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Molecular imaging has emerged as an integral part of oncologic imaging. Given the physiologic changes that precede anatomic changes, molecular imaging can enable early detection of disease and monitoring of response. [18F] Fluorodeoxyglucose (FDG) Positron emission tomography (PET) is the predominant molecular imaging modality used in oncologic assessment and can be performed using PET/CT or PET/MR. In pediatric patients, PET/MRI imaging is generally preferred due to low radiation exposure and PET/MRI is particularly advantageous for imaging musculoskeletal (MSK) diseases, as MRI provides superior characterization of tissue changes as compared to CT. In this article, we provide an overview of the typical role of PET CT/MRI in assessment of some common pediatric malignancies and benign MSK diseases with case examples. We also discuss the relative advantages of PET/MRI compared to PET/CT, and review published data with a primary focus on the use of PET/MR.
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Imagen por Resonancia Magnética , Enfermedades Musculoesqueléticas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Imagen por Resonancia Magnética/métodos , Enfermedades Musculoesqueléticas/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Niño , Imagen Multimodal/métodos , Imagen Molecular/métodosRESUMEN
Soft tissue sarcomas are a rare and heterogenous group of tumors that account for 2% of all cancer-related deaths. Molecular imaging with FDG PET can offer valuable metabolic information to help inform clinical management of soft tissue sarcomas that is unique and complementary to conventional diagnostic imaging techniques. FDG PET imaging often correlates with tumor grade, can help guide biopsy, and frequently detects additional sites of disease compared to conventional imaging in patients being considered for definitive or salvage therapy. Traditional size-based evaluation of treatment response is often inadequate in soft tissue sarcoma and changes in metabolic activity can add significant value to interim and end of treatment imaging for high-grade sarcomas. FDG PET can be used for detection of recurrence or malignant transformation and thus play a vital role in surveillance. This article reviews the evolving role of FDG PET in initial diagnosis, staging, treatment response assessment, and restaging. Further studies on the use of FDG PET in soft sarcoma are needed, particularly for rare histopathologic subtypes.
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Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Sarcoma , Humanos , Sarcoma/diagnóstico por imagen , Sarcoma/patología , Tomografía de Emisión de Positrones/métodos , Imagen Molecular/métodosRESUMEN
ABSTRACT: DOTATATE PET/CT is frequently used to evaluate indeterminant pulmonary nodules suspected to be pulmonary carcinoid. We report an unexpected case of pulmonary hamartoma demonstrating 64Cu-DOTATATE uptake in a 43-year-old woman with a slowly enlarging pulmonary nodule. Histopathological staining showed somatostatin receptor 2 expression on vascular endothelial cells and a proportion of cartilage and smooth muscle cells within the hamartoma.
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Hamartoma , Neoplasias Pulmonares , Tumores Neuroendocrinos , Compuestos Organometálicos , Femenino , Humanos , Adulto , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioisótopos de Cobre , Tumores Neuroendocrinos/patología , Células Endoteliales/patología , Receptores de Somatostatina/metabolismo , Compuestos Organometálicos/metabolismo , Neoplasias Pulmonares/patología , Hamartoma/diagnóstico por imagenRESUMEN
There has been tremendous growth in the development of theragnostics for personalized cancer diagnosis and treatment over the past two decades. In prostate cancer, the new generation of prostate specific membrane antigen (PSMA) small molecular inhibitor-based imaging agents achieve extraordinary tumor to background ratios and allow their therapeutic counterparts to deliver effective tumor doses while minimizing normal tissue toxicity. The PSMA targeted small molecule positron emission tomography (PET) agents 18F-DCFPyL (2-(3-{1-carboxy-5-((6-(18)F-fluoro-pyridine-3-carbonyl)-amino)-pentyl}-ureido)-pentanedioic acid) and Gallium-68 (68Ga)-PSMA-11 have been approved by the United States Food and Drug Administration (FDA) for newly diagnosed high risk prostate cancer patients and for patients with biochemical recurrence. More recently, the Phase III VISION trial showed that Lutetium-177 (177Lu)-PSMA-617 treatment increases progression-free survival and overall survival in patients with heavily pre-treated advanced PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we review the PSMA targeted theragnostic pairs under clinical investigation for detection and treatment of metastatic prostate cancer.
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OBJECTIVE: To show that augmented reality (AR) visualization of single-photon emission computed tomography (SPECT)/computed tomography (CT) data in 3D can be used to accurately localize targets in the head and neck region. MATERIALS AND METHODS: Eight head and neck styrofoam phantoms were painted with a mixture of radioactive solution (Tc-99m) detectable with a handheld gamma probe and fluorescent ink visible only under ultraviolet (UV) light to create 10-20 simulated lymph nodes on their surface. After obtaining SPECT/CT images of these phantoms, virtual renderings of the nodes were generated from the SPECT/CT data and displayed using a commercially available AR headset. For each of three physician evaluators, the time required to localize lymph node targets was recorded (1) using the gamma probe alone and (2) using the gamma probe while wearing the AR headset. In addition, the surface localization accuracy when using the AR headset was evaluated by measuring the misalignment between the locations visually marked by the evaluators and the ground truth locations identified using UV stimulation of the ink at the site of the nodes. RESULTS: For all three evaluators, using the AR headset significantly reduced the time to detect targets (P = 0.012, respectively) compared to using the gamma probe alone. The average misalignment between the location marked by the evaluators and the ground truth location was 8.6 mm. CONCLUSION: AR visualization of SPECT/CT data in 3D allows for accurate localization of targets in the head and neck region, and may reduce the localization time of targets.
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Realidad Aumentada , Melanoma , Ganglio Linfático Centinela , Humanos , Melanoma/diagnóstico por imagen , Melanoma/patología , Melanoma/cirugía , Biopsia del Ganglio Linfático Centinela/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Post-transplant lymphoproliferative disorders (PTLD) are a spectrum of heterogeneous lymphoproliferative conditions that are serious and possibly fatal complications after solid organ or allogenic hematopoietic stem cell transplantation. Most PTLD are attributed to Epstein-Barr virus reactivation in B-cells in the setting of immunosuppression after transplantation. Early diagnosis, accurate staging, and timely treatment are of vital importance to reduce morbidity and mortality. Given the often nonspecific clinical presentation and disease heterogeneity of PTLD, tissue biopsy and histopathological analysis are essential to establish diagnosis and most importantly, determine the subtype of PTLD, which guides treatment options. Advanced imaging modalities such as 18F-FDG PET/CT have played an increasingly important role and have shown high sensitivity and specificity in detection, staging, and assessing treatment response in multiple clinical studies over the last two decades. However, larger multicenter prospective validation is still needed to further establish the clinical utility of PET imaging in the management of PTLD. Significantly, new hybrid imaging modalities such as PET/MR may help reduce radiation exposure, which is especially important in pediatric transplant patients.
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Infecciones por Virus de Epstein-Barr , Trastornos Linfoproliferativos , Niño , Fluorodesoxiglucosa F18 , Herpesvirus Humano 4 , Humanos , Trastornos Linfoproliferativos/diagnóstico por imagen , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia , Estudios Multicéntricos como Asunto , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de PositronesRESUMEN
PURPOSE: To evaluate the diagnostic performance and clinical utility of 18F-fluciclovine PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). METHODS: 18F-Fluciclovine scans of 165 consecutive men with BCR after primary definitive treatment with prostatectomy (n = 102) or radiotherapy (n = 63) were retrospectively evaluated. Seventy patients had concurrent imaging with at least one other conventional modality (CT (n = 31), MRI (n = 31), or bone scan (n = 26)). Findings from 18F-fluciclovine PET were compared with those from conventional imaging modalities. The positivity rate and impact of 18F-fluciclovine PET on patient management were recorded. In 33 patients who underwent at least one other PET imaging (18F-NaF PET/CT (n = 12), 68Ga-PSMA11 PET/CT (n = 5), 18F-DCFPyL PET/CT (n = 20), and 68Ga-RM2 PET/MRI (n = 5)), additional findings were evaluated. RESULTS: The overall positivity rate of 18F-fluciclovine PET was 67 %, which, as expected, increased with higher prostate-specific antigen (PSA) levels (ng/ml): 15 % (PSA < 0.5), 50 % (0.5 ≤ PSA < 1), 56 % (1 ≤ PSA < 2), 68 % (2 ≤ PSA < 5), and 94 % (PSA ≥ 5), respectively. One hundred and two patients (62 %) had changes in clinical management based on 18F-fluciclovine PET findings. Twelve of these patients (12 %) had lesion localization on 18F-fluciclovine PET, despite negative conventional imaging. Treatment plans of 14 patients with negative 18F-fluciclovine PET were changed based on additional PET imaging with a different radiopharmaceutical. CONCLUSION: 18F-Fluciclovine PET/CT remains a useful diagnostic tool in the workup of patients with BCR PC, changing clinical management in 62 % of participants in our cohort.
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Ácidos Carboxílicos , Ciclobutanos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Radiofármacos , Estudios RetrospectivosRESUMEN
Fungal endocarditis is a rare subtype of infective endocarditis that often presents with nonspecific symptoms in patients with complex medical histories, making diagnosis challenging. Patients with a history of ALL may present with congestive heart failure, chemo-induced cardiomyopathy, acute coronary syndrome, cardiac lymphomatous metastasis, or infections. We present the case of a patient with a history of ALL who presented with acute coronary syndrome and imaging concerning for primary cardiac lymphoma, when in fact the patient ended up suffering from culture proven fungal endocarditis.
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18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoropyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) is a promising PET radiopharmaceutical targeting prostate-specific membrane antigen (PSMA). We present our experience with this single-academic-center prospective study evaluating the positivity rate of 18F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52-91 y old; mean ± SD, 71.5 ± 7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by 2 independent readers. Fifty-nine patients had scans concurrent with at least one other conventional scan: bone scanning (24), CT (21), MR (20), 18F-fluciclovine PET/CT (18), or 18F-NaF PET (14). Findings from 18F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on 18F-DCFPyL PET/CT was recorded from clinical chart review. Results:18F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate-specific antigen (PSA) levels (ng/mL): 50% (PSA < 0.5), 69% (0.5 ≤ PSA < 1), 100% (1 ≤ PSA < 2), 91% (2 ≤ PSA < 5), and 96% (PSA ≥ 5). 18F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20 of 41 (49%) CT or MRI scans had findings congruent with 18F-DCFPyL, whereas 18F-DCFPyL PET was positive in 17 of 41 (41%) cases with negative CT or MRI findings. For bone imaging, 26 of 38 (68%) bone or 18F-NaF PET scans were congruent with 18F-DCFPyL PET, whereas 18F-DCFPyL PET localized bone lesions in 8 of 38 (21%) patients with negative results on bone or 18F-NaF PET scans. In 8 of 18 (44%) patients, 18F-fluciclovine PET had located the same lesions as did 18F-DCFPyL PET, whereas 5 of 18 (28%) patients with negative 18F-fluciclovine findings had positive 18F-DCFPyL PET findings and 1 of 18 (6%) patients with negative 18F-DCFPyL findings had uptake in the prostate bed on 18F-fluciclovine PET. In the remaining 4 of 18 (22%) patients, 18F-DCFPyL and 18F-fluciclovine scans showed different lesions. Lastly, 43 of 72 (60%) patients had treatment changes after 18F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on 18F-DCFPyL PET, despite negative results on conventional imaging. Conclusion:18F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent PC, given the high positivity rate as compared with Food and Drug Administration-approved currently available imaging modalities and its impact on clinical management in 60% of patients.
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Centros Médicos Académicos , Lisina/análogos & derivados , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/metabolismo , Urea/análogos & derivados , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Antígeno Prostático Específico/metabolismo , RecurrenciaRESUMEN
[This corrects the article DOI: 10.1038/celldisc.2016.45.].
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Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner's syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance.
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Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Histonas/metabolismo , Mitocondrias/metabolismo , Acortamiento del Telómero/genética , Telómero/metabolismo , Acetilación , Animales , Línea Celular , Transformación Celular Neoplásica/genética , Inestabilidad Cromosómica/fisiología , Epigénesis Genética/fisiología , Fibroblastos , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Humanos , Lisina/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Mutación , Telomerasa/metabolismoRESUMEN
BACKGROUND: The purpose of this study was to determine the value of magnetic resonance imaging (MRI) and ultrasound-based imaging strategies in the evaluation of a hypothetical population with a symptomatic full-thickness supraspinatus tendon (FTST) tear using formal cost-effectiveness analysis. METHODS: A decision analytic model from the health care system perspective for 60-year-old patients with symptoms secondary to a suspected FTST tear was used to evaluate the incremental cost-effectiveness of 3 imaging strategies during a 2-year time horizon: MRI, ultrasound, and ultrasound followed by MRI. Comprehensive literature search and expert opinion provided data on cost, probability, and quality of life estimates. The primary effectiveness outcome was quality-adjusted life-years (QALYs) through 2 years, with a willingness-to-pay threshold set to $100,000/QALY gained (2016 U.S. dollars). Costs and health benefits were discounted at 3%. RESULTS: Ultrasound was the least costly strategy ($1385). MRI was the most effective (1.332 QALYs). Ultrasound was the most cost-effective strategy but was not dominant. The incremental cost-effectiveness ratio for MRI was $22,756/QALY gained, below the willingness-to-pay threshold. Two-way sensitivity analysis demonstrated that MRI was favored over the other imaging strategies over a wide range of reasonable costs. In probabilistic sensitivity analysis, MRI was the preferred imaging strategy in 78% of the simulations. CONCLUSION: MRI and ultrasound represent cost-effective imaging options for evaluation of the patient thought to have a symptomatic FTST tear. The results indicate that MRI is the preferred strategy based on cost-effectiveness criteria, although the decision between MRI and ultrasound for an imaging center is likely to be dependent on additional factors, such as available resources and workflow.
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Imagen por Resonancia Magnética/economía , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Ultrasonografía/economía , Análisis Costo-Beneficio , Humanos , Persona de Mediana Edad , Probabilidad , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Literatura de Revisión como Asunto , Lesiones del Manguito de los Rotadores/complicacionesRESUMEN
Neutral sphingomyelinase 2 (nSMase2, product of the SMPD3 gene) is a key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication. nSMase2 is activated by diverse stimuli, including the anionic phospholipid phosphatidylserine. Phosphatidylserine binds to an integral-membrane N-terminal domain (NTD); however, how the NTD activates the C-terminal catalytic domain is unclear. Here, we identify the complete catalytic domain of nSMase2, which was misannotated because of a large insertion. We find the soluble catalytic domain interacts directly with the membrane-associated NTD, which serves as both a membrane anchor and an allosteric activator. The juxtamembrane region, which links the NTD and the catalytic domain, is necessary and sufficient for activation. Furthermore, we provide a mechanistic basis for this phenomenon using the crystal structure of the human nSMase2 catalytic domain determined at 1.85-Å resolution. The structure reveals a DNase-I-type fold with a hydrophobic track leading to the active site that is blocked by an evolutionarily conserved motif which we term the "DK switch." Structural analysis of nSMase2 and the extended N-SMase family shows that the DK switch can adopt different conformations to reposition a universally conserved Asp (D) residue involved in catalysis. Mutation of this Asp residue in nSMase2 disrupts catalysis, allosteric activation, stimulation by phosphatidylserine, and pharmacological inhibition by the lipid-competitive inhibitor GW4869. Taken together, these results demonstrate that the DK switch regulates ceramide generation by nSMase2 and is governed by an allosteric interdomain interaction at the membrane interface.
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Sitio Alostérico , Ceramidas/biosíntesis , Esfingomielina Fosfodiesterasa/química , Compuestos de Anilina/química , Compuestos de Bencilideno/química , Dominio Catalítico , Membrana Celular/metabolismo , Cristalografía por Rayos X , Humanos , Lípidos/química , Células MCF-7 , Unión Proteica , Pliegue de Proteína , Saccharomyces cerevisiae , Transducción de SeñalRESUMEN
Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced transcription coactivator hnRNAP2 acetylates Lys 8 of H4 through an intrinsic histone lysine acetyltransferase (KAT) activity with Arg 48 and Arg 50 of hnRNAP2 being essential for acetyl-CoA binding and acetyltransferase activity. H4K8 acetylation at the mitochondrial stress-responsive promoters by hnRNAP2 is essential for transcriptional activation. We found that the previously described mitochondria-to-nucleus retrograde signaling-mediated transformation of C2C12 cells caused an increased expression of genes involved in various oncogenic processes, which is retarded in hnRNAP2 silenced or hnRNAP2 KAT mutant cells. Taken together, these data show that altered gene expression by mitochondria-to-nucleus retrograde signaling involves a novel hnRNAP2-dependent epigenetic mechanism that may have a role in cancer and other pathologies.
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Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.
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Compuestos Macrocíclicos/farmacología , Oligopéptidos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Compuestos Macrocíclicos/química , Modelos Moleculares , Estructura Molecular , Oligopéptidos/química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Familia-src Quinasas/metabolismoRESUMEN
8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) has high mutagenic potential as it is prone to mispair with deoxyadenine (dA). In order to maintain genomic integrity, post-replicative 8-oxo-dG:dA mispairs are removed through DNA polymerase lambda (Pol λ)-dependent MUTYH-initiated base excision repair (BER). Here, we describe seven novel crystal structures and kinetic data that fully characterize 8-oxo-dG bypass by Pol λ. We demonstrate that Pol λ has a flexible active site that can tolerate 8-oxo-dG in either the anti- or syn-conformation. Importantly, we show that discrimination against the pro-mutagenic syn-conformation occurs at the extension step and identify the residue responsible for this selectivity. This residue acts as a kinetic switch, shunting repair toward long-patch BER upon correct dCMP incorporation, thus enhancing repair efficiency. Moreover, this switch also provides a potential mechanism to increase repair fidelity of MUTYH-initiated BER.