Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling.

Parathyroid carcinoma (PC) is an ultra-rare malignancy with a high risk of recurrence after surgery. Tumour-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (b) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto-Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP-Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

[Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia]. / Insulinautoimmunsyndrom : Eine seltene, aber wichtige Differentialdiagnose der Hypoglykämie.

A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Acromegaly in Routine Clinical Practice in Germany, Austria and Switzerland.

BACKGROUND: Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment. METHODS: In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12. RESULTS: 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'. CONCLUSION: Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.

Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature.

BACKGROUND: Adrenocorticotropic hormone-producing extraadrenal paragangliomas are extremely rare. We present a case of severe hypercortisolemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma. CASE PRESENTATION: A 70-year-old Caucasian woman, was emergently admitted to our department with supraventricular tachycardia, oedema of face and extremities and hypertensive crisis. Initial laboratory evaluation revealed severe hypokalemia and hyperglycemia without ketoacidosis, although no diabetes mellitus was previously known. Computed tomography revealed a large tumor obliterating the left paranasal sinus and a left-sided adrenal mass. After cardiovascular stabilisation, a thorough hormonal assessment was performed revealing marked adrenocorticotropic hormone-dependent hypercortisolism. Due to the presence of a cardiac pacemaker magnetic resonance imaging of the hypophysis was not possible. [68Ga-DOTA]-TATE-Positron-Emission-Tomography was performed, showing somatostatin-receptor expression of the paranasal lesion but not of the adrenal lesion or the hypophysis. The paranasal tumor was resected and found to be an adrenocorticotropic hormone-producing paraganglioma of low-proliferative rate. Postoperatively the patient became normokaliaemic, normoglycemic and normotensive without further need for medication. Genetic testing showed no mutation of the succinatdehydrogenase subunit B- and D genes, thus excluding hereditary paragangliosis. CONCLUSION: Detection of the adrenocorticotropic hormone source in Cushing's syndrome can prove extremely challenging, especially when commonly used imaging modalities are unavailable or inconclusive. The present case was further complicated by the simultaneous detection of two tumorous lesions of initially unclear biochemical behaviour. In such cases, novel diagnostic tools - such as somatostatin-receptor imaging - can prove useful in localising hormonally active neuroendocrine tissue. The clinical aspects of the case are discussed and relevant literature is reviewed.

Procedure-related pulmonary hypertension in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection--role of ethanol, hemolysis, asymmetric dimethylarginine, and the nitric oxide system.

OBJECTIVE: Local percutaneous tumor ablation with ethanol injection (PEI) under general anesthesia is an established therapy for patients with nonresectable hepatocellular carcinoma (HCC). There are reports of sudden hypotension immediately after PEI therapy, which was attributed to an acute increase in pulmonary vascular resistance. The aim of our study was to objectively confirm pulmonary hypertension by right heart catheterization and to evaluate biochemical markers with relevance to the pulmonary circulation. DESIGN: Cross-sectional clinical study. SETTING: Interventional Gastroenterology in a tertiary care center. PATIENTS: We studied 40 patients with HCC who underwent percutaneous ethanol injection under general anesthesia for the treatment of nonresectable HCC. RESULTS: In patients with HCC, PEI leads to a significant increase in pulmonary arterial pressure. Concomitantly, free hemoglobin and blood ethanol level significantly increased, whereas the l-arginine/asymmetric dimethylarginine ratio, a parameter of nitric oxide (NO) production capacity, and nitrite, a marker of NO synthesis, significantly decreased. CONCLUSION: Procedure-related pulmonary hypertension in patients undergoing PEI is multifactorial. Plasma concentrations of the NO precursor l-arginine are reduced by arginase released from lysed erythrocytes, a condition further exacerbated by the increased concentrations of symmetric dimethylarginine, which may compete with the cellular uptake of l-arginine. The result would be reduced synthesis of NO, the concentration of which would be further decreased extracellularly through free hemoglobin. Predictably, the result would be severe endothelial dysfunction and pulmonary hypertension in patients undergoing PEI. These mechanisms might also be relevant in other states of (sudden) hemolysis.

Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation.

In advanced stages of polycystic liver disease, often associated with polycystic kidney disease, a curative therapy is liver or combined liver-kidney transplantation. However, little is known about long-term outcome and quality of life. Between 1990 and 2003, 36 patients (32 female, 4 male) with polycystic liver or combined liver-kidney disease underwent liver (n = 21) or liver-kidney (n = 15) transplantation at our center. Main indications for liver transplantation were cachexia, muscle atrophy, loss of weight, recurrent cyst infections, portal hypertension, and ascites. Apart from clinical parameters, 2 anonymous questionnaires (standard short form 36 and self-designed) addressing quality of life and social status were evaluated. Five patients (14 %) died due to sepsis or myocardial infarction with pneumonia, all within 61 days after transplantation. The follow-up time of the remaining 31 patients ranged from 5 to 156 months, with a mean of 62 months. Of the 23 (74%) answered the questionnaires, 91% of patients felt "much better" or "better," only 9% felt "worse" than before, and 52% of patients participated in sports regularly. Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after transplantation. Physical attractiveness and interest in sex increased as well. Professional occupation did not change for 71% of patients. Family situation before and after transplantation changed in 1 case only. Finally, 78% of patients said they would opt for transplantation again, while 17% were undecided; 1 patient would not repeat transplantation. In conclusion, patients with advanced polycystic liver or polycystic liver-kidney disease have an excellent survival rate and an improved quality of life after liver or combined liver-kidney transplantation.

Sympathoadrenal counterregulation in patients with hypothalamic craniopharyngioma.

In humans, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is unclear. To address this question, we investigated the counterregulatory response to acute insulin-induced hypoglycemia of glucagon, epinephrine, and norepinephrine in eight patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypothalamic region. We compared the patients' responses with those of four patients suffering from hypopituitarism and of six healthy subjects. After the i.v. injection of 0.1 U of human insulin per kg of body weight in the patients or 0.15 U in healthy subjects, the plasma glucose concentrations decreased to similar minimum levels within 30 min in all three groups. All subjects recovered spontaneously from hypoglycemia within 2 h. In five of eight craniopharyngioma patients, only a small counterregulatory rise in plasma epinephrine (< or =2-fold) and norepinephrine could be observed (P < 0.05 for epinephrine and P = 0.22 for norepinephrine vs. healthy controls). During hypoglycemia, virtually no adrenergic symptoms (tremor, heart pounding, and anxiety) were reported by these five patients, and changes in the heart rate were diminished. In three craniopharyngioma patients, the counterregulatory increase in catecholamines was unimpaired, adrenergic symptoms were reported and a rise in heart rate was observed during hypoglycemia. In all craniopharyngioma patients, the counterregulatory glucagon response to hypoglycemia was preserved and orthostasis increased both catecholamines and the heart rate similar to in the patients with hypopituitarism as well as in the healthy controls. Our results demonstrate selective impairment of counterregulatory sympathoadrenal activation in patients who had undergone surgery for a craniopharyngioma extending to the hypothalamic region. This strongly suggests the involvement of hypothalamic centers in hypoglycemia-induced activation of the sympathoadrenal axis in humans. It remains unclear as to whether hypoglycemia-induced glucagon secretion is also controlled by the hypothalamus. However, a common hypothalamic center controlling both counterregulatory catecholamine and glucagon release is unlikely, and sympathoadrenal activation is not required for hypoglycemia-induced glucagon secretion in humans.