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2.
J Nucl Med ; 61(5): 665-670, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31836680

RESUMO

The σ2 receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide (18F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of 18F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether 18F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Methods: Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of 18F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of 18F-ISO-1 was quantitated by SUVmax and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Results: Tumor SUVmax (median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUVmax, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUVmax greater than the low-Ki-67 (<20%) group (P = 0.02). SUVmax exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46, P = 0.01, n = 29). Partial-volume-corrected SUVmax was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51, P = 0.02, n = 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (P > 0.05). Conclusion: 18F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adulto , Idoso , Transporte Biológico , Neoplasias da Mama/diagnóstico por imagem , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
3.
Mol Ther ; 28(1): 42-51, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31668558

RESUMO

Cell-based therapeutics have considerable promise across diverse medical specialties; however, reliable human imaging of the distribution and trafficking of genetically engineered cells remains a challenge. We developed positron emission tomography (PET) probes based on the small-molecule antibiotic trimethoprim (TMP) that can be used to image the expression of the Escherichia coli dihydrofolate reductase enzyme (eDHFR) and tested the ability of [18F]-TMP, a fluorine-18 probe, to image primary human chimeric antigen receptor (CAR) T cells expressing the PET reporter gene eDHFR, yellow fluorescent protein (YFP), and Renilla luciferase (rLuc). Engineered T cells showed an approximately 50-fold increased bioluminescent imaging signal and 10-fold increased [18F]-TMP uptake compared to controls in vitro. eDHFR-expressing anti-GD2 CAR T cells were then injected into mice bearing control GD2- and GD2+ tumors. PET/computed tomography (CT) images acquired on days 7 and 13 demonstrated early residency of CAR T cells in the spleen followed by on-target redistribution to the GD2+ tumors. This was corroborated by autoradiography and anti-human CD8 immunohistochemistry. We found a high sensitivity of detection for identifying tumor-infiltrating CD8 CAR T cells, ∼11,000 cells per mm3. These data suggest that the [18F]-TMP/eDHFR PET pair offers important advantages that could better allow investigators to monitor immune cell trafficking to tumors in patients.

4.
Nucl Med Commun ; 40(7): 727-733, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033780

RESUMO

OBJECTIVE: Determine the prevalence of benign indium-111 (In) pentetreotide uptake in the pancreatic head and determine if a semi-quantitative method can be used to differentiate physiologic from pathologic uptake. PATIENTS AND METHODS: Institutional Review Board-approved, HIPAA-compliant retrospective review of 197 somatostatin receptor scintigraphy studies performed in 136 patients, from December 2012 to November 2013 at a large academic medical center. The pancreatic head uptake was visually graded and for all positive cases, two-dimensional and three-dimensional ratios of the pancreatic head to normal liver uptake were calculated. Statistical analysis using paired and two-sample t-tests was performed. RESULTS: Nineteen of one hundred twenty-nine (14.7%) patients had benign In pentetreotide uptake in the pancreatic head. Seven of seven (100%) patients with neuroendocrine (NE) tumors had definite visual uptake. Uptake was 2.7× more likely benign than malignant. Using a three-dimensional region of interest (ROI) method, the pancreatic head-to-liver ratio was 0.91±0.38 (0.37-1.63) for benign uptake and 8.2±7.3 (1.79-23.6) for pathologic uptake (P<0.001). A threshold of 1.67 provided 100% accuracy for determining the presence or absence of a pancreatic head NE tumor. Using a two-dimensional ROI method, the uptake ratio was 0.88±0.37 (0.28-1.73) for benign and 7.5±6.2 (1.85-19.6) for pathologic uptake (P<0.001); a ratio threshold of 1.62 provided 97% accuracy. There was no difference between the uptake ratios at 4 and 24 h. CONCLUSION: In pentetreotide uptake in the pancreatic head is common and more frequently benign than malignant. Using simple ROI ratiometric methods helps to differentiate benign physiologic from malignant NE tumor uptake.


Assuntos
Pâncreas/diagnóstico por imagem , Pâncreas/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Somatostatina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/metabolismo , Estudos Retrospectivos , Somatostatina/metabolismo , Adulto Jovem
5.
Nat Med ; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515

RESUMO

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia , Transcriptoma , Evasão Tumoral
6.
Cytotherapy ; 20(12): 1415-1418, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30385043

RESUMO

Molecular imaging with 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is an established modality for response assessment in patients with lymphoma undergoing treatment. However, patients treated with novel immunotherapies may have false-positive PET/CT findings due to tumor site and systemic inflammation. In particular, treatment with autologous chimeric antigen receptor modified T-cells redirected at CD19 (CTL019 CAR-T cells) is often complicated by "cytokine release syndrome" (CRS) due to a severe systemic inflammatory reaction. Infiltration of tumors by activated CTL019 cells may impact radiographic and functional imaging findings. The role of PET/CT in patients treated with CTL019 has not previously been described. We performed a pilot, single-arm, prospective study to explore the utility of early PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) undergoing treatment with CTL019 CAR-T cells. Patients had PET/CT prior to CTL019 infusion and then early PET/CT at 1 month after treatment. The primary outcome was the amount/change in metabolically active tumor volume (MTV) and FDG uptake. We enrolled seven patients (DLBCL, three; FL, four). Six of 7 had baseline PET/CT with active disease. On post-treatment PET/CT, three patients had no residual MTV, two patients had a decrease in MTV and two patients had an increase in MTV. The three patients with no residual MTV all remain in remission >2 years post-treatment. The patients with less than complete response all subsequently relapsed. Development of CRS did not confound PET/CT findings. In patients with DLBCL and FL receiving CTL019 CAR-T cells, early PET/CT may predict response to this novel immunotherapy.

7.
Br J Cancer ; 119(10): 1200-1207, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30318516

RESUMO

BACKGROUND: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. METHODS: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. RESULTS: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. CONCLUSIONS: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. CLINICAL TRIAL REGISTRATION: NCT02303990 ( www.clinicaltrials.gov ).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Hipofracionamento da Dose de Radiação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/radioterapia , Neoplasias Cutâneas/patologia
8.
Clin Nucl Med ; 43(11): 864-866, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30222684

RESUMO

Neuroendocrine tumors have a propensity to metastasize, but rarely to the orbits. A 69-year-old woman with history of neuroendocrine tumor of pancreatic primary underwent routine follow-up In-pentetreotide (OctreoScan) imaging, with 24-hour whole-body planar images showing subtle right periorbital tracer uptake that localized to extraocular muscles on subsequent SPECT/CT. Orbital MRI further defined the location of these highly suspicious orbital metastases, which were treated with external radiation, with follow-up MRI showing decreased size of the orbital metastases. Early identification and treatment of orbital metastases is critical to help preserve vision and quality of life.


Assuntos
Neoplasias Induzidas por Radiação/secundário , Tumores Neuroendócrinos/secundário , Neoplasias Orbitárias/secundário , Compostos Radiofarmacêuticos/efeitos adversos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/efeitos adversos , Somatostatina/análogos & derivados , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética , Neoplasias Induzidas por Radiação/etiologia , Tumores Neuroendócrinos/etiologia , Neoplasias Orbitárias/etiologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Somatostatina/efeitos adversos
9.
J Clin Invest ; 128(5): 2116-2126, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29509546

RESUMO

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent. METHODS: We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient-derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology. RESULTS: We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2-12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r2 = 0.60). CONCLUSION: This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02637934. FUNDING: Research reported in this publication was supported by the Department of Defense OC160269, a Basser Center team science grant, NIH National Cancer Institute R01CA174904, a Department of Energy training grant DE-SC0012476, Abramson Cancer Center Radiation Oncology pilot grants, the Marsha Rivkin Foundation, Kaleidoscope of Hope Foundation, and Paul Calabresi K12 Career Development Award 5K12CA076931.


Assuntos
Meios de Contraste/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias , Transplante de Neoplasias , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo
10.
Clin Nucl Med ; 43(5): e139-e141, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29561521

RESUMO

A 25-year-old man with IgA deficiency was treated with 2 months of chemotherapy and proton therapy for gastroesophageal junction adenocarcinoma. Restaging PET/CT 18 days posttherapy demonstrated 2 new foci of increased FDG uptake in the left hepatic lobe, which were favored to represent radiation injury as opposed to new metastases. Follow-up MRI with contrast 2 weeks later demonstrated hypoenhancement and T1/T2 hypointensity in the liver, without restricted diffusion, which correlated with the dominant FDG-avid focus. The hepatic lesions resolved on subsequent FDG PET/CT and MRI studies, confirming the diagnosis of acute radiation injury.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Terapia com Prótons , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/radioterapia , Adulto , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/radioterapia , Fluordesoxiglucose F18 , Humanos , Neoplasias Hepáticas/secundário , Masculino , Compostos Radiofarmacêuticos
11.
Medicine (Baltimore) ; 96(19): e6676, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28489744

RESUMO

BACKGROUND: We performed a systematic review and meta-analysis to assess the roles of SPECT, PET, and MRS in distinguishing primary central nervous system lymphoma (PCNSL) from other focal brain lesions (FBLs) in human immunodeficiency virus (HIV)-infected patients. METHODS: PubMed, Scopus, and Medline were systematically searched for eligible studies from 1980 to 2016. Two authors extracted characteristics of patients and their lesions using predefined criteria. RESULTS: Eighteen studies on SPECT containing 667 patients, 6 studies on PET containing 108 patients, and 3 studies on MRS containing 96 patients were included. SPECT had a pooled sensitivity of 0.92 (95% CI: 0.85-0.96) and specificity of 0.84 (95% CI: 0.74-0.90) in differentiating PCNSL from other FBLs. For the 6 studies that used only pathology and/or serology as the gold standard, the pooled sensitivity was 0.85 (95% CI: 0.72-0.97) and the pooled specificity was 0.73 (95% CI: 0.54-0.92). CONCLUSION: SPECT has good diagnostic accuracy for discriminating PCNSL from other FBL-causing disorders in HIV patients. However, the actual sensitivity and specificity of SPECT may be lower than expected if only pathology and/or serology was used as the gold standard. PET may be superior but has less supporting clinical data and is more expensive.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Infecções por HIV/complicações , Linfoma/diagnóstico por imagem , Espectroscopia de Ressonância Magnética , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único , Neoplasias do Sistema Nervoso Central/complicações , Infecções por HIV/diagnóstico por imagem , Humanos , Linfoma/complicações
12.
Oncotarget ; 8(15): 24213-24223, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-27655645

RESUMO

Inhibition of thymidylate synthase (TS) results in a transient "flare" in DNA thymidine salvage pathway activity measurable with FLT ([18F]thymidine)-positron emission tomography (PET). Here we characterize this imaging strategy for potential clinical translation in non-small cell lung cancer (NSCLC). Since pemetrexed acts by inhibiting TS, we defined the kinetics of increases in thymidine salvage pathway mediated by TS inhibition following treatment with pemetrexed in vitro. Next, using a mouse model of NSCLC, we validated the kinetics of the pemetrexed-mediated "flare" in thymidine salvage pathway activity in vivo using FLT-PET imaging. Finally, we translated our findings into a proof-of-principle clinical trial of FLT-PET in a human NSCLC patient. In NSCLC cells in vitro, we identified a burst in pemetrexed-mediated thymidine salvage pathway activity, assessed by 3H-thymidine assays, thymidine kinase 1 (TK1) expression, and equilibrative nucleoside transporter 1 (ENT1) mobilization to the cell membrane, that peaked at 2hrs. This 2hr time-point was also optimal for FLT-PET imaging of pemetrexed-mediated TS inhibition in murine xenograft tumors and was demonstrated to be feasible in a NSCLC patient. FLT-PET imaging of pemetrexed-induced TS inhibition is optimal at 2hrs from therapy start; this timing is feasible in human clinical trials.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Pemetrexede/farmacologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Timidilato Sintase/antagonistas & inibidores , Timidilato Sintase/metabolismo , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Pemetrexede/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Timidina , Timidina Quinase/metabolismo , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Clin Nucl Med ; 42(1): 70-72, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27846002

RESUMO

A 66-year-old woman with a history of papillary thyroid cancer status after total thyroidectomy underwent I radioiodine ablation therapy 3 months after surgery. Posttherapy whole body planar imaging revealed focal intense I uptake in the posterior right abdomen. SPECT/CT of this region localized the uptake to the medial lower pole of the right kidney. Further evaluation with MRI demonstrated a correlative suspicious right renal mass. The patient underwent right partial nephrectomy with pathology demonstrating that the renal mass was of thyroidal origin (papillary subtype).


Assuntos
Carcinoma Papilar/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Idoso , Carcinoma Papilar/secundário , Carcinoma Papilar/cirurgia , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Neoplasias Renais/secundário , Neoplasias Renais/cirurgia , Imagem por Ressonância Magnética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia
14.
JAMA Oncol ; 3(5): 695-701, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28033451

RESUMO

Importance: Individualized cancer treatment, tailored to a particular patient and the tumor's biological features (precision oncology), requires a detailed knowledge of tumor biology. Biological characterization is typically performed on biopsy material, but this approach can present challenges for widespread and/or heterogeneous disease and for performing serial assays to infer changes in response to therapy. Molecular imaging is a complementary approach that provides noninvasive and quantitative measures of the in vivo biology of the full disease burden and is well suited to serial assay. Observations: Molecular imaging can provide unique information to guide precision oncology that includes measuring the regional expression of therapeutic targets, measuring drug pharmacokinetics, measuring therapy pharmacodynamics, and providing a marker of therapeutic efficacy that is highly indicative of outcome. Thus far, most trials of novel molecular imaging in oncology have been small, single-center trials. Only a few methods have progressed to multicenter trials and even fewer have become part of clinical practice. Conclusions and Relevance: Molecular imaging holds great promise for precision oncology, complementing tissue-based markers to guide more effective, less toxic, and more cost-effective cancer treatments. Beyond logistical and technical challenges, moving new imaging tests from the laboratory to the clinic requires a compelling use case that will benefit patients and/or improve cost-effectiveness, and it requires the collaboration of imagers, oncologists, and industry to reach its true clinical potential.


Assuntos
Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Medicina de Precisão/métodos , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tomografia por Emissão de Pósitrons/métodos
15.
Handb Clin Neurol ; 135: 209-227, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27432667

RESUMO

Positron emission tomography (PET) is a minimally invasive imaging procedure with a wide range of clinical and research applications. PET allows for the three-dimensional mapping of administered positron-emitting radiopharmaceuticals such as (18)F-fluorodeoxyglucose (for imaging glucose metabolism). PET enables the study of biologic function in both health and disease, in contrast to magnetic resonance imaging (MRI) and computed tomography (CT), that are more suited to study a body's morphologic changes, although functional MRI can also be used to study certain brain functions by measuring blood flow changes during task performance. This chapter first provides an overview of the basic physics principles and instrumentation behind PET methodology, with an introduction to the merits of merging functional PET imaging with anatomic CT or MRI imaging. We then focus on clinical neurologic disorders, and reference research on relevant PET radiopharmaceuticals when applicable. We then provide an overview of PET scan interpretation and findings in several specific neurologic disorders such as dementias, epilepsy, movement disorders, infection, cerebrovascular disorders, and brain tumors.


Assuntos
Encefalopatias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Fluordesoxiglucose F18 , Humanos , Imagem por Ressonância Magnética , Tomografia Computadorizada por Raios X
16.
Semin Nucl Med ; 46(1): 47-56, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26687857

RESUMO

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient's cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods as companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has "hit" the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2-targeted therapy. The review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic.


Assuntos
Imagem Molecular/métodos , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Humanos , Terapia de Alvo Molecular , Medicina de Precisão
18.
Cancer J ; 21(3): 218-24, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26049702

RESUMO

The ability to measure biochemical and molecular processes to guide cancer treatment represents a potentially powerful tool for trials of targeted cancer therapy. These assays have traditionally been performed by analysis of tissue samples. However, more recently, functional and molecular imaging has been developed that is capable of in vivo assays of cancer biochemistry and molecular biology and is highly complementary to tissue-based assays. Cancer imaging biomarkers can play a key role in increasing the efficacy and efficiency of therapeutic clinical trials and also provide insight into the biologic mechanisms that bring about a therapeutic response. Future progress will depend on close collaboration between imaging scientists and cancer physicians and on public and commercial sponsors, to take full advantage of what imaging has to offer for clinical trials of targeted cancer therapy. This review will provide examples of how molecular imaging can inform targeted cancer clinical trials and clinical decision making by (1) measuring regional expression of the therapeutic target, (2) assessing early (pharmacodynamic) response to treatment, and (3) predicting therapeutic outcome. The review includes a discussion of basic principles of molecular imaging biomarkers in cancer, with an emphasis on those methods that have been tested in patients. We then review clinical trials designed to evaluate imaging tests as integrated markers embedded in a therapeutic clinical trial with the goal of validating the imaging tests as integral markers that can aid patient selection and direct response-adapted treatment strategies. Examples of recently completed multicenter trials using imaging biomarkers are highlighted.


Assuntos
Biomarcadores Tumorais/genética , Imagem Molecular , Terapia de Alvo Molecular , Neoplasias/diagnóstico por imagem , Ensaios Clínicos como Assunto , Perfilação da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Radiografia
19.
Cancer ; 120(22): 3433-45, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24947987

RESUMO

Positron emission tomography (PET) is a radiotracer imaging method that yields quantitative images of regional in vivo biology and biochemistry. PET, now used in conjunction with computed tomography (CT) in PET/CT devices, has had its greatest impact to date on cancer and is now an important part of oncologic clinical practice and translational cancer research. In this review of current applications and future directions for PET/CT in cancer, the authors first highlight the basic principles of PET followed by a discussion of the biochemistry and current clinical applications of the most commonly used PET imaging agent, (18) F-fluorodeoxyglucose (FDG). Then, emerging methods for PET imaging of other biologic processes relevant to cancer are reviewed, including cellular proliferation, tumor hypoxia, apoptosis, amino acid and cell membrane metabolism, and imaging of tumor receptors and other tumor-specific gene products. The focus of the review is on methods in current clinical practice as well as those that have been translated to patients and are currently in clinical trials.


Assuntos
Neoplasias/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Apoptose , Hipóxia Celular , Proliferação de Células , Didesoxinucleosídeos , Fluordesoxiglucose F18 , Humanos , Imagem Multimodal , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico
20.
Ann Nucl Med ; 27(7): 618-24, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23572210

RESUMO

OBJECTIVE: One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [(11)C]N-desmethyl-loperamide ([(11)C]dLop), for measuring P-gp function in the rat brain. METHODS: The precursor to [(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [(11)C]methyl iodide. [(11)C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function. RESULTS: Plasma levels of parent [(11)C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [(11)C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1). CONCLUSIONS: The rat brain demonstrates significantly increased uptake of [(11)C]dLop after P-gp inhibition. [(11)C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Loperamida/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ciclosporina/farmacologia , Cinética , Masculino , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
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