Update in Adrenocortical Carcinoma Fassnacht, Martin; Kroiss, Matthias; Allolio, Bruno
The journal of clinical endocrinology and metabolism,
2013-December, Letnik:
98, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review ...published in this journal in 2006.
The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown.
For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy.
In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive “-omic approaches” and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.
Retail customers increasingly use brick-and-mortar retailers as showrooms to try products and gather information, while then purchasing online at a lower price. This paper addresses how showroomers ...react to several low-investment tactics aimed at combating the effects of showrooming, as well as comparing showroomers and non-showroomers on these issues. Based on three scenario experiments, the paper addresses the effects of salesperson interaction quality and other tactics aimed at increasing buying intention. The findings indicate that high interaction quality increases showroomers' in-store buying intention – even when a salesperson matches the online price. The salesperson suggesting an alternative product or explaining the store's return policy also appear to be effective tactics to increase buying intentions. Interestingly, showroomers and non-showroomers reacted similarly to these strategies, indicating that the tactics can work for both parties.
•Salespeople can influence showroomers to purchase in the store with high quality interactions.•Interaction quality can influence showroomers' future buying intention in the store.•Matching online retailers' prices increases showroomers' buying intention, but interaction quality still matters.•A suggestion for a more suitable product can increase showroomers' buying intention in the store.•By explaining a store's return policy, salespeople can increase showroomers' buying intention.
Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of ...Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and ...SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.
Clinical management of adrenocortical carcinoma Fassnacht, Martin, MD; Allolio, Bruno, MD
Baillière's best practice & research. Clinical endocrinology & metabolism,
04/2009, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy, and most of the diagnostic and therapeutic strategies are not fully established according to criteria of evidence-based ...medicine. However, recently collaborative efforts (e.g. International Consensus Conference 2003 and networks like the European Network for the Study of Adrenal Tumours (ENSAT)) have significantly advanced the field. This article summarizes current standards in the management of ACC. In patients with suspected ACC a thorough endocrine and imaging work-up is followed by complete (Ro) resection of the tumour by an expert surgeon and initiation of adjuvant mitotane. In advanced disease not amenable to radical resection, cytotoxic drugs will be added to mitotane. The most promising regimens (etoposide, doxorubicin, cisplatin plus mitotane and streptozotocin plus mitotane) are currently compared in an international phase-III trial. Several targeted therapies are under investigation (e.g. IGF-1 inhibitors, sunitinib, sorafenib) and may lead to new treatment options.
The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often ...inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin.
From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked.
A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval CI, 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test.
The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).
CXCR4-targeted theranostics in oncology Buck, Andreas K.; Serfling, Sebastian E.; Lindner, Thomas ...
European journal of nuclear medicine and molecular imaging,
10/2022, Letnik:
49, Številka:
12
Journal Article
Recenzirano
Odprti dostop
A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging ...and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent
68
GaPentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition,
68
GaPentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent
177
Lu/
90
YPentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.
Purpose
Vertical line extension is an attractive growth strategy that allows brands to address heterogeneous consumer needs and react to competitive pressure. The purpose of this paper is to ...systematically review and summarize vertical line extension research to derive general insights into vertical upward and downward line extension.
Design/methodology/approach
Drawing on a systematic review of 536 academic articles and predefined inclusion criteria, this research identifies and evaluates all articles that add knowledge to the topic of vertical line extension (n = 64).
Findings
This research derives general insights in several vertical line extension-specific issues. Different forms of vertical line extension, conceptual differences between upward and downward extensions, as well as the role of perceived fit, extension degree and the parent brand are crucial for the study and evaluation of extension and parent brand feedback effects. Those effects are complex and often work in opposing directions not only for the parent brand but also for the extension. Future research needs to face that complexity as well as methodological issues and different research contexts to further advance the literature stream.
Originality/value
This paper provides a comprehensive, state-of-the-art review of vertical line extension research characteristics and results. It provides new insights on the characteristics and effects of vertical line extensions and guides future research on the topic.
Context:
The postoperative course of patients with subclinical hypercortisolism (SH) is yet to be clarified. The aims are to review the prevalence and predictive factors of postoperative adrenal ...insufficiency and the time to recover a normal adrenocortical function in patients with SH and Cushing's syndrome (CS).
Evidence Acquisition:
Using the PubMed database, we conducted a systematic review of the literature, selecting studies published from 1980 to 2013.
Evidence Synthesis:
Of the 1522 papers screened, 28 were selected (13 retrospective, 14 prospective, and one randomized controlled trial). The prevalence of postoperative adrenal insufficiency was 65.3% in 248 SH subjects and 99.7% in 377 CS patients. Patients with SH were reclassified according to the following diagnostic criteria: subjects defined by pathological dexamethasone test only (DEX), and those defined by the dexamethasone test with one (DEX+1) or two additional criteria (DEX+2); and they were compared with CS patients. The prevalence of adrenal insufficiency was 51.4, 60.6, 91.3, and 99.7%, respectively, with no significant difference between the two latter groups. The test with the best compromise between sensitivity (64%) and specificity (81%) in predicting adrenal insufficiency was the midnight serum cortisol. The time to achieve eucortisolism was lower in SH patients than in CS patients (6.5 vs 11.2 mo; P < .001).
Conclusions:
Adrenal insufficiency occurs in about half of the patients with SH if defined only by the pathological dexamethasone test. However, prevalence of adrenal insufficiency and time to recovery are tightly related to the degree of hypercortisolism and diagnostic criteria to define SH, which might help to better define SH for future studies.
PDF
