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"Fassnacht, Martin"
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Price Management : strategy, analysis, decision, implementation
In this book, the world's foremost experts on pricing integrate theoretical rigor and practical application to present a comprehensive resource that covers all areas of the field. This volume brings together quantitative and qualitative approaches and highlights the most current innovations in theory and practice.
Book
Personalized Management of Pheochromocytoma and Paraganglioma
Abstract
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.
Graphical Abstract
Graphical Abstract
Journal Article
CXCR4-targeted theranostics in oncology
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
Ga]PentixaFor 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
Ga]PentixaFor 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
Y]PentixaTher. 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.
Journal Article
Mutations in the deubiquitinase gene USP8 cause Cushing's disease
Martin Reincke, Martin Fassnacht and colleagues identify somatic mutations in the
USP8
deubiquitinase gene in corticotroph adenomas in Cushing's disease. The mutations enhanced proteolytic cleavage and catalytic activity of USP8, which led to activation of EGF receptor signaling.
Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the
USP8
deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in
USP8
cause Cushing's disease via activation of EGF receptor signaling.
Journal Article
How do performance feedback characteristics influence recipients’ reactions? A state-of-the-art review on feedback source, timing, and valence effects
One of the most important measures to stimulate individual performance is feedback, whose effectiveness highly depends on underlying feedback characteristics. Although an extensive body of research has stressed its importance, a conclusive overall picture on feedback characteristics effects is missing. However, synthesized knowledge is important when one is willing to implement feedback systems to effectively influence recipients’ reactions. To address this issue, we organize and summarize the findings regarding the main effects of feedback source, feedback timing, and feedback valence as well as regarding their interactions with the source, message, task, and recipients’ individual characteristics from different disciplines. Based on an analysis of 64 empirical articles, we show that main effects have been considered very context-specific and are often inconsistent, while the occurrence of certain source, message, task, and individual characteristics even inverts the generally assumed main relationships. Based on an extract of our findings, we provide specific research propositions and offer avenues for future research, which will be of value for researchers and feedback-providing practitioners.
Journal Article
Integrated genomic characterization of adrenocortical carcinoma
Jérôme Bertherat, Aurélien de Reyniès and colleagues perform integrated genomic analyses of adrenocortical carcinomas. They discover recurrent alterations in several new driver genes, including
ZNRF3
,
DAXX
,
TERT
and
MED12
, and identify two distinct molecular subgroups with opposite clinical outcomes.
Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland
1
. Despite overall poor prognosis, ACC outcome is heterogeneous
2
,
3
. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes
4
,
5
(
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
6
, 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.
Journal Article
Expression and Prognostic Relevance of PD-1, PD-L1, and CTLA-4 Immune Checkpoints in Adrenocortical Carcinoma
Abstract
Context
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous.
Objective
Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors.
Methods
The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed.
Results
PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells.
Conclusion
The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.
Journal Article
Biochemical Diagnosis of Chromaffin Cell Tumors in Patients at High and Low Risk of Disease: Plasma versus Urinary Free or Deconjugated O-Methylated Catecholamine Metabolites
Measurements of plasma or urinary metanephrines are recommended for diagnosis of pheochromocytoma and paraganglioma (PPGL). What test offers optimal diagnostic accuracy for patients at high and low risk of disease, whether urinary free metanephrines offer advantages over deconjugated metanephrines, and what advantages are offered by including methoxytyramine in panels all remain unclear.
A population of 2056 patients with suspected PPGLs underwent prospective screening for disease using mass spectrometric-based measurements of plasma free, urinary deconjugated, and urinary free metanephrines and methoxytyramine. PPGLs were confirmed in 236 patients and were excluded in others on follow-up evaluation.
Measurements of plasma free metabolites offered higher (
< 0.01) diagnostic sensitivity (97.9%) than urinary free (93.4%) and deconjugated (92.9%) metabolites at identical specificities for plasma and urinary free metabolites (94.2%) but at a lower (
< 0.005) specificity for deconjugated metabolites (92.1%). The addition of methoxytyramine offered little value for urinary panels but provided higher (
< 0.005) diagnostic performance for plasma measurements than either urinary panel according to areas under ROC curves (0.991 vs 0.972 and 0.964). Diagnostic performance of urinary and plasma tests was similar for patients at low risk of disease, whereas plasma measurements were superior to both urinary panels for high-risk patients.
Diagnosis of PPGLs using plasma or urinary free metabolites provides advantages of fewer false-positive results compared with commonly measured deconjugated metabolites. The plasma panel offers better diagnostic performance than either urinary panel for patients at high risk of disease and, with appropriate preanalytics, provides the test of choice. Measurements of methoxytyramine in urine show limited diagnostic utility compared with plasma.
Journal Article
Vertical line extension: a systematic review of research on upward and downward line extension
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.
Journal Article
Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome
Corticotropin-independent Cushing's syndrome occurs with adrenocortical tumors or hyperplasia. The authors report that germline duplications of
PRKACA
lead to bilateral adrenal hyperplasia, whereas somatic mutations lead to unilateral cortisol-producing adrenal adenomas.
Endogenous hypercortisolism, referred to as Cushing's syndrome, is associated with substantial morbidity and mortality.
1
When Cushing's syndrome is severe, patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae.
2
Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production. Adrenal adenomas are common, with a prevalence of at least 3% among persons older than 50 years of age.
3
Whereas only a subset of these tumors is associated with overt Cushing's syndrome, some degree of cortisol excess is present, . . .
Journal Article