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OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.
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Paraganglioma , Neoplasias de la Vejiga Urinaria , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/diagnóstico , Femenino , Masculino , Adulto , Paraganglioma/diagnóstico , Paraganglioma/cirugía , Europa (Continente) , Estados Unidos , Anciano , ChinaRESUMEN
PURPOSE: To investigate the [68Ga]DOTATOC PET radiomic profile of head and neck paragangliomas (HNPGLs) and identify radiomic characteristics useful as predictors of succinate dehydrogenase genes (SDHx) pathogenic variants. METHODS: Sporadic and SDHx HNPGL patients, who underwent [68Ga]DOTATOC PET/CT, were retrospectively included. HNPGLs were analyzed using LIFEx software, and extracted features were harmonized to correct for batch effects and confronted testing for multiple comparison. Stepwise discriminant analysis was conducted to remove redundancy and identify best discriminating features. ROC analysis was used to define optimal cut-offs. Multivariate decision-tree analysis was performed using CHAID method. RESULTS: 34 patients harboring 60 HNPGLs (51 SDHx in 25 patients) were included. Three sporadic and nine SDHx HNPGLs were metastatic. At stepwise discriminant analysis, both GLSZM-Zone Size Non-Uniformity (ZSNU, reflecting tumor heterogeneity) and IB-TLSRE (total lesion somatostatin receptor expression) were independent predictors of genetic status, with 96.4% of lesions and 91.6% of patients correctly classified after cross validation (p < 0.001). Among non-metastatic patients, GLSZM-ZSNU and IB-TLSRE were significantly higher in sporadic than SDHx HNPGLs (p < 0.001). No differences were revealed in metastatic patients. Decision-tree analysis highlights multifocality and IB-TLSRE as useful variables, correctly identifying 6/9 sporadic and 24/25 SDHx patients. Model failed to classify one SDHA and three sporadic patients (2 metastatic). CONCLUSION: Radiomics features GLSZM-ZSNU and IB-TLSRE appear to reflect HNPGLs SDHx status and tumor behavior (metastatic vs. non-metastatic). If validated, especially IB-TLSRE might represent a simple and time-efficient radiomic index for SDHx variants early screening and prediction of tumor behavior in HNPGL cases.
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Neoplasias de Cabeza y Cuello , Octreótido , Compuestos Organometálicos , Paraganglioma , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/genética , Femenino , Masculino , Persona de Mediana Edad , Paraganglioma/genética , Paraganglioma/diagnóstico por imagen , Octreótido/análogos & derivados , Proyectos Piloto , Adulto , Anciano , Estudios Retrospectivos , Succinato Deshidrogenasa/genética , Procesamiento de Imagen Asistido por Computador/métodos , RadiómicaRESUMEN
OBJECTIVE: To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)-related spinal bone metastases. MATERIALS AND METHODS: Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. RESULTS: Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). CONCLUSIONS: [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. CLINICAL RELEVANCE STATEMENT: In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). KEY POINTS: ⢠Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. ⢠[68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. ⢠[68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.
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OBJECTIVE: This white paper provides practical guidance for clinicians encountering bilateral adrenal masses. METHODS: A case-based approach to the evaluation and management of bilateral adrenal masses. Specific clinical scenarios presented here include cases of bilateral adrenal adenomas, hemorrhage, pheochromocytomas, metastatic disease, myelolipomas, as well as primary bilateral macronodular adrenal hyperplasia. RESULTS: Bilateral adrenal masses represent approximately 10% to 20% of incidentally discovered adrenal masses. The general approach to the evaluation and management of bilateral adrenal masses follows the same protocol as the evaluation of unilateral adrenal masses, determined based on the patient's clinical history and examination as well as the imaging characteristics of each lesion, whether the lesions could represent a malignancy, demonstrate hormone excess, or possibly represent a familial syndrome. Furthermore, there are features unique to bilateral adrenal masses that must be considered, including the differential diagnosis, the evaluation, and the management depending on the etiology. Therefore, considerations for the optimal imaging modality, treatment (medical vs surgical therapy), and surveillance are included. These recommendations were developed through careful examination of existing published studies as well as expert clinical opinion consensus. CONCLUSION: The evaluation and management of bilateral adrenal masses require a comprehensive systematic approach which includes the assessment and interpretation of the patient's clinical history, physical examination, dynamic hormone evaluation, and imaging modalities to determine the key radiographic features of each adrenal nodule. In addition, familial syndromes should be considered. Any final treatment options and approaches should always be considered individually.
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Phonocardiography (PCG) is used as an adjunct to teach cardiac auscultation and is now a function of PCG-capable stethoscopes (PCS). To evaluate the efficacy of PCG and PCS, the authors investigated the impact of providing PCG data and PCSs on how frequently murmurs, rubs, and gallops (MRGs) were correctly identified by third-year medical students. Following their internal medicine rotation, third-year medical students from the Georgetown University School of Medicine completed a standardized auscultation assessment. Sound files of 10 different MRGs with a corresponding clinical vignette and physical exam location were provided with and without PCG (with interchangeable question stems) as 10 paired questions (20 total questions). Some (32) students also received a PCS to use during their rotation. Discrimination/difficulty indexes, comparative chi-squared, and McNemar test p-values were calculated. The addition of phonocardiograms to audio data was associated with more frequent identification of mitral stenosis, S4, and cardiac friction rub, but less frequent identification of ventricular septal defect, S3, and tricuspid regurgitation. Students with a PCS had a higher frequency of identifying a cardiac friction rub. PCG may improve the identification of low-frequency, usually diastolic, heart sounds but appears to worsen or have little effect on the identification of higher-frequency, often systolic, heart sounds. As digital and phonocardiography-capable stethoscopes become more prevalent, insights regarding their strengths and weaknesses may be incorporated into medical school curricula, bedside rounds (to enhance teaching and diagnosis), and telemedicine/tele-auscultation efforts.
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Estetoscopios , Estudiantes de Medicina , Fonocardiografía/métodos , Humanos , Auscultación Cardíaca/métodos , Soplos Cardíacos/diagnóstico , Soplos Cardíacos/fisiopatología , Ruidos Cardíacos/fisiologíaRESUMEN
BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. New drug targets and proteins that would assist sensitive PPGL imagining could improve therapy and quality of life of patients with PPGL, namely those with recurrent or metastatic disease. Using a combined proteomic strategy, we looked for such clinically relevant targets among integral membrane proteins (IMPs) upregulated on the surface of tumor cells and non-membrane druggable enzymes in PPGL. METHODS: We conducted a detailed proteomic analysis of 22 well-characterized human PPGL samples and normal chromaffin tissue from adrenal medulla. A standard quantitative proteomic analysis of tumor lysate, which provides information largely on non-membrane proteins, was accompanied by specific membrane proteome-aimed methods, namely glycopeptide enrichment using lectin-affinity, glycopeptide capture by hydrazide chemistry, and enrichment of membrane-embedded hydrophobic transmembrane segments. RESULTS: The study identified 67 cell surface integral membrane proteins strongly upregulated in PPGL compared to control chromaffin tissue. We prioritized the proteins based on their already documented direct role in cancer cell growth or progression. Increased expression of the seven most promising drug targets (CD146, CD171, ANO1, CD39, ATP8A1, ACE and SLC7A1) were confirmed using specific antibodies. Our experimental strategy also provided expression data for soluble proteins. Among the druggable non-membrane enzymes upregulated in PPGL, we identified three potential drug targets (SHMT2, ARG2 and autotaxin) and verified their upregulated expression. CONCLUSIONS: Application of a combined proteomic strategy recently presented as "Pitchfork" enabled quantitative analysis of both, membrane and non-membrane proteome, and resulted in identification of 10 potential drug targets in human PPGL. Seven membrane proteins localized on the cell surface and three non-membrane druggable enzymes proteins were identified and verified as significantly upregulated in PPGL. All the proteins have been previously shown to be upregulated in several human cancers, and play direct role in cancer progression. Marked upregulation of these proteins along with their localization and established direct roles in tumor progression make these molecules promising candidates as drug targets or proteins for sensitive PPGL imaging.
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Paediatric phaeochromocytomas and paragangliomas (PPGLs), though rare tumours, are associated with significant disability and death in the most vulnerable of patients early in their lives. However, unlike cryptogenic and insidious disease states, the clinical presentation of paediatric patients with PPGLs can be rather overt, allowing early diagnosis, granted that salient findings are recognized. Additionally, with prompt and effective intervention, prognosis is favourable if timely intervention is implemented. For this reason, this review focuses on four exemplary paediatric cases, succinctly emphasizing the now state-of-the-art concepts in paediatric PPGL management.
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Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. In tandem, we constructed cell lines and a transgenic mouse model bearing the corresponding identified mutation in HIF-2α from which we extracted primary hepatocytes. Lipid accumulation was evaluated in these cells and liver tissue from the mouse model using Oil Red O staining and biochemical measurements. We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups. Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.
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Dislipidemias , Neoplasias Hepáticas , Animales , Humanos , Ratones , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Dislipidemias/genética , Lípidos , MutaciónRESUMEN
Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
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Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Tumores Neuroectodérmicos/tratamiento farmacológico , Fosfoproteínas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/metabolismo , Xenoinjertos , Humanos , Ratones , Neoplasias/genética , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/metabolismo , Fosfoproteínas/análisis , Fosfoproteínas/genética , FosforilaciónRESUMEN
PURPOSE: Paraganglioma of the urinary bladder (UBPGL) is a rare neuroendocrine tumor diagnosed in many patients only after surgery. We, therefore, assessed clinical clues relevant to presurgical diagnosis and clinical consequences in patients with a missed presurgical diagnosis of UBPGL. MATERIALS AND METHODS: Case reports describing a UBPGL (published from 1-1-2001 and 31-12-2020) were identified in Pubmed. Two authors independently performed data extraction and assessed data quality according to the PRISMA guideline. Patients were divided into two groups: UBPGL diagnosis before and after surgery. RESULTS: We included 177 articles reporting 194 cases. In 90 (46.4%) patients, the UBPGL was diagnosed before and in 104 (53.6%) after surgery. In presurgically diagnosed UBPGL, hypertension and catecholamine-associated symptoms were 2- to 3-fold (p < 0.001) more frequent than in postsurgically diagnosed patients whereas hematuria was twofold (p = 0.003) more prevalent in those with postsurgical diagnosis. Hypertension was an independent factor for presurgical biochemical testing (OR 4.45, 95% CI 1.66-11.94) while hematuria (OR 0.23, 95% CI 0.09-0.60) was an independent factor for not performing presurgical biochemical testing. Most patients diagnosed after surgery were not pretreated with alpha-adrenoceptor blockade (95.2%), underwent more frequently transurethral resection instead of cystectomy (70.2% vs. 23.1%) and had more frequent peroperative complications and residual tumor mass. CONCLUSIONS: In nearly half of all patients with a UBPGL, the diagnosis was not established before surgery. Hypertension and hematuria contributed independently to a presurgical diagnosis. Postsurgical diagnosis, which was associated with suboptimal presurgical and surgical management, resulted in more peroperative complications and incomplete tumor resections.
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Paraganglioma , Neoplasias de la Vejiga Urinaria , Cistectomía/métodos , Hematuria , Humanos , Paraganglioma/diagnóstico , Paraganglioma/patología , Paraganglioma/cirugía , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
BACKGROUND. Recent professional society guidelines for radionuclide imaging of sporadic pheochromocytoma (PHEO) recommend 18F-fluorodihydroxyphenylala-nine (18F-FDOPA) as the radiotracer of choice, deeming 68Ga-DOTATATE and FDG to be second- and third-line agents, respectively. An additional agent, 18F-fluorodopamine (18F-FDA), remains experimental for PHEO detection. A paucity of research has performed head-to-head comparison among these agents. OBJECTIVE. The purpose of this study was to perform an intraindividual comparison of 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, CT, and MRI in visualization of sporadic primary PHEO. METHODS. This prospective study enrolled patients referred with clinical suspicion for sporadic PHEO. Patients were scheduled for 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, whole-body staging CT (portal venous phase), and MRI within a 3-month period. PET/CT examinations were reviewed by two nuclear medicine physicians, and CT and MRI were reviewed by two radiologists; differences were resolved by consensus. Readers scored lesions in terms of confidence in diagnosis of PHEO (1-5 scale; 4-5 considered positive for PHEO). Lesion-to-liver SUVmax was computed using both readers' measurements. Interreader agreement was assessed using intraclass correlation coefficients (ICCs) for SUVmax. Analysis included only patients with histologically confirmed PHEO on resection. RESULTS. The analysis included 14 patients (eight women, six men; mean age, 52.4 ± 16.8 [SD] years) with PHEO. Both 68Ga-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, 18F-FDOPA PET/CT in 11, 18F-FDA PET/CT in 7, CT in 12, and MRI in 12. Mean conspicuity score for PHEO was 5.0 ± 0.0 for 18F-FDOPA PET/CT, 4.7 ± 0.5 for MRI, 4.6 ± 0.8 for 18F-FDA PET/CT, 4.4 ± 1.0 for 68Ga-DOTATATE PET/CT, 4.3 ± 1.0 for CT, and 4.1 ± 1.5 for FDG PET/CT. The positivity rate for PHEO was 100.0% (11/11) for 18F-FDOPA PET/CT, 100.0% (12/12) for MRI, 85.7% (6/7) for 18F-FDA PET/CT, 78.6% (11/14) for FDG PET/CT, 78.6% (11/14) for 68Ga-DOTATATE PET/CT, and 66.7% (8/12) for CT. Lesion-to-liver SUVmax was 10.5 for 18F-FDOPA versus 3.0-4.2 for the other tracers. Interreader agreement across modalities ranged from 85.7% to 100.0% for lesion positivity with ICCs of 0.55-1.00 for SUVmax measurements. CONCLUSION. Findings from this small intraindividual comparative study support 18F-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PHEO. CLINICAL IMPACT. This study provides data supporting current guidelines for imaging evaluation of suspected PHEO. TRIAL REGISTRATION. ClinicalTrials.gov NCT00004847.
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Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Radioisótopos de Galio , Imagen por Resonancia Magnética/métodos , Feocromocitoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos , Glándulas Suprarrenales/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Octreótido/análogos & derivados , Compuestos Organometálicos , Estudios Prospectivos , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/métodosRESUMEN
Pheochromocytomas and paragangliomas continue to be defined by significant morbidity and mortality despite their several recent advances in diagnosis, localization, and management. These adverse outcomes are largely related to mass effect as well as catecholamine-induced hypertension, tachyarrhythmias and consequent target organ damage, acute coronary syndromes, and strokes (ischemic and hemorrhagic stroke). Thus, a proper understanding of the physiology and pathophysiology of these tumors and recent advances are essential to affording optimal care. These major developments largely include a redefinition of metastatic behavior, a novel clinical categorization of these tumors into 3 genetic clusters, and an enhanced understanding of catecholamine metabolism and consequent specific biochemical phenotypes. Current advances in imaging of these tumors are shifting the paradigm from poorly specific anatomical modalities to more precise characterization of these tumors using the advent and development of functional imaging modalities. Furthermore, recent advances have revealed new molecular events in these tumors that are linked to their genetic landscape and, therefore, provide new therapeutic platforms. A few of these prospective therapies translated into new clinical trials, especially for patients with metastatic or inoperable tumors. Finally, outcomes are ever-improving as patients are cared for at centers with cumulative experience and well-established multidisciplinary tumor boards. In parallel, these centers have supported national and international collaborative efforts and worldwide clinical trials. These concerted efforts have led to improved guidelines collaboratively developed by healthcare professionals with a growing expertise in these tumors and consequently improving detection, prevention, and identification of genetic susceptibility genes in these patients.
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Neoplasias , HumanosRESUMEN
Alcohol use disorder (AUD) is characterized by escalating alcohol consumption, preoccupation with alcohol, and continued alcohol consumption despite adverse consequences. Dopamine has been implicated in neural and behavioral processes involved in reward and reinforcement and is a critical neurotransmitter in AUD. Clinical and preclinical research has shown that long-term ethanol exposure can alter dopamine release, though most of this work has focused on nucleus accumbens (NAc). Like the NAc, the dorsal striatum (DS) is implicated in neural and behavioral processes in AUD. However, little work has examined chronic ethanol effects on DS dopamine dynamics. Therefore, we examined the effect of ethanol consumption and withdrawal on dopamine release and its presynaptic regulation with fast-scan cyclic voltammetry in C57BL/6J mice. We found that one month of ethanol consumption did not alter maximal dopamine release or dopamine tissue content. However, we did find that D2 dopamine autoreceptors were sensitized. We also found a decrease in cholinergic control of dopamine release via ß2-containing nAChRs on dopamine axons. Interestingly, both effects were reversed following withdrawal, raising the possibility that some of the neuroadaptations in AUD might be reversible in abstinence. Altogether, this work elucidates some of the chronic alcohol-induced neurobiological dysfunctions in the dopamine system.
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Autorreceptores , Dopamina , Consumo de Bebidas Alcohólicas , Animales , Colinérgicos/farmacología , Dopamina/farmacología , Etanol/farmacología , Ratones , Ratones Endogámicos C57BL , Núcleo AccumbensRESUMEN
Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited.
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Mitocondrias/enzimología , Succinato Deshidrogenasa/metabolismo , Animales , Humanos , Inflamación/metabolismo , Mitocondrias/metabolismoRESUMEN
Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths, and its therapy remains a challenge. Our proposed therapeutic approach is based on the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 antibody (thus termed MBTA therapy), and has shown promising results in the elimination of subcutaneous murine melanoma, pheochromocytoma, colon carcinoma, and smaller pancreatic adenocarcinoma (Panc02). Here, we tested the short- and long-term effects of MBTA therapy in established subcutaneous Panc02 tumors two times larger than in previous study and bilateral Panc02 models as well as the roles of CD4+ and CD8+ T lymphocytes in this therapy. The MBTA therapy resulted in eradication of 67% of Panc02 tumors with the development of long-term memory as evidenced by the rejection of Panc02 cells after subcutaneous and intracranial transplantations. The initial Panc02 tumor elimination is not dependent on the presence of CD4+ T lymphocytes, although these cells seem to be important in long-term survival and resistance against tumor retransplantation. The resistance was revealed to be antigen-specific due to its inability to reject B16-F10 melanoma cells. In the bilateral Panc02 model, MBTA therapy manifested a lower therapeutic response. Despite numerous combinations of MBTA therapy with other therapeutic approaches, our results show that only simultaneous application of MBTA therapy into both tumors has potential for the treatment of the bilateral Panc02 model.
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Adenocarcinoma/patología , Antígenos CD40/antagonistas & inhibidores , Imidazoles/farmacología , Lipopolisacáridos/farmacología , Mananos/farmacología , Neoplasias Pancreáticas/patología , Poli I-C/farmacología , Ácidos Teicoicos/farmacología , Adenocarcinoma/inmunología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inmunoterapia , Ligandos , Ratones , Neoplasias Pancreáticas/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Receptores Toll-Like , Neoplasias PancreáticasRESUMEN
BACKGROUND: Measurements of plasma free metanephrines are recommended for diagnosing pheochromocytomas and paragangliomas (PPGL). Metanephrines can be detected in saliva with LC-MS/MS with sufficient analytical sensitivity and precision. Because collecting saliva is noninvasive and less cumbersome than plasma or urine sampling, we assessed the diagnostic accuracy of salivary metanephrines in diagnosing PPGL. METHODS: This 2-center study included 118 healthy participants (44 men; mean age: 33 years (range: 19--74 years)), 44 patients with PPGL, and 54 patients suspected of PPGL. Metanephrines were quantified in plasma and saliva using LC-MS/MS. Diagnostic accuracy; correlation between plasma and salivary metanephrines; and potential factors influencing salivary metanephrines, including age, sex, and posture during sampling, were assessed. RESULTS: Salivary metanephrines were significantly higher in patients with PPGL compared with healthy participants (metanephrine (MN): 0.19 vs 0.09 nmol/L, P < 0.001; normetanephrine (NMN): 2.90 vs 0.49 nmol/L, P < 0.001). The diagnostic sensitivity and specificity of salivary metanephrines were 89% and 87%, respectively. Diagnostic accuracy of salivary metanephrines was 88%, with an area under the ROC curve of 0.880. We found a significant correlation between plasma and salivary metanephrines (Pearson correlation coefficient: MN, 0.86, P < 0.001; NMN, 0.83, P < 0.001). Salivary NMN concentrations were higher when collected in a seated position compared with supine (P < 0.001) and increased with age (P < 0.001). CONCLUSIONS: Salivary metanephrines are a promising tool in the biochemical diagnosis of PPGL. Salivary metanephrines correlate with plasma free metanephrines and are increased in patients with PPGL. At this time, however, salivary metanephrines cannot replace measurement of plasma free metanephrines.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Cromatografía Liquida , Humanos , Masculino , Metanefrina , Normetanefrina , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Espectrometría de Masas en TándemRESUMEN
Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a hereditary background in over one-third of patients. Mutations in succinate dehydrogenase (SDH) genes increase the risk for PPGLs and several other tumours. Mutations in subunit B (SDHB) in particular are a risk factor for metastatic disease, further highlighting the importance of identifying SDHx mutations for patient management. Genetic variants of unknown significance, where implications for the patient and family members are unclear, are a problem for interpretation. For such cases, reliable methods for evaluating protein functionality are required. Immunohistochemistry for SDHB (SDHB-IHC) is the method of choice but does not assess functionality at the enzymatic level. Liquid chromatography-mass spectrometry-based measurements of metabolite precursors and products of enzymatic reactions provide an alternative method. Here, we compare SDHB-IHC with metabolite profiling in 189 tumours from 187 PPGL patients. Besides evaluating succinate:fumarate ratios (SFRs), machine learning algorithms were developed to establish predictive models for interpreting metabolite data. Metabolite profiling showed higher diagnostic specificity compared to SDHB-IHC (99.2% versus 92.5%, p = 0.021), whereas sensitivity was comparable. Application of machine learning algorithms to metabolite profiles improved predictive ability over that of the SFR, in particular for hard-to-interpret cases of head and neck paragangliomas (AUC 0.9821 versus 0.9613, p = 0.044). Importantly, the combination of metabolite profiling with SDHB-IHC has complementary utility, as SDHB-IHC correctly classified all but one of the false negatives from metabolite profiling strategies, while metabolite profiling correctly classified all but one of the false negatives/positives from SDHB-IHC. From 186 tumours with confirmed status of SDHx variant pathogenicity, the combination of the two methods resulted in 185 correct predictions, highlighting the benefits of both strategies for patient management. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Aprendizaje Automático , Metabolómica , Paraganglioma/diagnóstico por imagen , Feocromocitoma/diagnóstico , Succinato Deshidrogenasa/genética , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Estudios de Cohortes , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Mutación , Paraganglioma/genética , Paraganglioma/patología , Feocromocitoma/genética , Feocromocitoma/patologíaRESUMEN
BACKGROUND: Treatment options for severe ocular von Hippel-Lindau (VHL) disease are limited. This trial evaluated preliminary safety and potential efficacy of combination intravitreous injection with ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, and E10030, a PDGF inhibitor, for eyes with VHL disease-associated retinal hemangioblastoma (RH) not amenable or responsive to thermal laser photocoagulation. METHODS: This was a prospective, single-arm, open-label phase 1/2 study, comprised of three adults with VHL-associated RH and vision loss. Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were given unilaterally every 4 weeks in the study eye through 16 weeks, then every 8 weeks through 48 weeks. Supplementary standard care therapies were allowed without restriction after 40 weeks. The primary outcome was the ocular and systemic adverse effect profile at 52 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA), RH size, exudation, epiretinal proliferation and retinal traction, and need for ablative treatment of RH or ocular surgery at week 52. RESULTS: Three participants each received nine injections prior to week 52 and were followed for 104 weeks. One participant manifested mild episodic ocular hypertension in the study eye. Change in BCVA in the study eye at week 52 for the three participants was -5, -12 and +2 letters. No reduction in RH size was measured at 52 weeks. Variable mild improvements in exudation in two participants at week 16 were not sustained through week 52. CONCLUSIONS: Combination intravitreous injection with ranibizumab and E10030 demonstrated a reasonable preliminary safety profile, but limited treatment effect.
Asunto(s)
Aptámeros de Nucleótidos , Enfermedad de von Hippel-Lindau , Adulto , Inhibidores de la Angiogénesis/uso terapéutico , Aptámeros de Nucleótidos/uso terapéutico , Humanos , Inyecciones Intravítreas , Estudios Prospectivos , Ranibizumab/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Enfermedad de von Hippel-Lindau/tratamiento farmacológicoRESUMEN
The foundation of precision immunotherapy in oncology is rooted in computational biology and patient-derived sample sequencing to enrich for and target immunogenic epitopes. Discovery of these tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, these therapeutic successes are far from universal, especially with cancers that carry high intratumoral heterogeneity such as glioblastoma (GBM). Herein, we present the technical aspects of Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) vaccine immunotherapy, an investigational therapeutic that potentially circumvents the need for in silico tumor-neoantigen enrichment. We then review the most promising GBM vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluate the underlying principles that validate its clinical applicability. Finally, we showcase the translational potential of MBTA vaccination as a potential immunotherapy in GBM, along with established surgical and immunologic cancer treatment paradigms.
Asunto(s)
Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Antígenos CD40/inmunología , Glioblastoma/inmunología , Glioblastoma/terapia , Inmunoterapia/métodos , Animales , Células Presentadoras de Antígenos/química , Vacunas contra el Cáncer , Biología Computacional , Epítopos/química , Humanos , Inmunofenotipificación , Ligandos , Oncología Médica/tendencias , Ratones , Metástasis de la Neoplasia , Péptidos/química , Resultado del TratamientoRESUMEN
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human paraganglioma (PGL) samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1800 integral membrane proteins (IMPs). We found 45 "tumor enriched" proteins, i.e., proteins identified in all five PGLs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well-established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well-characterized human PPGL samples. Compared to control chromaffin tissue, PSMA was markedly overexpressed in high-risk PPGLs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including SDHB, VHL, and EPAS1 mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA overexpression in PPGLs which could translate to therapeutic and diagnostic applications of anti-PSMA radio-conjugates in high-risk PPGLs.