The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC.
Patients with ...advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 ‘before surgery’; model 2 ‘post-surgery’.
Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥20%, P = 0.06) in model 2.
The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.
Background
Metastatic pheochromocytomas and paragangliomas (PPGLs) occur in about 5–26% of cases and are characterized by a heterogeneous prognosis. Metastases can be synchronous at the initial ...diagnosis, but they can occur also many years after surgery for the primary tumor. To date, the treatment of patients affected by metastatic PPGLs represents a clinical challenge because of the lack of guidelines.
Aim
The aim of this article is to review the available management options and their impact on the outcomes of patients with metastatic PPGLs.
Results
Generally, treatments are not curative. Surgery, when possible, can be used to reduce hormonal symptoms and cardiovascular morbidity. Chemotherapy plays a role in patients with high burden tumor and rapid disease progression. Tyrosine kinases inhibitors (TKIs) might be considered for their ability to block the angiogenesis and cell growth. Radiation therapy and interventional radiology techniques can help in the management of local metastases to control symptoms and avoid tumor progression. On the other hand, peptide receptor radionuclide therapy (PRRT), using
90
Y or
177
Lu-DOTATATE, could be a promising therapy. In addition, high specific
131
I-MIBG was approved by the Food and Drug Administration (FDA) in the US for the treatment of patients affected by metastatic and unresectable
131
I-MIBG positive PPGLs. Considering the different pathways involved in the pathogenesis of PPGLs, several target therapies have been proposed and are under evaluation in clinical trials.
Conclusions
The choice of the appropriate treatment should be based on multidisciplinary and personalized approach taking into account the rarity and the variability of these tumors.
Phaeochromocytomas and paragangliomas (PPGLs) are highly heterogeneous tumours with variable catecholamine biochemical phenotypes and diverse hereditary backgrounds. This analysis of 18 ...catecholamine-related plasma and urinary biomarkers in 365 patients with PPGLs and 846 subjects without PPGLs examined how catecholamine metabolomic profiles are impacted by hereditary background and relate to variable hormone secretion. Catecholamine secretion was assessed in a subgroup of 156 patients from whom tumour tissue was available for measurements of catecholamine contents. Among all analytes, the free catecholamine O-methylated metabolites measured in plasma showed the largest tumour-related increases relative to the reference group. Patients with tumours due to multiple endocrine neoplasia type 2 and neurofibromatosis type 1 (NF1) showed similar catecholamine metabolite and secretory profiles to patients with adrenaline-producing tumours and no evident hereditary background. Tumours from these three patient groups contained higher contents of catecholamines, but secreted the hormones at lower rates than tumours that did not contain appreciable adrenaline, the latter including PPGLs due to von Hippel–Lindau (VHL) and succinate dehydrogenase (SDH) gene mutations. Large increases of plasma dopamine and its metabolites additionally characterised patients with PPGLs due to the latter mutations, whereas patients with NF1 were characterised by large increases in plasma dihydroxyphenylglycol and dihydroxyphenylacetic acid, the deaminated metabolites of noradrenaline and dopamine. This analysis establishes the utility of comprehensive catecholamine metabolite profiling for characterising the distinct and highly diverse catecholamine metabolomic and secretory phenotypes among different groups of patients with PPGLs. The data further suggest developmental origins of PPGLs from different populations of chromaffin cell progenitors.
Introduction Les cancers présentent de nombreuses mutations somatiques, identifiables par le séquençage d’exomes. Certains gènes sont également inactivés par délétion homozygote ou activés par ...amplification génique dans la tumeur. L’objectif était d’identifier les gènes altérés dans les corticosurrénalomes. Matériel et méthodes L’exome de 45 corticosurrénalomes a été comparé à l’ADN non tumoral correspondant. Neuf gènes récurrents ont été séquencés sur 77 autres couples tumeurs/leucocytes. Le génome de ces tumeurs a été également analysé par puce SNP. Résultats Les corticosurrénalomes présentent une médiane de 30 mutations somatiques, sauf deux corticosurrénalomes hypermutés (517 et 1364 mutations). Le taux de mutation est corrélé à la survie à 5 ans (Wilcoxon p = 0,003) et au score de Weiss (ANOVA p = 0,02). Neuf gènes sont altérés dans au moins 3/45 corticosurrénalomes passés en exome et en puce SNP : ZNRF43, CTNNB1, TP53, RB1, MEN1, CDKN2A, TERT, DAXX et MED12 . Parmi ces gènes, ZNRF3 , est un nouveau gène suppresseur de tumeurs identifié par cette étude. Il est altéré dans 26 des 122 corticosurrénalomes (21 %). ZNRF3 semble moduler la voie Wnt-βcaténine. Dans la même voie, CTNNB1 est muté dans 20/122 des corticosurrénalomes (16 %). Les altérations de ZNRF3 et CTNNB1 sont mutuellement exclusives. Enfin TP53 est altéré dans 20/122 corticosurrénalomes (16 %). Les mutations récurrentes sont retrouvées principalement dans les corticosurrénalomes « agressif » tels que définis par la classification non supervisée du transcriptome. Conclusion Il existe deux types de corticosurrénalomes, l’un de mauvais pronostic avec des mutations spécifiques (voie Wnt-βcaténine et voie p53 principalement), l’autre sans mutation récurrente.
Purpose
Adrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of ...carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC.
Results/methods
CAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (
n
= 14) (fold increase FI = 7.4 ± 0.1,
P
< 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06,
P
< 0.001), compared with lower stages (
n
= 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11,
P
< 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1,
P
< 0.01, respectively).
Conclusion
Our findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.
Background
Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5–26% of cases. ...To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines.
Aim
The aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs.
Methods
Clinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27.
Results
Nine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years 30–55. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases
.
An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt
p
= 0.028; OSmtx
p
< 0.001), abdominal PGLs (OSpt
p
= 0.007; OSmtx
p
= 0.041), larger tumors (OSpt
p
= 0.008; OSmtx
p
= 0.025) and sporadic disease (OSpt
p
= 0.013; OSmtx
p
= 0.008).
Conclusion
Our data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.
Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC ...patients.
The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells.
Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC.
In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation.
In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R.
Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only.
In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
•In ACC cell lines FLNA interacts with IGF1R and IR.•FLNA silencing increases IGF1R and decreases IR expression.•Low levels of FLNA enhance IGF2 proliferative effects in ACC cells.•FLNA knockdown potentiates antiproliferative effects of IGF1R inhibitors in H295R.•The loss of FLNA might be a biomarker for Linsitinib responsiveness.
Over the last decade, the development of novel and high penetrance genomic approaches to analyze biological samples has provided very new insights in the comprehension of the molecular biology and ...genetics of tumors. The use of these techniques, consisting of exome sequencing, transcriptome, miRNome, chromosome alteration, genome, and epigenome analysis, has also been successfully applied to adrenocortical carcinoma (ACC). In fact, the analysis of large cohorts of patients allowed the stratification of ACC with different patterns of molecular alterations, associated with different outcomes, thus providing a novel molecular classification of the malignancy to be associated with the classical pathological analysis. Improving our knowledge about ACC molecular features will result not only in a better diagnostic and prognostic accuracy, but also in the identification of more specific therapeutic targets for the development of more effective pharmacological anti-cancer approaches. In particular, the specific molecular alteration profiles identified in ACC may represent targetable events by the use of already developed or newly designed drugs enabling a better and more efficacious management of the ACC patient in the context of new frontiers of personalized precision medicine.
Buried Layer Low Gain Avalanche Diodes Apresyan, A.; Giacomini, G.; Heller, R. ...
Journal of physics. Conference series,
11/2022, Letnik:
2374, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We report on the design, simulation and test of Low Gain Avalanche Diodes (LGADs) which utilize a buried gain layer. The buried layer is formed by patterned implantation of a 50-micron thick float ...zone substrate wafer-bonded to a low resistivity carrier. This is then followed by epitaxial deposition of a ≈ 3 micron-thick high resistivity amplification region. The topside is then processed with junction edge termination and guard ring structures and incorporates an AC-coupled cathode implant. This design allows for independent adjustment of gain layer depth and density, increasing design flexibility. A higher gain layer dopant density can also be achieved by controlling the process thermal budget, improving radiation hardness. A first set of demonstration devices has been fabricated, including a variety of test structures. We report on TCAD design and simulation, fabrication process flow, and preliminary measurements of prototype devices.
Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed ...the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224–6.343; OR 1.467 95% CI 1.202–1.792, respectively; Hosmer–Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930–0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866–0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285–2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.
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