAOD profit from femoro-distal bypasses. An aggressive vasosurgical reconstructive therapy is indicated for these patients.

[Gastrointestinal stromal tumor of the abdominal wall. An unusual localization of a rare tumor]. / Gastrointestinaler Stromatumor der Bauchwand. Ungewöhnliche Lokalisation eines seltenen Tumors.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. We describe here for the first time a patient with a huge GIST of the abdominal wall without any relation to the gastrointestinal tract, omentum, or mesentery. With regard to the size of 24 cm and a low mitotic index, this GIST is considered an intermediate risk for metastasis. Radical surgical resection was performed with negative pathologic resection margins. The classic immunohistochemical phenotype of the tumor described facilitates the differential diagnosis to exclude abdominal desmoid tumor and solitary fibrous tumor (SFT). In the case of metastasis, therapeutic nihilism no longer seems justified with the availability of imatinib, a tyrosine kinase inhibitor, which shows encouraging results in the therapy of metastatic GIST.

[First successful clinical small intestine transplantation. Tactics and surgical technic]. / Erste erfolgreiche klinische Dünndarmtransplantation. Taktik und chirurgische Technik.

A case of successful clinical small bowel transplantation is demonstrated. A segment of 60 cm of jejunum and ileum has been harvested from the sister of the recipient and has been brought in heterotopic position in the first operative step. It was anastomosed to the recipient's GI-tract 6 weeks later. This procedure has the advantage that the graft can recover from ischemic damage in heterotopic position and that an immunological steady state can be achieved. This case of successful clinical small bowel transplantation offers a new causal therapy for patients with short gut syndrome.

[Primary glomangioma of the liver. A new differential benign liver tumor diagnosis]. / Primäres Glomangiom der Leber. Eine neue Differenzialdiagnose benigner Lebertumoren.

Glomus organs are arteriovenous anastomoses which control the thermoregulation of the extremities. Benign tumors of these glomus organs, termed "glomangiomas", are therefore most frequently located in the fingers and toes. Case reports of primary glomangiomas in the respiratory- and gastrointestinal tracts as well as in the genital organs have been published. On the other hand, glomus tumors of the liver have not yet been described. We report the case of a 61-year-old patient with a smooth subcapsular lesion within the liver detected by a routine ultrasound scan. Further diagnostic imaging did not match with one of the common liver tumors. The diagnosis of a glomangioma was finally made by liver biopsy and subsequent histology. A review of the literature revealed a potential transformation of glomangiomas. Since the patient reported on inappetence weight loss and the tumor showed growth tendency, the indication for surgical excision was made. Final histologic investigation revealed no signs of malignancy. The primary glomangioma of the liver is a new differential diagnosis of benign liver tumors. As there is a possibility of malignant degeneration, we propose the decision for surgical removal once there are clinical symptoms and a growth tendency of the lesion.

[Combined liver-islet transplantation after epigastric exenteration in carcinoma of Vater's ampulla]. / Kombinierte Leber-Insel-Transplantation nach Oberbauchexenteration bei Papillencarcinom.

A 44 year old female underwent an upper abdominal exenteration because of an adenocarcinoma of the pancreas with liver metastases (T1 N1 M1). Reconstruction was performed by orthotopic liver transplantation and intraportal islet transplantation. Due to initial non function of the first liver graft, a second liver transplantation was performed. Thereafter, the patient received 375,000 islet equivalents of the primary liver donor in addition to 295,400 islet equivalents of another donor. Six months postoperatively, the patient is off insulin except irregular injections of 4-6 units of insulin to protect her from hyperglycemia after lunch. CT scans of the liver do not show any signs of tumor recurrence. Upper abdominal exenteration with consecutive islet transplantation offers a good method of reconstruction after radical surgery in the upper abdomen. The oncological aspects of the procedure have to be further investigated.

[Not all vocal cord failure following thyroid surgery is recurrent paresis due to damage during operation. Statement of the German Interdisciplinary Study Group on Intraoperative Neuromonitoring of Thyroid Surgery concerning recurring paresis due to intubation]. / Nicht jeder Stimmlippenstillstand nach Schilddrüsenoperation ist eine chirurgischbedingte Rekurrensparese. Stellungnahme der "Interdisziplinären Studiengruppe Intraoperatives Neuromonitoring Schilddrüsenchirurgie" zur Problematik intubationsbedingter Rekurrensparesen.

Since the phoniatrician H. Bauer described the first case of recurrent laryngeal nerve palsy most likely caused by intubation some 45 years ago, several case reports have been published. However, systematic analyses regarding the frequency of recurrent laryngeal nerve palsies due to intubation are scarce, and none of them has used the proper methods to demonstrate clearly that such a mechanism exists. Currently available data justify the assumption that not every recurrent laryngeal nerve palsy following thyroid surgery is due to the operation itself and that the damage caused by intubation, however, may only account for a minority of these cases. The differential diagnosis of postoperative recurrent laryngeal nerve palsy requires the use of specific tools which go beyond simple laryngoscopy and include stroboscopy as well as intra- and extralaryngeal electromyography. A partial palsy of recurrent laryngeal nerve due to intubation would be associated with severe dysphonia or aphonia, not with dyspnea because of the typical intermediate position of the paralyzed vocal folds with a normal electromyographic function of the cricothyroid muscle. The use of these methods to identify the nature of postoperative recurrent laryngeal nerve palsy is recommended in cases of regular intraoperative neuromonitoring but postoperatively impaired function of the vocal cords.

[Effectiveness and results of intraoperative neuromonitoring in thyroid surgery. Statement of the Interdisciplinary Study Group on Intraoperative Neuromonitoring of Thyroid Surgery]. / Zuverlässigkeit und Konsequenzen des intraoperativen Neuromonitorings in der Schilddrüsenchirurgie. Stellungnahme der "Interdisziplinären Studiengruppe Intraoperatives Neuromonitoring Schilddrüsenchirurgie"

Intraoperative neuromonitoring (IONM) has yielded an increasing effect on thyroid surgery. During IONM, the recurrent laryngeal nerve is stimulated electrically and an acoustically transformed electromyographic signal is derived via either a needle electrode placed in the vocalis muscle or an electrode adjusted to the intubation tube. The IONM is used for identifying and predicting the function of the recurrent laryngeal nerve. Especially under difficult anatomic conditions, IONM has proven a valuable tool for identification of recurrent laryngeal nerves. This can lead to decreased occurrence of nerve palsy rates, as shown in numerous studies. The reliability of the IONM signal (defined as the correlation between intraoperative signal interpretation and postoperative vocal cord function) is reflected by a specificity as high as 98.2%, as shown by German multicenter studies. Thus, normal vocal cord function could be demonstrated postoperatively in over 98.2% of patients with intraoperatively unchanged neuromonitoring signals. If the neuromonitoring signal changed during operation, 39% of the patients suffered from transient vocal cord immobility and 12% had permanent loss of vocal cord function.

[Restoration of blood circulation in reperfusion of ischemic tissues]. / Vidnovlennia krovobihu pry reperfusiï ishemizovanykh tkanyn.

In experiment there were studied changes of the tissue blood circulation and microcirculation during postischemic reperfusion of skeletal muscles with various density of capillaries. It was established that reactive hyperemia, caused mainly by enhancement of extracapillary tissue blood flow. While persistence of durable arterial hypertension the capillaries quantity and potential volume of microcirculatory bed are reducing, negatively influencing the blood circulation restoration process during postischemic reperfusion. In chronic ischemia the potential volume of microcirculation is increasing, securing complete restoration of blood circulation in postischemic reperfusion.