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.

[Case volume and complications after thyroid gland surgery in Germany: an analysis of routine data from 48,387 AOK patients]. / Fallvolumen und Komplikationen nach Schilddrüsenoperationen in Deutschland: eine Routinedatenanalyse von 48.387 AOK-Patienten.

BACKGROUND: Many studies showed that hospital and surgeon volume have a significant influence on the complication rates of thyroid surgery. The present study investigates whether this relationship applies in subtotal as well as total lobe resections. Furthermore, it is still unclear which threshold for the hospital-related case volume can be determined, above which the risk of complications lies below the current national average. MATERIAL AND METHODS: The study was based on nationwide routine data for persons insured with the Local General Sickness Fund (AOK) who had undergone thyroid surgery in 2014-2016. Permanent vocal cord palsy, bleeding and wound infection needing revision were recorded using indicators. The effect of the case volume on the indicators and the case number threshold was determined using logistic regression. RESULTS: Permanent vocal cord palsy was observed in 1.3% and bleeding or wound infections needing revision in 1.6% and 0.3% of the cases. Compared to hospitals with >450 surgeries per year, the risk of permanent vocal cord palsy in hospitals with fewer than 201, 101 and 51 surgeries was significantly increased (OR [95% CI]: 1.5 [1.1-2.1]; 1.5 [1.1-2.1]; 1.8 [1.3-2.5]). The threshold needed to achieve a risk for permanent vocal cord palsy below the national average (1.3%) was 265 thyroid surgeries per year (95% CI: 110-420). For bleeding or wound infection in need of revision, no association between volume and outcome was found. CONCLUSION: The present study showed that the risk of postoperative permanent vocal cord palsy decreased with increasing case volume. The broad confidence interval of the threshold makes clear case volume recommendation difficult. In order that the risk for a postoperative permanent vocal cord palsy is not likely above the national average, the annual case volume should reach 110 thyroid interventions.

[Speech therapy after thyroid gland operations in Germany: analysis of routine data from 50,676 AOK patients]. / Logopädie nach Schilddrüsenoperationen in Deutschland: eine Routinedatenanalyse von 50.676 AOK-Patienten.

BACKGROUND: This study investigated the frequency of postoperative speech therapy in the context of vocal cord palsy after thyroid surgery based on nationwide routine data. Additionally, volume-outcome relationships were examined. MATERIAL AND METHODS: Nationwide routine data from insured patients of the Local Health Insurance Fund (AOK) who underwent thyroid surgery for a benign thyroid disease between 2013 and 2015 were analyzed. Postoperative speech therapy was determined based on prescription data. Transient and permanent vocal cord palsy were determined using indicators. The effect of hospital volumes (volume quintiles) on prescription of postoperative speech therapy was determined by multivariate logistic regression. RESULTS: A total of 50,676 thyroid gland operations were identified. The overall frequency of postoperative speech therapy prescription was 6.5%. In AOK patients with transient or permanent vocal cord palsy, the frequencies of postoperative speech therapy prescription were 56.1% and 75.2%, respectively. The prescription volume of the normal case (≥21 units of speech therapy) was exceeded in 0.7% of the AOK patients. In the two lowest case volume categories the risk of postoperative speech therapy exceeding the prescription volume of the normal case was significantly higher compared to the highest case volume hospitals (odds ratios: 1.2 and 1.8, respectively). CONCLUSION: This study presents the reality of healthcare with respect to the frequency of speech therapy prescription after thyroid gland surgery in Germany. In addition, it was determined that the risk of postoperative speech therapy prescription exceeding the volume of the normal case after thyroid gland operations decreases with increasing case volumes of hospitals.

[Complications after thyroid gland operations in Germany : A routine data analysis of 66,902 AOK patients]. / Komplikationen nach Schilddrüsenoperationen in Deutschland : Eine Routinedatenanalyse von 66.902 AOK-Patienten.

BACKGROUND: Routine data from hospitals in the public healthcare system allow the analysis of large patient datasets without generating additional documentation efforts for hospitals. This study reports the frequencies of postoperative complications after thyroid surgery based on routine nationwide data. Moreover, volume-outcome relationships were investigated. MATERIAL AND METHODS: Nationwide routine data from insured patients of the Local Health Insurance Fund (AOK) who underwent thyroid surgery between 2008 and 2010 were analyzed. Complications were determined based on indicators for permanent vocal cord palsy, re-bleeding with re-operations and wound infections with specific treatment. The effect of hospital volumes (volume quintiles) on the indicators was determined by multivariate logistic regression. RESULTS: A total of 66,902 thyroid gland operations were identified. The overall frequency of permanent vocal cord palsy was 1.5 %, re-bleeding 1.8 % and wound infections 0.4 %. In the four lowest case volume categories the risk of permanent vocal cord palsy was significantly higher compared to the highest case volume hospitals (odds ratio 1.5, 1.7, 1.7 and 2.2, respectively). CONCLUSION: This study represents the reality of healthcare for thyroid surgery in Germany. Additionally, it was determined that the risk for permanent vocal cord palsy after thyroid gland operations decreased with increasing case volumes of hospitals.

No influence of immunosuppression on insulin sensitivity and beta-cell function in living donor liver transplantation.

In liver transplantation alterations of glucose metabolism are common but not well understood. Influence of immunosuppression is widely presumed but has not proven until now. Using a frequently sampled intravenous glucose tolerance test with a minimal modeling technique of glucose disappearance we analyzed insulin sensitivity (SI) and beta-cell function (first and second phase of pancreatic beta-cell secretion, Phi 1 and Phi 2) in living donor liver transplantation of the right lobe. Initial immunosuppression in recipients was done with tacrolimus, prednisolone, and basiliximab induction. Donors and recipients were investigated before and 10 days, 6 months, and 1 year after operation. Normal SI of controls (donors before operation) decreased markedly 10 days after right lobectomy to SI 2.22 +/- 0.35 x 10(-4) min(-1) x microU/mL (P < .001); Phi 2 was compensatory increased. All parameters normalized within 1 year. Recipients were insulin-resistant with hyperinsulinemia before transplantation. After transplantation no parameter was significantly different from donors; all normalized equally to donors over 1-year follow-up. Thus, immunosuppression in recipients has no influence on glucose metabolism because liver function itself seems to play a more pronounced role than known until now.

[Characterization of hepatic tumors with contrast-enhanced ultrasound and digital grey-scale analysis]. / Charakterisierung von Lebertumoren durch kontrastverstärkte Sonographie und digitale Graustufenbestimmung.

PURPOSE: The characterization of different liver tumors is of therapeutic and prognostic relevance and has been the purpose of several studies. Although ultrasound offers the opportunity to detect hepatic tumors without ionizing radiation, its previous techniques did not lead toward a definitive differentiation of different tumor entities. The purpose of this study was the clinical evaluation of contrast enhanced ultrasound followed by quantitative digital analysis in patients with focal hepatic tumors. MATERIALS AND METHODS: In a prospective study, 50 patients (18 females, 32 males, age 28 to 83 years, mean age 59.4 years) with liver tumors previously detected by CT (n = 47) or MRI (n = 3) were examined by ultrasound of the upper abdomen using conventional technique and phase inversion technique after intravenous application of sulfur-based contrast enhancer SonoVue. At scheduled intervals after application of the contrast enhancer, a digital image was stored and the characteristic signal course of each lesion determined semiquantitatively. The gold standard was either resection (n = 17), percutaneous needle biopsy (n = 19) or the clinical course (n = 14). RESULTS: While the percentage of tumors correctly characterized by CT/MRI amounted to 78 %, the percentage increased from 60 % using conventional ultrasound to 86 % using contrast enhanced ultrasound including grey-scale analysis. Typical graphs were achieved for different tumor entities on digital grey-scale analysis. The optimal intervals for the differentiation of particular entities were 20 and 100 seconds after injection. CONCLUSION: Quantification of contrast enhanced ultrasound is an addition to the previous diagnostic procedure in hepatic tumors. It offers the possibility of an investigator-independent characterization of lesions and should be evaluated in further studies.

Role of F18-FDG PET for monitoring of radiochemotherapy -- estimation of detectable number of tumour cells.

BACKGROUND: FDG-PET has been proven to be useful for the diagnosis of pancreatic cancer. However, no quantitative data exist concerning its sensitivity for treatment monitoring or early diagnosis. CASE REPORT: We report on a 61-year-old patient with locally advanced cancer of the pancreas head who received sequential radiochemotherapy including gemcitabine and 5-FU/FA. Under this regimen, MR and CT showed a partial remission with a residual mass which seemed to allow surgical treatment for this patient. A pre-operative FDG-PETScan displayed a count rate close to the detection limit of vital residual tumour. An R0 resection was performed successfully. However, histopathology revealed residual tumour at the core of the resected mass that had gone undetected by all imaging modalities. CONCLUSION: The number of vital tumour cells within this specimen was estimated to be 10(6)-10(7). The detection threshold for FDG-PET in pancreatic carcinoma appears to be within this range.

Diagnosis of neuroendocrine tumours by retrospective image fusion: is there a benefit?

This study evaluated the use of image fusion in the preoperative staging of neuroendocrine tumors (NET) of the pancreas and the gastrointestinal tract (GIT). Thirty-eight patients suffering from a metastasized NET with location of the primary in the pancreas ( n=15) or the GIT ( n=23) were examined by somatostatin receptor scintigraphy (SRS) and computed tomography (CT). Consecutive image registration and fusion were performed using custom-built software integrated in AVS/Express (Advanced Visual Systems, Waltham, MA, USA). Registration was performed by a voxel-based algorithm based on normalized mutual information. Image fusion was feasible in 36/38 patients. A total of 87 foci were assigned to anatomical regions (e.g. gut, pancreas, liver, lymph node or others) by two independent observers in both SRS and SRS/CT fusion images. The assignments used a binary ranking system (1="definite", 0="not definite"). These results were then retrospectively compared to the classification of the foci, based on postoperative histology or clinical follow-up. Imaging by SRS allowed a definite anatomical assignment in 57% (50/87) and 61% (53/87) of all lesions in the case of observers A and B, respectively. Image fusion improved the topographic assignment to 91% (79/87) and to 93% (81/87). The number classified as "definite" by both observers increased from 54% (47/87) to 86% (77/87). The increase in definite assignments was highly significant for both observers ( P<0.0001 for each). In the case of foci classified as liver metastases, image fusion allowed improved assignment to the corresponding liver segment from 45% (18/40) to 98% (39/40) and from 58% (23/40) to 100% (40/40) by observers A and B, respectively. Furthermore, the improved assignment of foci classified as lesions by image fusion was relevant for therapy in 7/36 patients (19%). Therefore, the image fusion technique presented herein appears to be a very useful method for clinical routine.

Clinical extracorporeal hybrid liver support--phase I study with primary porcine liver cells.

The objective of this study was to evaluate the feasibility and safety of a hybrid liver support system with extracorporeal plasma separation and bioreactor perfusion in patients with acute liver failure (ALF) who had already fulfilled the criteria for high urgency liver transplantation (LTx). Eight patients (one male, seven female) were treated in terms of bridging to transplantation. The mean age was 36.5 yr (range 20 to 58). Etiology of liver failure was drug-related in two patients, hepatitis B infection in three patients, and unknown for three patients. The bioreactors were charged with primary liver cells from specific pathogen-free pigs. Cell viability varied between 91 and 98%. Continuous liver support treatment over a period of 8 to 46 h (mean 27.3 h) was safely performed and well-tolerated by all patients. No complications associated with the therapy were observed during the follow-up period. Thrombocytopenia was considered to be an effect of the plasma separation. Subsequently, all patients were transplanted successfully and were observed over at least 3 yr with an organ and patient survival rate of 100%. Screening of patient's sera for antibodies specific for porcine endogenous retroviruses (PERVs) showed no reactivity--either prior to application of the system, or after extracorporeal treatment. The results encourage us to continue the development of the technology, and further studies appear to be justified. The bioreactor technology has been integrated into a modular extracorporeal liver support (MELS) system, combining biologic liver support with artificial detoxification technology.

[Accuracy of the CT-estimated weight of the right hepatic lobe prior to living related liver donation (LRLD) for predicting the intraoperatively measured weight of the graft]. / Voraussagegenauigkeit der präoperativen CT-gestützten Gewichtsbestimmung des rechten Leberlappens bezüglich des intraoperativen Transplantatgewichts bei Leberlappen-Lebendspendern.

PURPOSE: Due to the shortage of cadaver donors, living related liver donation (LRLD) has emerged as an alternative to cadaver donation. The expected graft weight is one of the main determinants for donor selection. This study investigates the accuracy of preoperatively performed CT-volumetry to predict the actual weight of the right liver lobe graft. MATERIALS AND METHODS: In a prospective study the weight of the right hepatic lobe was calculated by volumetric analysis based on CT in 33 patients (21 females, 12 males, mean age 42.1 years, median age 41 years) prior to living related liver donation. Graft weight was calculated as the product of CT-based graft volume and 1.00 g/ml (the approximated density of healthy liver parenchyma). The calculated weight was compared with the intraoperatively measured weight of the harvested right hepatic lobe. The difference was used to determine a correction factor for estimating the actual graft weight. RESULTS: Based on the assumption of a parenchymal density of 1.00 g/ml, the preoperatively estimated graft weight (mean 980 g +/- 168 g) deviated +33 % from the intraoperatively measured right hepatic lobe weight (mean 749 g +/- 170 g). By reducing the preoperatively predicted weight of the right hepatic lobe with a correction factor of 0.75, the actual graft weight can be calculated. CONCLUSION: Preoperative estimation of the weight of the right hepatic lobe based on CT of living related liver donors predicts the weight of the right lobe graft with sufficient accuracy by applying a single correction factor. Intraoperative fluid loss (i.e., blood, bile) from the harvested liver as well as variations in parenchymal density may contribute to the observed preoperative overestimation of the actual graft volume by CT-based volumetry.

Review article: liver transplantation for hepatocellular carcinoma.

Despite recent advances in techniques of in situ tumour ablation, surgical therapy remains at present the mainstay treatment for primary hepatic malignancies. After an initial endeavour in the establishment of liver transplantation as a treatment option, in particular for unresectable liver tumours, only a few indications, for example early hepatocellular carcinoma in cirrhosis, are currently agreed upon. Other indications, such as peripheral cholangiocarcinoma and hepatocellular carcinoma in noncirrhotics have largely been abandoned or are still under debate, as is the case with fibrolamellar carcinoma. The selection of patients suffering from hepatocellular carcinoma in cirrhosis for liver transplantation is still based on tumour size and node number, because the current state of diagnostic imaging fails to reliably predict the most important prognostic parameter: vascular infiltration. Other selection criteria are under investigation. Studies on multimodal therapy are also underway but have not yet demonstrated a clear benefit.

Complete bile duct sequestration after liver transplantation, caused by ischemic-type biliary lesions.

Ischemic-type biliary lesions (ITBLs) are the most frequent cause of nonanastomotic biliary strictures in liver grafts, affecting about 2-19 % of patients after liver transplantation. ITBL is characterized by bile duct destruction, subsequent stricture formation, and sequestration. We report here the case of a patient affected by extremely severe ITBL, with sequestration and disintegration of the entire bile duct system, in which it was possible to extract the complete biliary tree endoscopically in a single piece. Histological examination revealed that all cells of the bile duct wall had been destroyed within 3 months after liver transplantation and replaced by connective tissue. Subsequently, biliary stricture formation occurred at the hepatic hilum, as well as the adjacent large bile ducts. It may be hypothesized that cellular rejection of small bile ducts leads to the vanishing bile duct syndrome, whereas cellular rejection of large bile ducts results in ITBL. The strictures were repeatedly dilated by endoscopic means, allowing successful control of stricture formation, as well as maintenance of liver function. At the time of writing, the grafted organ and the patient had survived for more than 3 years in good health. This is the first detailed report on a sequestration of the entire bile duct system caused by ITBL, successfully treated for several years by endoscopic means.

Technique of bile duct reconstruction and management of biliary complications in right lobe living donor liver transplantation.

From December 1999 to January 2002, 50 right lobe living donor liver transplantations were performed. The donor operations included an intraoperative cholangiography to elicit variations in bile duct anatomy. The biliary reconstruction was done whenever possible as an end-to-end microanastomosis of the donor right hepatic duct with the recipient's bile duct. As a result of the early segmental branching of the donor biliary tree, two segment bile ducts had to be anastomosed in 20 patients and three segment bile ducts in three patients. In 12 patients, a Roux-en-Y hepaticojejunostomy was performed. All anastomoses were drained externally. We observed two leakages at the resection surface which could be treated successfully by an external drainage. Six leaks occurred at the site of end-to-end biliary anastomoses. Twice the problem could be conservatively solved placing a stent percutaneously. In two patients a hepaticojejunostomy was performed after a bile duct necrosis. In two patients with an anastomotic leak, occurring 3 d, respectively, 3 month after the original transplantation, the bile duct could be directly reconstructed over a T-tube. Two anastomotic stenoses were observed, one in combination with a leak treated by percutaneous stent implantation and the second, 3 month after transplantation which was treated surgically. Biliary reconstruction after living donor liver transplantation requires microsurgical techniques and can be performed as a direct end-to-end anastomosis in most cases. Biliary complications were treated by percutaneous drainage or surgical revision in all cases.

[Orthotopic liver transplantation in case of TIPS stent dislocation]. / Orthotope Lebertransplantation bei disloziertem TIPS-Stent.

Transjugular intrahepatic portosystemic shunts (TIPS) are indicated in patients with liver cirrhosis and portal hypertension for treatment of variceal bleeding or refractory ascites. Additionally implantation of stents may lead to stent dislocation or thrombosis in up to 20 % of cases. Detailed information about stent dislocation and its impact on subsequent orthotopic liver transplantation (OLT) is rare regarding the literature. We report on a patient suffering from ethyltoxic liver cirrhosis in which OLT was technically complicated by a thrombosed TIPS stent, dislocated in the portal vein. This stent was implanted prior to OLT due to refractory ascites and partial portal vein thrombosis. We conclude that TIPS stent insertion, especially in liver transplant candidates, should only be performed by radiologists in centers with expertise and experience.

Combination prophylaxis with Hepatitis B immunoglobulin and lamivudine after liver transplantation minimizes HBV recurrence rates unless evolution of pretransplant lamivudine resistance.

BACKGROUND: Survival rates of hepatitis B patients after liver transplantation improved significantly by introduction of passive immunoprophylaxis. Due to viral escape mutations recurrence still occurs, but recently a combination prophylaxis with hepatitis B immunoglobuline plus lamivudine is evaluated in transplant centers in terms of a further reduction of recurrence rates. PATIENTS AND METHODS: Between 1996 and 2000 a postoperative combination prophylaxis with HBIg and lamivudine was initiated in 44 HBsAg positive liver transplant recipients. In total 14 patients were HBV-DNA negative and 30 were HBV-DNA positive at the time of evaluation. In 22 HBV-DNA positive patients a pre-operative lamivudine treatment (150 mg/die) was started. Five of them developed pre-transplant lamivudine resistance with high viral replication (mean HBV-DNA prior to transplantation 728 +/- 219 pg/ml). In all patients passive immunoprophylaxis was started in the anhepatic phase with application of 10.000 units hepatitis B immunoglobuline. It was continued after seroconversion to HBsAg negativity with an aimed titer of more than 100 U/l and only stopped in case of HBV recurrence. Lamivudine was also continued indefinitely after liver transplantation. RESULTS: Overall recurrence rate in the 44 patients, including retransplantations and patients with pretransplant lamivudine resistance, was 11.5 % under combination prophylaxis. Recurrence was seen only in one of 39 patients (2.6 %) without preoperative lamivudine resistance, in contrast 4 out of 5 patients (80 %) with pre-existing lamivudine resistance suffered from early hepatitis B recurrence. The single patient without preoperative lamivudine resistance, who developed recurrence was pre-transplant HBV-DNA negative without lamivudine treatment, but a postoperative seroconversion to negative HBsAg could not be achieved. The overall 3 year patient survival rate was 91 % in the study population. One patient, who was retransplanted with preoperative lamivudine resistance, died 4.5 months after retransplantation due to hepatitis B recurrence and sepsis, three other patients died for reasons not related to hepatitis B recurrence. Combination prophylaxis was well tolerated in all patients and no severe side effects were observed. CONCLUSION: Combination prophylaxis with hepatitis B immunoglobulin and lamivudine is safe and highly effective in prevention of HBV recurrence after liver transplantation, even in case of positive viral replication. In accordance with the results of other centers it should therefore be the standard regimen. However it fails in the majority of patients with preoperative evolution of YMDD mutations, in which the optimal management has to be determined yet. To minimize preoperative resistance formation universal preoperative antiviral treatment of HBV-DNA positive patients should be replaced by individualized indication for preoperative treatment.