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Resumen Introduccion La nefrotoxicidad y la hematotoxicidad despues de la terapia con peptidos marcados con radionuclidos (PRRT) se han descrito en multiples estudios usando diferentes actividades acumulativas, numero de ciclos o peptidos marcados con radionuclidos. Aunque los tumores neuroendocrinos (NET) altamente diferenciados con metastasis tienen una larga supervivencia libre de progresion, pueden progresar. Analizamos los efectos secundarios a largo plazo en un esquema de tratamiento homogeneo en pacientes con PRRT y su impacto en el futuro tratamiento oncologico en caso de progresion. Metodos De nuestra base de datos se analizaron 89 de 384 pacientes que recibieron la misma PRRT (Lu-177-DOTATATE o Y-90-DOTATOC) cuatro veces cada 10 a 12 semanas y un seguimiento a los 12 meses. Un paciente recibio tres y 11 pacientes recibieron dos veces cuatro ciclos de PRRT, lo que dio lugar a 102 casos. Se compararon el indice de filtrado glomerular estimado (FGe), la Hb, los globulos blancos y las plaquetas antes del primer ciclo de terapia y un ano despues del cuarto ciclo. La clasificacion del FGe se realizo segun la clasificacion de la enfermedad renal cronica (ERC) y la clasificacion de la hematotoxicidad segun los Criterios Terminologicos Comunes para Eventos Adversos (CTCAE). Tambien se evaluo el impacto de la edad, el sexo, la actividad acumulada y el tipo de PRRT en la toxicidad a largo plazo. Resultados El grado 1-2 del FGe se redujo de 87/102 al inicio a 71 casos en el seguimiento (p Conclusion En aproximadamente 20% de los casos se observa un aumento de la gradacion de la nefrotoxicidad o hematotoxicidad. En estos pacientes, excepto en uno, los niveles de toxicidad fueron leves o moderados un ano despues de completar cuatro ciclos de PRRT con analogos de Y-90 o Lu-177-SST. En terminos de seguridad, la PRRT no tiene un impacto critico en las opciones de tratamiento oncologico posterior en caso de progresion de la enfermedad.

PURPOSE Rhabdoid tumor of the kidney (RTK) is one of the most aggressive childhood renal tumors. Overall survival ranges from 22% to 47%. The indication for radiation therapy (RT) in usually very young patients is an ongoing discussion. Recent protocols recommend RT independent of local stage, the latter being a good discriminator in other childhood kidney tumors. In this study, we analyze the evidence for RT in regard to risk factors, including tumor stage. METHODS AND MATERIALS This study analyzed 58 patients with RTK from Austria, Switzerland, and Germany treated in the framework of 4 consecutive, prospective renal/rhabdoid tumor studies from 1991 to 2014. All treatment protocols included multimodality treatment, including high-intensity chemotherapy, surgery, and RT. RESULTS Local stage distribution was not applicable, I, II, and III in 1, 6, 11, and 40, respectively. Twenty-nine (50%) patients had stage IV disease at diagnosis. Thirty-seven patients (64%) achieved complete remission, and 49% (18/37) relapsed. Thirty-four patients (60%) patients had progressive disease and died, 17 had local disease, 10 had combined disease, and 7 had distant disease; 2 treatment-related deaths were reported (3%). Twenty-one patients received RT during first-line treatment, 18 of them to all involved sites. Eight of the 34 cases of progressive disease occurred in irradiated patients. The local failure rate of treated patients with local stage II or III disease was 29% (6/18) in patients irradiated to all sites compared with 68% (15/22) in nonirradiated patients. One of 6 stage I patients received RT, and 1 patient experienced distant relapse (2-year progression-free and overall survival both 83% ± 15%). Progression-free survival for local stage II and III disease treated with RT, adjusted for early relapse or treatment abandonment, was 67% ± 11%, compared with 15% ± 7% without RT (P < .0001). CONCLUSION The 68% local failure rate in nonirradiated patients underlines the importance of local treatment. Our experience supports the use of RT for local control in higher stage disease. In contrast, no local relapse in 6 local stage I patients, including 5 nonirradiated patients, suggests omission of RT in this favorable subset of usually infant patients with RTK.

Background\ud \ud The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing).\ud \ud \ud \ud Methods\ud \ud We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800–0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50–138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants.\ud \ud \ud \ud Findings\ud \ud Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53–68]; median follow-up 7·0 years [IQR 4·7–10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19–1·94) and autonomous cortisol secretion (1·77, 1·20–2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93–9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values

Daniela Kroiss obtained her MSc degree in biotechnology at BOKU and is currently a PhD student in the biochemistry program at CUNY, where she works on a joint project between the Nanoscience Initiative and the University of Strathclyde. Gonen Ashkenasy is head of the Laboratory for Systems Chemistry at the Ben-Gurion University Chemistry Department. His research focuses on the design and analysis of synthetic replication networks. Adam Braunschweig earned his PhD in organic chemistry at the University of California and is an associate professor in the CUNY Nanoscience Initiative. His research focuses on the interface of organic chemistry with biology and material science. Tell Tuttle obtained his PhD in theoretical chemistry at Goteborg University and is a professor of theoretical chemistry at the University of Strathclyde. His research focuses on the directed discovery of peptide-based materials. Rein Ulijn gained his PhD in physical chemistry at the University of Strathclyde and is founding director of the Nanoscience Initiative at the CUNY Advanced Science Research Center. His research focuses on nanotechnology inspired by living systems.

Objectives The importance of the Calcitonin-gene-related-peptide-pathway (CGRP) as neuronal modulator of innate immune responses in mice has been previously demonstrated. The CGRP-receptor is composed of two subunits: the receptor-activity-modifying-protein-1 (RAMP1) and the calcitonin-receptor-like-receptor (CLR). CGRP can influence immune cells and their capacity of producing inflammatory cytokines. Using a RAMP1 knockout-mouse (RAMP1−/−) we examined the role of the CGRP-receptor in the acute-phase of cerulein-induced pancreatitis. Methods Hourly cerulein-injections for a period of 8 h in RAMP1−/− and wild-type mice were performed. To compare severity and extent of inflammation in RAMP1−/− and wild-type mice, histological analyses were done and cytokine levels were assessed using qRT-PCR 8 h, 24 h, 2 days, and 7 days post-cerulein-treatment. Furthermore, serum activities of LDH and lipase were determined. Results After 8 h RAMP1−/− mice showed a higher pancreas-to-body-weight-ratio, increased tissue edema and immune cell infiltration with higher amount of F4/80-positive cells as compared to wild-type mice. Overall infiltration of immune cells at 24 h was increased in RAMP1−/− mice and composed predominantly of MPO-positive neutrophils. In addition, after 24 h RAMP1−/− mice presented a higher pancreas-to-body-weight-ratio, higher expression of Ccl3, Il6, and Il1b and increased number of cleaved caspase 3 positive cells. Serum lipase correlated with the extent of tissue damage in RAMP1−/− compared to wild-type mice 24 h post-cerulein treatment. Conclusion Mice lacking RAMP1 showed increased inflammation, tissue edema, and pancreas injury particularly in the early phase of acute pancreatitis. This study highlights the essential role of CGRP for dampening the innate immune response in acute pancreatitis.

Purpose 18F-Fluoro-L-dihydroxyphenylalanine ([18F]FDOPA) PET offers high sensitivity and specificity in the imaging of non-malignant head and neck paraganglioma (HNPGL) but lower sensitivity in metastatic disease of these neuroendocrine tumours (NET). In contrast to the radiotracer [18F]FDOPA, both 123I-meta-iodo-benzylguanidine ([123I]MIBG) and 68Ga-DOTA-Tyr3-octreotide ([68Ga]Ga-DOTA-TOC) offer valuable clinical information on norepinephrine and somatostatin (SST) receptor status for planning 131I-MIBG and radionuclide peptide therapy (PRRT), respectively. Therefore, we compared [68Ga]Ga-DOTA-TOC and [18F]FDOPA PET/CT with [123I]MIBG planar and SPECT/CT imaging, for the detection of HNPGL. Combined cross-sectional imaging was the reference standard. Methods A total of 3 men and 7 women (age range 22 to 73 years) with anatomical and/or histologically proven HNPGL were included in this study. Of these patients, 3 patients had metastatic HNPGL. Comparative evaluation included morphological imaging with CT and functional imaging with [68Ga]Ga-DOTA-TOC and [18F]FDOPA PET, including [123I]MIBG imaging. The imaging results were analysed on a per-patient and per-lesion basis. Results On a per-patient analysis, the detection rate of both [68Ga]Ga-DOTA-TOC PET/CT and [18F]FDOPA PET/CT was 100%, that of planar [123I]MIBG imaging 10.0% and that of SPECT/CT 20.0%. On a per-lesion basis and in reference to diagnostic CT, the sensitivity of [68Ga]Ga-DOTA-TOC PET/CT was 100% (McNemar, P Conclusion [68Ga]Ga-DOTA-TOC PET/CT is superior for imaging, non-malignant and metastatic HNPGL compared to [18F]FDOPA PET/CT and planar [123I]MIBG imaging, including SPECT/CT, particularly in bone lesions. Combined functional/anatomical imaging ([68Ga]Ga-DOTA-TOC PET/CT) enables excellent delineation of tumour extent in these rare tumour entities. Compared to [123I]MIBG scintigraphy, [68Ga]Ga-DOTA-TOC PET appears far more useful for planning radionuclide therapy in patients with surgically inoperable tumours or metastatic disease.

Purpose 18F-Fluoro- l -dihydroxyphenylalanine (18F-DOPA) PET offers high sensitivity and specificity in the imaging of non-malignant extra-adrenal paraganglioma (PGL) and pheochromocytoma (PHEO) but lower sensitivity in metastatic disease. These tumours are of neuroendocrine origin and can be detected by 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTA-TOC) PET. Therefore, we compared 68Ga-DOTA-TOC and 18F-DOPA as radiolabels for PET/CT imaging for the diagnosis of metastatic extra-adrenal PGL and PHEO. Combined cross-sectional imaging was the reference standard. Methods A total of 6 men and 4 women (age range 22–72 years) with anatomical and/or histologically proven metastatic PGL and PHEO were included in this study. Of these patients, 2 male patients suffered from PHEO, while the remaining 8 patients were diagnosed as metastatic extra-adrenal PGL disease. Comparative evaluation included morphological imaging with CT and functional imaging with 68Ga-DOTA-TOC and 18F-DOPA PET. The imaging results were analyzed on a per-lesion basis. The maximum standardized uptake value (SUVmax) of each functional imaging modality in concordant tumour lesions was measured. Results Compared with anatomical imaging, the per-lesion detection rate of 68Ga-DOTA-TOC was 100% (McNemar, P Conclusion 68Ga-DOTA-TOC PET offers the highest detection rate in metastatic extra-adrenal PGL and PHEO compared to 18F-DOPA PET and even to diagnostic CT, particularly in bone lesions. Combined functional/anatomical imaging (68Ga-DOTA-TOC PET/CT) enables exact tumour extension to be detected in these rare tumour entities, especially in the case of unclear anatomical correlation.

Resumen Objetivo La PET con 18F-fluoro-L-dihidroxifenilalanina (18F-DOPA) ofrece alta sensibilidad y especificidad en el diagnostico del paraganglioma extraadrenal no maligno (PGL) y el feocromocitoma (FEO), pero menor sensibilidad en la enfermedad metastasica. Estos tumores son de origen neuroendocrino y pueden detectarse mediante PET con 68Ga-DOTA-Tyr3-octreotido (68Ga-DOTA-TOC). Por tanto, comparamos 68Ga-DOTA-TOC y 18F-DOPA como radiotrazadores para PET/TC para el diagnostico de PGL extradrenal metastasico y FEO. Las imagenes tomograficas anatomicas y funcionales fusionadas se utilizaron como estandar de referencia. Metodos Se incluyo en el estudio a un total de 6 varones y 4 mujeres (rango de edad de 22 a 72 anos), con PGL metastasico y FEO anatomica y/o histologicamente demostrados. De entre estos pacientes, 2 varones padecian FEO y los 8 pacientes restantes PGL extraadrenal metastasico. La evaluacion comparativa incluyo imagen morfologica con TC e imagen funcional mediante PET con 68Ga-DOTA-TOC y 18F-DOPA. Se analizaron los resultados de las imagenes por lesion. Se midio el valor maximo de captacion estandarizado (SUVmax) de cada modalidad de imagen funcional en las lesiones tumorales concordantes. Resultados En comparacion con la imagen anatomica, la tasa de deteccion por lesion mediante PET con 68Ga-DOTA-TOC fue del 100% (McNemar, p Conclusion La PET con 68Ga-DOTA-TOC proporciona un indice de deteccion mas elevado en el PGL extra-adrenal metastasico y PHEO, en comparacion con la PET con 18F-DOPA, e incluso con la TC diagnostica, particularmente en lo referente a lesiones oseas. La imagen funcional/anatomica combinada (PET/TC con 68Ga-DOTA-TOC) permite detectar la extension exacta del tumor en estas entidades tumorales infrecuentes, especialmente en caso de correlacion anatomica incierta.

Contains fulltext : 286890.pdf (Publisher’s version ) (Open Access) BACKGROUND: Arterial hypertension is a major cardiovascular risk factor. Identification of secondary hypertension in its various forms is key to preventing and targeting treatment of cardiovascular complications. Simplified diagnostic tests are urgently required to distinguish primary and secondary hypertension to address the current underdiagnosis of the latter. METHODS: This study uses Machine Learning (ML) to classify subtypes of endocrine hypertension (EHT) in a large cohort of hypertensive patients using multidimensional omics analysis of plasma and urine samples. We measured 409 multi-omics (MOmics) features including plasma miRNAs (PmiRNA: 173), plasma catechol O-methylated metabolites (PMetas: 4), plasma steroids (PSteroids: 16), urinary steroid metabolites (USteroids: 27), and plasma small metabolites (PSmallMB: 189) in primary hypertension (PHT) patients, EHT patients with either primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) or Cushing syndrome (CS) and normotensive volunteers (NV). Biomarker discovery involved selection of disease combination, outlier handling, feature reduction, 8 ML classifiers, class balancing and consideration of different age- and sex-based scenarios. Classifications were evaluated using balanced accuracy, sensitivity, specificity, AUC, F1, and Kappa score. FINDINGS: Complete clinical and biological datasets were generated from 307 subjects (PA=113, PPGL=88, CS=41 and PHT=112). The random forest classifier provided ∼92% balanced accuracy (∼11% improvement on the best mono-omics classifier), with 96% specificity and 0.95 AUC to distinguish one of the four conditions in multi-class ALL-ALL comparisons (PPGL vs PA vs CS vs PHT) on an unseen test set, using 57 MOmics features. For discrimination of EHT (PA + PPGL + CS) vs PHT, the simple logistic classifier achieved 0.96 AUC with 90% sensitivity, and ∼86% specificity, using 37 MOmics features. One PmiRNA (hsa-miR-15a-5p) and two PSmallMB (C9 and PC ae C38:1) features were found to be most discriminating for all disease combinations. Overall, the MOmics-based classifiers were able to provide better classification performance in comparison to mono-omics classifiers. INTERPRETATION: We have developed a ML pipeline to distinguish different EHT subtypes from PHT using multi-omics data. This innovative approach to stratification is an advancement towards the development of a diagnostic tool for EHT patients, significantly increasing testing throughput and accelerating administration of appropriate treatment. FUNDING: European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 633983, Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to Z.E. and F.B.), and Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1).

90 kDa heat shock proteins (Hsp90) act as protein chaperones and play a role in modulating endoplasmic reticulum (ER) stress. Hsp90 inhibitors are under clinical investigation as cancer treatment. Mitotane therapy of adrenocortical carcinoma (ACC) has been shown to act through lipid-induced ER-stress. To explore the potential of Hsp90 inhibitors in ACC as a single agent and in combination with mitotane, we analyzed two independent gene expression data sets of adrenal tumors in silico and treated the ACC cell line model NCI-H295 with Hsp90 inhibitors BIIB021 (B) and CCT18159 (C) alone and in combination with mitotane. ER-stress markers were monitored by immunoblotting. Drug synergism was quantified using the median effect model with cell viability as read-out. Cytosolic Hsp90 isoforms AA1 and AB1 were significantly overexpressed in ACC. Viability of H295 cells was impaired by B and C as single agents with an EC50 of 5.7 × 10−6M and 12.1 × 10−6M. B but not C dose-dependently increased XBP1 splicing and CHOP expression indicative of ER-stress activation. ER-stress marker expression was enhanced by co-incubation of B with 10 μM but not 5 μM mitotane. Maximal CHOP expression was induced by 25 μM mitotane alone with no additional effect of B. Combination indices (CI) of B and C with mitotane ranged from 0.64 to 1.38 and 0.68 to 1.30, respectively where CI values

Purpose Giant cell granuloma (GCG) of the jaw is a rare disease with high morbidity. Various treatment options have been discussed in the past. Since 2010, a pharmaceutical therapy with denosumab seems to have been successful for giant cell tumors of the femur. The authors hypothesized the equally successful use of denosumab for GCGs of the jaws. Materials and Methods In the present retrospective cohort study, 5 patients with large GCGs of the jaws were treated with denosumab with a follow-up of 25 to 49 months. Frequent clinical follow-ups and a radiologic follow-up were performed and systematically analyzed. Results All patients showed a curative treatment response and complete metabolic resolution of the GCGs under treatment with denosumab. Conclusion A brief review of the relevant literature and a detailed evaluation of current cases led to the conclusion that denosumab therapy should be considered a therapeutic option for large central GCGs of the jaws. The results of this study suggest denosumab is a successful treatment option. A treatment length no shorter than 12 months is recommended and monitoring of treatment response can be well managed by positron-emission tomographic computed tomography or magnetic resonance imaging.