Background: Preoperative α-blockade in phaeochromocytoma surgery is recommended by all guidelines to prevent intraoperative cardiocirculatory events. The aim of this meta-analysis was to assess the benefit of such preoperative treatment compared with no treatment before adrenalectomy for phaeochromocytoma. Methods: A systematic literature search was undertaken in MEDLINE, Web of Science and CENTRAL without language restrictions. Randomized and non-randomized comparative studies investigating preoperative α-blockade in phaeochromocytoma surgery were included. Data on perioperative safety, effectiveness and outcomes were extracted. Pooled results were calculated as an odds ratio or mean difference with 95 per cent confidence interval. Results: A total of four retrospective comparative studies were included investigating 603 patients undergoing phaeochromocytoma surgery. Mortality, cardiovascular complications, mean maximal intraoperative systolic and diastolic BP, and mean maximal intraoperative heart rate did not differ between patients with or without α-blockade. The certainty of the evidence was very low owing to the inferior quality of studies. Conclusion: This meta-analysis has shown a lack of evidence for preoperative α-blockade in surgery for phaeochromocytoma. RCTs are needed to evaluate whether preoperative α-blockade can be abandoned.

The chromatin remodeler NAP1L1, which is upregulated in small intestinal neuroendocrine neoplasms (NENs), has been implicated in cell cycle progression. As p57^Kip2 (CDKN1C), a negative regulator of proliferation and a tumor suppressor, is controlled by members of the NAP1 family, we tested the hypothesis that NAP1L1 may have a mechanistic role in regulating pancreatic NEN proliferation through regulation of p57^Kip2. NAP1L1 silencing (siRNA and shRNA/lipofectamine approach) decreased proliferation through inhibition of mechanistic (mammalian) target of rapamycin pathway proteins and their phosphorylation (p < 0.05) in the pancreatic neuroendocrine neoplasm cell line BON in vitro (p < 0.0001) and resulted in significantly smaller (p < 0.05) and lighter (p < 0.05) tumors in the orthotopic pancreatic NEN mouse model. Methylation of the p57 ^Kip2 promoter was decreased by NAP1L1 silencing (p < 0.05), and expression of p57^Kip2 (transcript and protein) was upregulated. For methylation of the p57 ^Kip2 promoter, NAP1L1 bound directly to the promoter (−164 to +21, chromatin immunoprecipitation). In 43 pancreatic NEN samples (38 primaries and 5 metastasis), NAP1L1 was over-expressed in metastasis (p < 0.001), expression which was inversely correlated with p57^Kip2 (p < 0.01) on mRNA and protein levels. Menin was not differentially expressed. NAP1L1 is over-expressed in pancreatic neuroendocrine neoplasm metastases and epigenetically promotes cell proliferation through regulation of p57 ^Kip2 promoter methylation.

Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS. Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK–ERK1/2 axis as critical FGFR1 effector pathway. Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK–ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962–73. ©2016 AACR.

Surgical management of renal secondary hyperparathyroidism (sHPT) is varying. Total parathyroidectomy with heterotopic autotransplantation (TPTX + AT) is one of the standard surgical procedures in sHPT, but there is no consensus about the optimal site for graft insertion. At the surgical department of the University Hospital of Heidelberg we prefer the autotransplantation into the tibialis anterior muscle. The aim of this study was to assess the long-term function of the auto-transplanted parathyroid tissue in this type of surgical procedure. The function of the autograft of 42 patients was assessed 8.2 ± 2.5 years after surgery, using a modified Casanova-test of the leg bearing the parathyroid tissue. Ischemic blockage was induced by tourniquet and the levels of parathyroid hormone (PTH) were assessed during the test. At the point of assessment, the ischemic blockage led to a significant reduction in the concentration of PTH (≥50 % of the baseline value) in 19 patients (45 %) indicating well-functioning autografts. In 11 patients (26 %), ischemic blockage did not cause any change in the concentration of PTH (≤20 % of the baseline value), indicating functioning residual parathyroid tissue from another site. The source of PTH production was classified as unidentifiable in five patients (12 %). Two patients had developed graft-dependent recurrent HPT (5 %) without therapeutic consequences and three patients suffered from persistent symptomatic hypoparathyroidism (7 %). These results indicate that TPTX + AT into the tibialis anterior muscle is a successful surgical treatment for renal HPT and that the modified Casanova-test is a suitable diagnostic tool for autografts function.