Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly.

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7-16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 µg/l) or a suppressed GH nadir (< 0.4/µg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity.

Diabetes insipidus and syndrome of inappropriate antidiuresis (SIADH) after pituitary surgery: incidence and risk factors.

Electrolyte disorders are relatively frequent and potentially serious complications after pituitary surgery. Both DI (diabetes insipidus) and SIADH (syndrome of inappropriate antidiuresis) can complicate and prolong hospital and intensive care unit stay, and the latter may even be preventable. We aim to assess the incidence of both electrolyte disorders and their risk factors. From a prospective registry of patients who underwent endoscopic transnasal transsphenoidal surgery (TSS) for pituitary adenoma, patients with postoperative DI and SIADH were identified. Univariable and multivariable statistics were carried out to identify factors independently associated with the occurrence of either DI or SIADH. A total of 174 patients were included, of which 73 (42%) were female. Mean age was 54 years (range 20-88). During postoperative hospital stay, 13 (7.5%) patients presenting with DI and 11 (6.3%) with SIADH were identified. Patients who developed DI after surgery had significantly longer hospital stays (p = 0.022), as did those who developed SIADH (p = 0.002). Four (2.3%) patients were discharged with a diagnosis of persistent DI, and 2 (1.1%) with the diagnosis of SIADH. At the last follow-up, 5 (2.9%) patients presented with persistent DI, while none of the patients suffered from SIADH. Younger age (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.94-1.01, p = 0.166) and pituitary apoplexy (OR 2.69, 95% CI 0.53-10.65, p = 0.184) were weakly associated with the occurrence of DI. We identified younger age (OR 0.96, 95% CI 0.92-0.99, p = 0.045) and lower preoperative serum sodium (OR 0.83, 95% CI 0.71-0.95, p = 0.008) as independent risk factors for SIADH. Although we found a weak association among age, pituitary apoplexy, and the occurrence of DI, no independent predictor was identified for DI. For postoperative SIADH however, lower age and preoperative serum sodium were identified as significant predictors. None of these findings were sufficiently supported by preexisting literature. Both electrolyte disorders are exquisitely hard to predict preoperatively, and further research into their early detection and prevention is warranted.

Feasibility of machine learning based predictive modelling of postoperative hyponatremia after pituitary surgery.

PURPOSE: Hyponatremia after pituitary surgery is a frequent finding with potential severe complications and the most common cause for readmission. Several studies have found parameters associated with postoperative hyponatremia, but no reliable specific predictor was described yet. This pilot study evaluates the feasibility of machine learning (ML) algorithms to predict postoperative hyponatremia after resection of pituitary lesions. METHODS: Retrospective screening of a prospective registry of patients who underwent transsphenoidal surgery for pituitary lesions. Hyponatremia within 30 days after surgery was the primary outcome. Several pre- and intraoperative clinical, procedural and laboratory features were selected to train different ML algorithms. Trained models were compared using common performance metrics. Final model was internally validated on the testing dataset. RESULTS: From 207 patients included in the study, 44 (22%) showed a hyponatremia within 30 days postoperatively. Hyponatremic measurements peaked directly postoperatively (day 0-1) and around day 7. Bootstrapped performance metrics of different trained ML-models showed largest area under the receiver operating characteristic curve (AUROC) for the boosted generalized linear model (67.1%), followed by the Naïve Bayes classifier (64.6%). The discriminative capability of the final model was assessed by predicting on unseen dataset. Large AUROC (84.3%; 67.0-96.4), sensitivity (81.8%) and specificity (77.5%) with an overall accuracy of 78.4% (66.7-88.2) was reached. CONCLUSION: Our trained ML-model was able to learn the complex risk factor interactions and showed a high discriminative capability on unseen patient data. In conclusion, ML-methods can predict postoperative hyponatremia and thus potentially reduce morbidity and improve patient safety.

Assessing the surgical outcome of the "chopsticks" technique in endoscopic transsphenoidal adenoma surgery.

OBJECTIVE: The "chopsticks" technique is a 3-instrument, 2-hand mononostril technique that has been recently introduced in endoscopic neurosurgery. It allows a dynamic surgical view controlled by one surgeon only while keeping bimanual dissection. Being a mononostril approach, it requires manipulation of the mucosa of one nasal cavity only. The rationale of the technique is to reduce nasal morbidity without compromising surgical results and complication rates. There are, however, no data available on its results in endoscopic surgery (transsphenoidal surgery [TSS]) for pituitary adenoma. METHODS: The authors performed a cohort analysis of prospectively collected data on 144 patients (156 operations) undergoing TSS using the chopsticks technique with 3T intraoperative MRI. All patients had at least 3 months of postoperative neurosurgical, endocrinological, and rhinological follow-up (Sino-Nasal Outcome Test-20 [SNOT-20] and Sniffin' Sticks). The surgical technique is described, and the achieved gross-total resection (GTR) and extent of resection (EOR) together with patients' clinical outcomes and complications are descriptively reported. RESULTS: On 3-month postoperative MRI, GTR was achieved in 71.2% of patients with a mean EOR of 96.7%. GTR was the surgical goal in 122 of 156 cases and was achieved in 106 of 122 (86.9%), with a mean EOR of 98.7% (median 100%, range 49%-100%). There was no surgical mortality. At a median follow-up of 15 months (range 3-70 months), there was 1 permanent neurological deficit. As of the last available follow-up, 11.5% of patients had a new pituitary single-axis deficit, whereas 26.3% had improvement in endocrinological function. Three patients had new postoperative hyposmia. One patient had severe impairment of sinonasal function (SNOT-20 score > 40). The operation resulted in endocrine remission in 81.1% of patients with secreting adenomas. CONCLUSIONS: This study shows that the chopsticks technique confers resection and morbidity results that compare favorably with literature reports of TSS. This technique permits a single surgeon to perform effective endoscopic bimanual dissection through a single nostril, reducing manipulation of healthy tissue and thereby possibly minimizing surgical morbidity.

Tinnitus With Unexpected Spanish Roots: Head and Neck Paragangliomas Caused by SDHAF2 Mutation.

It is estimated that up to 40% of all head and neck paragangliomas (HNPGL) have a hereditary background with the most common mutations being found in the succinate dehydrogenase (SDH) genes. SDHAF2 mutation leads to the rare paraganglioma syndrome 2. The authors present the case of a 15-year-old male patient with 2, non-secretory HNPGLs, presenting with left-sided, pulsatile tinnitus, and hearing loss. Imaging led to the suspicion of a jugulotympanic paraganglioma on the left, as well as a carotid body tumor on the right. After resection of the jugulotympanic tumor, histology confirmed the presence of a paraganglioma; immunohistochemistry furthermore suggested a loss of SDHB expression. Genetic testing revealed a rare germline, loss-of-function mutation in the SDHAF2 gene, previously described to cause hereditary paraganglioma syndrome 2. Twenty months after the first operation, the patient underwent a resection of the right carotid body paraganglioma. Plasma-free metanephrines/catecholamines always remained within the reference range; the patient is under regular follow-up, and his relatives will be screened. Our findings emphasize the relevance of genetic testing in patients with HNPGL, also with negative family history, especially when the patients present at a young age and with multiple lesions.

Akt1 signalling supports acinar proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis.

Molecular signalling mediated by the phosphatidylinositol-3-kinase (PI3K)-Akt axis is a key regulator of cellular functions. Importantly, alteration of the PI3K-Akt signalling underlies the development of different human diseases, thus prompting the investigation of the pathway as a molecular target for pharmacologic intervention. In this regard, recent studies showed that small molecule inhibitors of PI3K, the upstream regulator of the pathway, reduced the development of inflammation during acute pancreatitis, a highly debilitating and potentially lethal disease. Here we investigated whether a specific reduction of Akt activity, by using either pharmacologic Akt inhibition, or genetic inactivation of the Akt1 isoform selectively in pancreatic acinar cells, is effective in ameliorating the onset and progression of the disease. We discovered that systemic reduction of Akt activity did not protect the pancreas from initial damage and only transiently delayed leukocyte recruitment. However, reduction of Akt activity decreased acinar proliferation and exacerbated acinar-to-ductal metaplasia (ADM) formation, two critical events in the progression of pancreatitis. These phenotypes were recapitulated upon conditional inactivation of Akt1 in acinar cells, which resulted in reduced expression of 4E-BP1, a multifunctional protein of key importance in cell proliferation and metaplasia formation. Collectively, our results highlight the critical role played by Akt1 during the development of acute pancreatitis in the control of acinar cell proliferation and ADM formation. In addition, these results harbour important translational implications as they raise the concern that inhibitors of PI3K-Akt signalling pathways may negatively affect the regeneration of the pancreas. Finally, this work provides the basis for further investigating the potential of Akt1 activators to boost pancreatic regeneration following inflammatory insults. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

18F-NaF-PET/CT in patients with primary hyperparathyroidism and brown tumors.

INTRODUCTION: Brown tumors (BT) are non-neoplastic bone lesions infrequently occurring in patients with long-standing severe hyperparathyroidism (HPT). BT may be identified and characterized using 18-F-sodium fluoride-positron-emission-tomography/computed tomography (18F-NaF-PET/CT). We present a retrospective series of eight primary hyperparathyroidism (pHPT) patients with BT imaged with 18F-NaF-PET/CT. MATERIALS AND METHODS: Imaging assessment included location, diameter, maximum standardized uptake value (SUVmax), metabolically active lesion volume (PETvol) of BT, total metabolically active bone volume (TMBvol) per patient and several computed tomography (CT) features of BT. Where appropriate, we analyzed the association between characteristic features of BT in 18F-NaF-PET/CT, histopathology, clinical symptomatology and laboratory parameters. RESULTS: In our cohort of 8 patients (median age, 49 years, range, 26-73), 72 BT were found. The mean PETvol of BT was 89.48 cm3 ± 122.81 cm3 and the mean SUVmax was 17.5 ± 7.8. The total PETvol of BT per patient correlated positively with serum calcium (r = 0.810, p = 0.015), and negatively with glomerular filtration rate (GFR) (r = - 0.762, p = 0.028). TMBvol correlated significantly with serum PTH (r = 0.810, p = 0.015), alkaline phosphatase (r = 0.762, p = 0.028), and duration of postoperative hospitalization (r = 0.826, p = 0.011, 24.3 days ± 19.8 days). CONCLUSION: 18F-NaF-PET/CT is a valuable non-invasive whole-body imaging technique for the assessment of patients with pHPT and BT. TMBvol is associated with PTH and alkaline phosphatase, and the requirement for intense postoperative calcium substitution, which determines the duration of hospitalization.

The Zurich Pituitary Score predicts utility of intraoperative high-field magnetic resonance imaging in transsphenoidal pituitary adenoma surgery.

BACKGROUND: It is currently unclear if there are subsets of patients undergoing transsphenoidal surgery (TSS) in which intraoperative high-field magnetic resonance imaging (3T-iMRI) is particularly advantageous. We aimed to investigate whether a radiological grading scale predicts the utility of 3T-iMRI in pituitary adenoma (PA) TSS. METHODS: From a prospective registry, patients who underwent endoscopic TSS for PA using 3T-iMRI were identified. Adenomas were graded using the Zurich Pituitary Score (ZPS). We assessed improvement after 3T-iMRI in terms of gross total resection (GTR), residual volume (RV), and extent of resection (EOR). RESULTS: Among 95 patients, rates of conversion to GTR after 3T-iMRI decreased steadily from 33% for grade I to 0% for grade IV adenomas, with a statistically significant conversion rate only for grade I (p = 0.008) and grade II (p < 0.001). All grade I adenomas were completely resected after 3T-iMRI. Median RV change was statistically significant for grades I to III, but not for grade IV (p = 0.625). EOR improvement ranged from a median change of 0.0% (IQR 0.0-4.5%) for grade I to 4.4% (IQR 0.0-9.0%) for grade IV, with a significant improvement only for grades I to III (p < 0.05). CONCLUSIONS: Interestingly, this study shows that clinical utility of 3T-iMRI is highest in the more "simple" adenomas (ZPS grades I-II) than for the more "complex" ones (ZPS grade III-IV). Grade I adenomas are amenable to GTR if 3T-iMRI is implemented. In grade III adenomas, EOR and RV can be improved to clinically relevant levels. Conversely, in grade IV adenomas, 3T-iMRI may be of limited use.

Soluble delta-like 1 homolog decreases in patients with acromegaly following pituitary surgery: A potential mediator of adipogenesis suppression by growth hormone?

OBJECTIVE: GH excess in acromegaly leads to lower fat mass and insulin resistance; both reverse following pituitary surgery. Soluble delta like-1 homolog (sDlk1) inhibits adipocyte differentiation and may mediate the antiadipogenic effects of GH. It is released into the circulation by ectodomain shedding through 'A Disintegrin And Metalloproteinase domain 17' (ADAM17), which also sheds soluble α-Klotho (sKlotho). Klotho is a transmembrane protein, which influences life span. sKlotho inhibits insulin signalling, and is markedly elevated in acromegaly and decreases after surgery. Therefore, we examined if sDlk1 parallels the course of sKlotho, which could explain the well-known changes in fat mass in patients with acromegaly after surgery. DESIGN: We measured serum levels of GH, IGF-1, sDlk1 and sKlotho (both by ELISA) in 42 treatment-naïve acromegaly patients (20 females/22 males) before and 1-3 months after transsphenoidal surgery. Data are presented as median(interquartile range). RESULTS: GH decreased in all patients postoperatively (in 32/42 to <1 ng/ml during oral glucose tolerance testing). Likewise, IGF-1 and sKlotho decreased in all patients, from 587 (432-708) to 195 (133-270) ng/ml, and from 4.0 (2.7-5.9) to 0.7 (0.6-1.2) ng/ml, respectively; sDlk1 fell in 40/42 subjects, from 10.7 (5.8-13.4) to 7.1 (3.7-10.4) ng/ml following pituitary surgery. P < 0.0001 for all parameters. CONCLUSIONS: sDlk1 declined after pituitary surgery in our patients with acromegaly, but to a lesser extent than sKlotho. It remains to be seen whether this may contribute to the well-known postoperative changes in body composition. Our findings may extend beyond the scope of acromegaly, and thus further elucidate mechanisms in the fields of obesity and anti-ageing.

Cystatin C in adipose tissue and stimulation of its production by growth hormone and triiodothyronine in 3T3-L1 cells.

Cystatin C (CysC) is a marker for estimation of glomerular filtration rate (GFR). CysC levels may depend not only on clearance/GFR but possibly also on changes in production. Our studies on tissue distribution of CysC protein in mice showed that adipose tissue expresses significant amounts of CysC, suggesting that adipocytes could contribute to circulating CysC levels in vivo. As growth hormone (GH) and triiodothyronine (T3) increase both GFR and CysC (increased in acromegaly and hyperthyroidism) in vivo, we studied whether they could increase CysC production in 3T3-L1 adipocytes in vitro. CysC accumulated in culture media of 3T3-L1 adipocytes in a time-dependent fashion. GH and T3 both (10 nmol/l) increased accumulation of CysC, to 373 ±â€¯14 and 422 ±â€¯20, respectively, vs 298 ±â€¯10 ng per well over 4 days in controls. Thus, GH and T3 enhance the production of CysC by adipocytes in vitro.

Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients. METHODS: Histologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score. RESULTS: Serum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available. CONCLUSIONS: Treatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.

[Modern Management of Pituitary Adenomas - Current State of Diagnosis, Treatment and Follow-Up]. / Modernes Management von Hypophysenadenomen ­ gegenwärtiger Stand in Diagnostik, Therapie und Nachsorge.

Modern Management of Pituitary Adenomas - Current State of Diagnosis, Treatment and Follow-Up Abstract. Pituitary adenomas (PA) are benign neoplasms originating from parenchymal cells of the anterior pituitary. Tumor mass effect can cause headaches, visual deficits by compression of the optic chiasm, and partial or complete hypopituitarism. Hormone secreting PA can cause several forms of specific syndromes such as Cushing's disease or acromegaly depending on the type of hormone. Endoscopic transsphenoidal resection is the preferred treatment option for most symptomatic or growing PA. Nowadays techniques like high definition intraoperative MRI can assist the surgeon in his goal of maximal safe resection. An exception are prolactinomas which can usually be treated medically with dopamine agonists. Therapy of PA is complex and should be managed in a high-volume center with an interdisciplinary team approach including neurosurgeons and endocrinologists.

Islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation.

The aim of this study was to assess safety and efficacy of islet transplantation after initial pancreas transplantation with subsequent organ failure. Patients undergoing islet transplantation at our institution after pancreas organ failure were compared to a control group of patients with pancreas graft failure, but without islet transplantation and to a group receiving pancreas retransplantation. Ten patients underwent islet transplantation after initial pancreas transplantation failed and were followed for a median of 51 months. The primary end point of HbA1c <7.0% and freedom of severe hypoglycemia was met by nine of 10 patients after follow-up after islet transplantation and in all three patients in the pancreas retransplantation group, but by none of the patients in the group without retransplantation (n = 7). Insulin requirement was reduced by 50% after islet transplantation. Kidney function (eGFR) declined with a rate of -1.0 mL ± 1.2 mL/min/1.73 m2 per year during follow-up after islet transplantation, which tended to be slower than in the group without retransplantation (P = .07). Islet transplantation after deceased donor pancreas transplant failure is a method that can safely improve glycemic control and reduce the incidence of severe hypoglycemia and thus establish similar glycemic control as after initial pancreas transplantation, despite the need of additional exogenous insulin.

Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice.

Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.

Specific and redundant roles of PKBα/AKT1 and PKBß/AKT2 in human pancreatic islets.

Protein kinase Bα (PKBα)/AKT1 and PKBß/AKT2 are required for normal peripheral insulin action but their role in pancreatic ß cells remains enigmatic as indicated by the relatively mild islet phenotype of mice with deficiency for either one of these two isoforms. In this study we have analysed proliferation, apoptosis, ß cell size and glucose-stimulated insulin secretion in human islets overexpressing either PKBα or PKBß. Our results reveal redundant and specific functions. Overexpression of either isoform resulted in increased ß cell size, but insulin production and secretion remained unchanged. Proliferation and apoptosis of ß cells were only significantly stimulated and inhibited, respectively, by PKBα/AKT1. Importantly, overexpression of PKBα/AKT1 in dissociated islets increased the ratio of ß cells to non-ß cells. These results confirm our previous findings obtained with rodent islets and strongly indicate that PKBα/AKT1 can regulate ß cell mass also in human islets.

Catecholamine metabolism in paraganglioma and pheochromocytoma: similar tumors in different sites?

Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine ß-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.

Glycemia, Hypoglycemia, and Costs of Simultaneous Islet-Kidney or Islet After Kidney Transplantation Versus Intensive Insulin Therapy and Waiting List for Islet Transplantation.

BACKGROUND: Long-term data of patients with type 1 diabetes mellitus (T1D) after simultaneous islet-kidney (SIK) or islet-after-kidney transplantation (IAK) are rare and have never been compared to intensified insulin therapy (IIT). METHODS: Twenty-two patients with T1D and end-stage renal failure undergoing islet transplantation were compared to 70 patients matched for age and diabetes duration treated with IIT and to 13 patients with kidney transplantation alone or simultaneous pancreas-kidney after loss of pancreas function (waiting list for IAK [WLI]). Glycemic control, severe hypoglycemia, insulin requirement, and direct medical costs were analyzed. RESULTS: Glycated hemoglobin decreased significantly from 8.2 ± 1.5 to 6.7 ± 0.9% at the end of follow-up (mean 7.2 ± 2.5 years) in the SIK/IAK and remained constant in IIT (7.8 ± 1.0% and 7.6 ± 1.0) and WLI (7.8 ± 0.8 and 7.9 ± 1.0%). Daily insulin requirement decreased from 0.53 ± 0.15 to 0.29 ± 0.26 U/kg and remained constant in IIT (0.59 ± 0.19 and 0.58 ± 0.23 U/kg) and in WLI (0.76 ± 0.28 and 0.73 ± 0.11 U/kg). Severe hypoglycemia dropped in SIK/IAK from 4.5 ± 9.7 to 0.3 ± 0.7/patient-year and remained constant in IIT (0.1 ± 0.7 and 0.2 ± 0.8/patient-year). Detailed cost analysis revealed US $57,525 of additional cost for islet transplantation 5 years after transplantation. Based on a 5- and 10-year analysis, cost neutrality is assumed to be achieved 15 years after transplantation. CONCLUSIONS: This long-term cohort with more than 7 years of follow-up shows that glycemic control in patients with T1D after SIK/IAK transplantation improved, and the rate of severe hypoglycemia decreased significantly as compared to control groups. Cost analysis revealed that islet transplantation is estimated to be cost neutral at 15 years after transplantation.