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1.
J Nucl Med ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38782459

RESUMO

Despite the inclusion of multiple agents within the prostate cancer treatment landscape, new treatment options are needed to address the unmet need for patients with metastatic castration-resistant prostate cancer (mCRPC). Although prostate-specific membrane antigen is the only cell-surface target to yield clinical benefit in men with advanced prostate cancer, additional targets may further advance targeted immune, cytotoxic, radiopharmaceutical, and other tumor-directed therapies for these patients. Human kallikrein 2 (hK2) is a novel prostate-specific target with little to no expression in nonprostate tissues. This first-in-human phase 0 trial uses an 111In-radiolabeled anti-hK2 monoclonal antibody, [111In]-DOTA-h11B6, to credential hK2 as a potential target for prostate cancer treatment. Methods: Participants with progressive mCRPC received a single infusion of 2 mg of [111In]-DOTA-h11B6 (185 MBq of 111In), with or without 8 mg of unlabeled h11B6 to assess antibody mass effects. Sequential imaging and serial blood samples were collected to determine [111In]-DOTA-h11B6 biodistribution, dosimetry, serum radioactivity, and pharmacokinetics. Safety was assessed within a 2-wk follow-up period from the time of [111In]-DOTA-h11B6 administration. Results: Twenty-two participants received [111In]-DOTA-h11B6 and are included in this analysis. Within 6-8 d of administration, [111In]-DOTA-h11B6 visibly accumulated in known mCRPC lesions, with limited uptake in other organs. Two treatment-emergent adverse events unrelated to treatment occurred, including tumor-related bleeding in 1 patient, which led to early study discontinuation. Serum clearance, biodistribution, and tumor targeting were independent of total antibody mass (2 or 10 mg). Conclusion: This first-in-human study demonstrates that tumor-associated hK2 can be identified and targeted using h11B6 as a platform as the h11B6 antibody selectively accumulated in mCRPC metastases with mass-independent clearance kinetics. These data support the feasibility of hK2 as a target for imaging and hK2-directed agents as potential therapies in patients with mCRPC.

2.
Transl Oncol ; 37: 101767, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37657154

RESUMO

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

3.
Clin Lymphoma Myeloma Leuk ; 20(11): 749-756.e1, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32800518

RESUMO

BACKGROUND: Mantle-cell lymphoma (MCL) is sensitive to radiotherapy, and the CD20 antigen is relatively highly expressed in MCL. Therefore, radioimmunotherapy using radiolabeled anti-CD20 monoclonal antibodies has the potential to treat MCL. The objective of this study was to investigate the efficacy, pharmacokinetics, and safety of tositumomab (TST) and iodine-131 tositumomab (I-131 TST) followed by 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with previously untreated MCL (ClinicalTrials.govNCT00022945). PATIENTS AND METHODS: In this phase 2 open-label study, patients received dosimetric (day 0: 450 mg TST, then 35 mg I-131 TST [5 mCi]) and therapeutic (between days 7 and 14: 450 mg TST, then an individualized dose of I-131 TST [65-75 cGy]) TST/I-131 TST, with CHOP treatment commencing approximately 13 weeks after the therapeutic dose. The primary end point was the MCL response rate to treatment; secondary end points included confirmed complete response rate and total body residence time. RESULTS: Twenty-six patients were enrolled, and 25 were included in the intent-to-treat population. The overall unconfirmed response rate was 84%, and the confirmed complete response rate was 44%. The median progression free-survival was 27.6 months. The median total body residence time was 94.5 hours. No new or unexpected safety signals were identified. CONCLUSION: Patients with previously untreated MCL who received radioimmunotherapy with TST/I-131 TST followed by CHOP had a high response rate and a long duration of response, indicating that radioimmunotherapy is a therapeutic option in this patient population.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
4.
Psychopharmacology (Berl) ; 237(2): 519-527, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773210

RESUMO

RATIONALE: F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917-1924, 2019). OBJECTIVE: This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [11C]-(+)-PHNO. METHODS: PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC50) calculated. RESULTS: Both doses of F17464 robustly blocked [11C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h post-administration, which increased at 6-9 h (89-98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%). F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC50 was 19 ng ml-1 (~ 40 nM). CONCLUSION: Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.


Assuntos
Antipsicóticos/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores de Dopamina D3/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
6.
Ann Surg Oncol ; 22(10): 3296-301, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26202566

RESUMO

BACKGROUND: As many as 40 % of breast cancer patients undergoing axillary lymph node dissection (ALND) and radiotherapy develop lymphedema. We report our experience performing lymphatic-venous anastomosis using the lymphatic microsurgical preventive healing approach (LYMPHA) at the time of ALND. This technique was described by Boccardo, Campisi in 2009. METHODS: LYMPHA was offered to node-positive women with breast cancer requiring ALND. Afferent lymphatic vessels, identified by injection of blue dye in the ipsilateral arm, were sutured into a branch of the axillary vein distal to a competent valve. Follow-up was with pre- and postoperative lymphoscintigraphy, arm measurements, and (L-Dex®) bioimpedance spectroscopy. RESULTS: Over 26 months, 37 women underwent attempted LYMPHA, with successful completion in 27. Unsuccessful attempts were due to lack of a suitable vein (n = 3) and lymphatic (n = 5) or extensive axillary disease (n = 1). There were no LYMPHA-related complications. Mean follow-up time was 6 months (range 3-24 months). Among completed patients, 10 (37%) had a body mass index of ≥30 kg/m(2) (mean 27.9 ± 6.8 kg/m(2), range 17.4-47.6 kg/m(2)), and 17 (63%) received axillary radiotherapy. Excluding two patients with preoperative lymphedema and those with less than 3-month follow-up, the lymphedema rate was 3 (12.5%) of 24 in successfully completed and 4 (50 %) of 8 in unsuccessfully treated patients. CONCLUSIONS: Our transient lymphedema rate in this high-risk cohort of patients was 12.5%. Early data show that LYMPHA is feasible, safe, and effective for the primary prevention of breast cancer-related lymphedema.


Assuntos
Neoplasias da Mama/cirurgia , Excisão de Linfonodo/efeitos adversos , Vasos Linfáticos/cirurgia , Linfedema/prevenção & controle , Complicações Pós-Operatórias , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Linfedema/diagnóstico , Linfedema/etiologia , Microcirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prevenção Primária , Prognóstico , Estudos Retrospectivos
7.
EJNMMI Res ; 5: 28, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25984435

RESUMO

BACKGROUND: J591 is a monoclonal antibody that targets the external domain of the prostate-specific membrane antigen (PSMA). Besides prostate cancer cells, it also targets the neovasculature of non-prostate solid tumors. We provide an analysis of the antibody mass-dose dependency of lesion uptake and normal tissue retention, together with an assessment of lesion detectability using (111)In-J591 imaging, compared with conventional imaging in patients with a variety of solid tumors. METHODS: Twenty patients in six cohorts received fixed amounts (5, 10, 20, 40, 60, and 100 mg) of J591 in a phase I trial. A maximum of four administrations per patient was given, with each administration separated by 3 weeks. All antibody administrations included 370 MBq (10 mCi) of (111)In labeled to 2 mg of J591 via the chelating agent DOTA. Three whole body (WB) gamma camera scans with at least one SPECT scan, along with multiple WB count-rate measurements and blood samples, were obtained for all patients. The effect of escalating antibody mass on lesion uptake and normal tissue retention was evaluated using lesion, liver, serum, and WB residence times and ratios thereof for each treatment cycle. Lesion detectability using (111)In-J591 imaging was compared to the standard imaging on a lesion-by-lesion basis. RESULTS: A total of 170 lesions in 20 patients were detected by standard or (111)In-J591 imaging. (111)In-J591 targeted both skeletal and soft tissue diseases in all tumor types. (111)In-J591 imaging identified 74% (20/27) of skeletal lesions, 53% (18/34) of nodes, and 64% (70/109) of other soft tissue/organ lesions. There was increasing (111)In-J591 uptake in lesions with increasing antibody mass-dose, coupled with decreasing retention in the liver for increments up to 20 mg, and no significant change at higher antibody mass. CONCLUSIONS: Radiolabeled J591 antibody has potential as a targeting agent for solid tumor vasculature and lesion detection. Bone and soft tissue lesions arising from tumors of diverse origin were targeted by the anti-PSMA antibody J591. For the detection of lesions in these tumors by J591 antibody scans, an antibody mass of 20 mg is adequate. The optimal time of imaging is 5 to 7 days post-injection.

8.
Clin Cancer Res ; 20(23): 5888-97, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25294899

RESUMO

Detection of lytic bone lesions is crucial in the workup for multiple myeloma and very often dictates the decision to start treatment. Conventional radiography, despite decades of use, is often insufficient for detection of bone disease in multiple myeloma. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Novel whole-body low-dose computed tomography (WBLDCT) protocols allow for collection of superior image detail of the skeleton at doses of radiation similar to those used for conventional planar radiography. Several studies have shown that WBLDCT has a superior detection rate for lytic bone lesions compared with whole-body X-ray (WBXR), potentially leading to restaging and changes in therapy. MRI and PET provide imaging data important for assessing disease activity and prognostication. Because of several advantages over WBXR, WBLDCT is already the standard imaging technique for use in patients with multiple myeloma in many European institutions. However, the radiographic skeletal survey or WBXR is still the initial study of choice used to screen for myeloma bone disease in many institutions. In this review, we aim to explore the changing landscape of imaging for myeloma bone disease through use of modern imaging techniques.


Assuntos
Doenças Ósseas/diagnóstico , Doenças Ósseas/etiologia , Diagnóstico por Imagem/métodos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total , Humanos , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos
9.
Cancer Biol Ther ; 15(4): 443-51, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24553243

RESUMO

UNLABELLED: Tumor endothelial marker 1 (TEM1, endosialin) is a tumor vascular marker with significant diagnostic and therapeutic potential. However, in vivo small animal models to test affinity reagents specifically targeted to human (h)TEM1 are limited. We describe a new mouse tumor model where tumor vascular endothelial cells express hTEM1 protein. METHODS: Immortalized murine endothelial cells MS1 were engineered to express hTEM1 and firefly luciferase and were inoculated in nude mice either alone, to form hemangioma-like endothelial grafts, or admixed with ID8 ovarian tumor cells, to form chimeric endothelial-tumor cell grafts. MORAb-004, a monoclonal humanized IgG 1 antibody specifically recognizing human TEM1 was evaluated for targeted theranostic applications, i.e., for its ability to affect vascular grafts expressing hTEM1 as well as being a tool for molecular positron emission tomography (PET) imaging. RESULTS: Naked MORAb-004 treatment of mice bearing angioma grafts or chimeric endothelial-tumor grafts significantly suppressed the ability of hTEM1-positive endothelial cells, but not control endothelial cells, to form grafts and dramatically suppressed local angiogenesis. In addition, highly efficient radioiodination of MORAb-004 did not impair its affinity for hTEM1, and [ (124)I]-MORAb-004-PET enabled non-invasive visualization of tumors enriched with hTEM1-positive, but not hTEM1 negative vasculature with high degree of specificity and sensitivity. CONCLUSION: The development of a new robust endothelial graft model expressing human tumor vascular proteins will help accelerate the development of novel theranostics targeting the tumor vasculature, which exhibit affinity specifically to human targets but not their murine counterparts. Our results also demonstrate the theranostic potential of MORAb-004 as PET imaging tracer and naked antibody therapy for TEM1-positive tumor.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/terapia , Compostos Radiofarmacêuticos/farmacocinética , Animais , Linhagem Celular Tumoral , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/metabolismo , Xenoenxertos , Radioisótopos do Iodo , Camundongos Nus , Neoplasias Experimentais/irrigação sanguínea , Tomografia por Emissão de Pósitrons , Distribuição Tecidual
10.
J Nucl Med ; 55(3): 500-507, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24525208

RESUMO

UNLABELLED: Tumor endothelial marker 1 (TEM1/endosialin) is a tumor vascular marker highly overexpressed in multiple human cancers with minimal expression in normal adult tissue. In this study, we report the preparation and evaluation of (124)I-MORAb-004, a humanized monoclonal antibody targeting an extracellular epitope of human TEM1 (hTEM1), for its ability to specifically and sensitively detect vascular cells expressing hTEM1 in vivo. METHODS: MORAb-004 was directly iodinated with (125)I and (124)I, and in vitro binding and internalization parameters were characterized. The in vivo behavior of radioiodinated MORAb-004 was characterized in mice bearing subcutaneous ID8 tumors enriched with mouse endothelial cells expressing hTEM1 and by biodistribution and small-animal immuno-PET studies. RESULTS: MORAb-004 was radiolabeled with high efficiency and isolated in high purity. In vitro studies demonstrated specific and sensitive binding of MORAb-004 to MS1 mouse endothelial cells expressing hTEM1, with no binding to control MS1 cells. (125)I-MORAb-004 and (124)I-MORAb-004 both had an immunoreactivity of approximately 90%. In vivo biodistribution experiments revealed rapid, highly specific and sensitive uptake of MORAb-004 in MS1-TEM1 tumors at 4 h (153.2 ± 22.2 percentage injected dose per gram [%ID/g]), 24 h (127.1 ± 42.9 %ID/g), 48 h (130.3 ± 32.4 %ID/g), 72 h (160.9 ± 32.1 %ID/g), and 6 d (10.7 ± 1.8 %ID/g). Excellent image contrast was observed with (124)I-immuno-PET. MORAb-004 uptake was statistically higher in TEM1-positive tumors than in control tumors. Binding specificity was confirmed by blocking studies using excess nonlabeled MORAb-004. CONCLUSION: In our preclinical model, with hTEM1 exclusively expressed on engineered murine endothelial cells that integrate into the tumor vasculature, (124)I-MORAb-004 displays high tumor-to-background tissue contrast for detection of hTEM1 in easily accessible tumor vascular compartments. These studies strongly suggest the clinical utility of (124)I-MORAb-004 immuno-PET in assessing TEM1 tumor-status.


Assuntos
Anticorpos Monoclonais , Antígenos CD/imunologia , Vasos Sanguíneos/metabolismo , Proteínas de Neoplasias/imunologia , Neoplasias/irrigação sanguínea , Tomografia por Emissão de Pósitrons/métodos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Linhagem Celular , Feminino , Humanos , Radioisótopos do Iodo , Marcação por Isótopo , Camundongos
11.
Cancer ; 120(1): 77-85, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24108668

RESUMO

BACKGROUND: Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS: A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m(2) loading, 250 mg/m(2) maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS: Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV(max)) for those treated initially with everolimus was -24% (2% to -54%), and with cetuximab was -5% (-23 to 36%). The K(trans) measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS: Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab , Relação Dose-Resposta a Droga , Everolimo , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Cintilografia , Compostos Radiofarmacêuticos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
12.
EJNMMI Res ; 3(1): 42, 2013 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-23731770

RESUMO

BACKGROUND: Hypoxia within solid tumors confers radiation resistance and a poorer prognosis. 124I-iodoazomycin galactopyranoside (124I-IAZGP) has shown promise as a hypoxia radiotracer in animal models. We performed a clinical study to evaluate the safety, biodistribution, and imaging characteristics of 124I-IAZGP in patients with advanced colorectal cancer and head and neck cancer using serial positron emission tomography (PET) imaging. METHODS: Ten patients underwent serial whole-torso (head/neck to pelvis) PET imaging together with multiple whole-body counts and blood sampling. These data were used to generate absorbed dose estimates to normal tissues for 124I-IAZGP. Tumors were scored as either positive or negative for 124I-IAZGP uptake. RESULTS: There were no clinical toxicities or adverse effects associated with 124I-IAZGP administration. Clearance from the whole body and blood was rapid, primarily via the urinary tract, with no focal uptake in any parenchymal organ. The tissues receiving the highest absorbed doses were the mucosal walls of the urinary bladder and the intestinal tract, in particular the lower large intestine. All 124I-IAZGP PET scans were interpreted as negative for tumor uptake. CONCLUSIONS: It is safe to administer 124I-IAZGP to human subjects. However, there was insufficient tumor uptake to support a clinical role for 124I-IAZGP PET in colorectal cancer and head and neck cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00588276.

13.
Urology ; 81(4): 707-13, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23453080

RESUMO

OBJECTIVE: To clearly define the proportions of benign vs malignant histologic findings in resected renal masses through an in-depth review of the contemporary medical data to assist in preoperative risk assessment. MATERIALS AND METHODS: PubMed and select oncology congresses were searched for publications that identify the histologic classification of resected renal masses in a representative sample from the contemporary data: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit 2003-2011. RESULTS: We identified 26 representative studies meeting the inclusion criteria and incorporating 27,272 patients. The frequency of benign tumors ranged from 7% to 33%, with most studies within a few percentage points of the mean (14.5% ± 5.2%, median 13.9%). Clear cell renal cell carcinoma occurred in 46% to 83% of patients, with a mean of 68.3% (median 61.3; SD = 11.9%). An inverse relationship between tumor size and benign pathologic features was identified in 14 of 19 (74%) studies that examined an association between tumor size and pathologic characteristics. A statistically significant correlation between clear cell renal cell carcinoma and tumor size was identified in 13 of 19 studies (63%). The accuracy of preoperative cross-sectional imaging was low in the 2 studies examining computed tomography (17%). CONCLUSION: Benign renal tumors represent ∼15% of detected surgically resected renal masses and are more prevalent among small clinical T1a lesions. Noninvasive preoperative differentiation between more and less aggressive renal masses would be an important clinical advance that could allow clinicians greater diagnostic confidence and guide patient management through improved risk stratification.


Assuntos
Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Humanos , Medição de Risco
14.
J Clin Oncol ; 31(2): 187-94, 2013 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-23213092

RESUMO

PURPOSE: A clinical study to characterize renal masses with positron emission tomography/computed tomography (PET/CT) was undertaken. PATIENTS AND METHODS: This was an open-label multicenter study of iodine-124 ((124)I) -girentuximab PET/CT in patients with renal masses who were scheduled for resection. PET/CT and contrast-enhanced CT (CECT) of the abdomen were performed 2 to 6 days after intravenous (124)I-girentuximab administration and before resection of the renal mass(es). Images were interpreted centrally by three blinded readers for each imaging modality. Tumor histology was determined by a blinded central pathologist. The primary end points-average sensitivity and specificity for clear cell renal cell carcinoma (ccRCC)-were compared between the two modalities. Agreement between and within readers was assessed. RESULTS: (124)I-girentuximab was well tolerated. In all, 195 patients had complete data sets (histopathologic diagnosis and PET/CT and CECT results) available. The average sensitivity was 86.2% (95% CI, 75.3% to 97.1%) for PET/CT and 75.5% (95% CI, 62.6% to 88.4%) for CECT (P = .023). The average specificity was 85.9% (95% CI, 69.4% to 99.9%) for PET/CT and 46.8% (95% CI, 18.8% to 74.7%) for CECT (P = .005). Inter-reader agreement was high (κ range, 0.87 to 0.92 for PET/CT; 0.67 to 0.76 for CECT), as was intrareader agreement (range, 87% to 100% for PET/CT; 73.7% to 91.3% for CECT). CONCLUSION: This study represents (to the best of our knowledge) the first clinical validation of a molecular imaging biomarker for malignancy. (124)I-girentuximab PET/CT can accurately and noninvasively identify ccRCC, with potential utility for designing best management approaches for patients with renal masses.


Assuntos
Anticorpos Monoclonais , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/diagnóstico , Radioisótopos do Iodo , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/diagnóstico , Compostos Radiofarmacêuticos , Carcinoma de Células Renais/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
16.
J Nucl Med ; 53(4): 615-21, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22414633

RESUMO

UNLABELLED: Bone marrow is usually dose-limiting for radioimmunotherapy. In this study, we directly estimated red marrow activity concentration and the self-dose component of absorbed radiation dose to red marrow based on PET/CT of 2 different (124)I-labeled antibodies (cG250 and huA33) and compared the results with plasma activity concentration and plasma-based dose estimates. METHODS: Two groups of patients injected with (124)I-labeled monoclonal antibodies (11 patients with renal cancer receiving (124)I-cG250 and 5 patients with colorectal cancer receiving (124)I- huA33) were imaged by PET or PET/CT on 2 or 3 occasions after infusion. Regions of interest were drawn over several lumbar vertebrae, and red marrow activity concentration was quantified. Plasma activity concentration was also quantified using multiple patient blood samples. The red marrow-to-plasma activity concentration ratio (RMPR) was calculated at the times of imaging. The self-dose component of the absorbed radiation dose to the red marrow was estimated from the images, from the plasma measurements, and using a combination of both sets of measurements. RESULTS: RMPR was observed to increase with time for both groups of patients. Mean (±SD) time-dependent RMPR (RMPR(t)) for the cG250 group increased from 0.13 ± 0.06 immediately after infusion to 0.23 ± 0.09 at approximately 6 d after infusion. For the huA33 group, mean RMPR(t) was 0.10 ± 0.04 immediately after infusion, 0.13 ± 0.05 approximately 2 d after infusion, and 0.20 ± 0.09 approximately 7 d after infusion. Plasma-based estimates of red marrow self-dose tended to be greater than image-based values by, on average, 11% and 47% for cG250 and huA33, respectively, but by as much as -73% to 62% for individual patients. The hybrid method combining RMPR(t) and plasma activity concentration provided a closer match to the image-based dose estimates (average discrepancies, -2% and 18% for cG250 and huA33, respectively). CONCLUSION: These results suggest that the assumption of time-independent proportionality between red marrow and plasma activity concentration may be too simplistic. Individualized imaged-based dosimetry is probably required for the optimal therapeutic delivery of radiolabeled antibodies, which does not compromise red marrow and may allow, for some patients, a substantial increase in administered activity and thus tumor dose.


Assuntos
Medula Óssea/diagnóstico por imagem , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Anticorpos Monoclonais/sangue , Feminino , Humanos , Injeções , Radioisótopos do Iodo/administração & dosagem , Marcação por Isótopo , Vértebras Lombares/diagnóstico por imagem , Masculino , Radiometria , Estudos Retrospectivos , Fatores de Tempo
17.
J Nucl Med ; 53(1): 98-105, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22173839

RESUMO

UNLABELLED: Recently, there has been a renewed interest in the study of tumor metabolism above and beyond the Warburg effect. Studies on cancer cell metabolism have provided evidence that tumor-specific activation of signaling pathways, such as the upregulation of the oncogene myc, can regulate glutamine uptake and its metabolism through glutaminolysis to provide the cancer cell with a replacement of energy source. METHODS: We report a convenient procedure to prepare l-[5-(11)C]-glutamine. The tracer was evaluated in 9L and SF188 tumor cells (glioma and astrocytoma cell lines). The biodistribution of l-[5-(11)C]-glutamine in rodent tumor models was investigated by dissection and PET. RESULTS: By reacting (11)C-cyanide ion with protected 4-iodo-2-amino-butanoic ester, the key intermediate was obtained in good yield. After hydrolysis with trifluoroacetic and sulfonic acids, the desired optically pure l-[5-(11)C]-glutamine was obtained (radiochemical yield, 5% at the end of synthesis; radiochemical purity, >95%). Tumor cell uptake studies showed maximum uptake of l-[5-(11)C]-glutamine reached 17.9% and 22.5% per 100 µg of protein, respectively, at 60 min in 9L and SF188 tumor cells. At 30 min after incubation, more than 30% of the activity appeared to be incorporated into cellular protein. Biodistribution in normal mice showed that l-[5-(11)C]-glutamine had significant pancreas uptake (7.37 percentage injected dose per gram at 15 min), most likely due to the exocrine function and high protein turnover within the pancreas. Heart uptake was rapid, and there was 3.34 percentage injected dose per gram remaining at 60 min after injection. Dynamic small-animal PET studies in rats bearing xenografted 9L tumors and in transgenic mice bearing spontaneous mammary gland tumors showed a prominent tumor uptake and retention. CONCLUSION: The data demonstrated that this tracer was favorably taken up in the tumor models. The results suggest that l-[5-(11)C]-glutamine might be useful for probing in vivo tumor metabolism in glutaminolytic tumors.


Assuntos
Astrocitoma/diagnóstico por imagem , Astrocitoma/metabolismo , Glioma/diagnóstico por imagem , Glioma/metabolismo , Glutamina/química , Radioquímica/métodos , Animais , Astrocitoma/patologia , Transporte Biológico , Radioisótopos de Carbono , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Cianetos/química , Glioma/patologia , Glutamina/metabolismo , Glutamina/farmacocinética , Humanos , Hidrólise , Masculino , Camundongos , Camundongos Transgênicos , Tomografia por Emissão de Pósitrons , Ratos
18.
J Nucl Med ; 52(12): 1878-85, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22068895

RESUMO

UNLABELLED: The primary aim of this analysis was to examine the quantitative features of antibody-antigen interactions in tumors and normal tissue after parenteral administration of antitumor antibodies to human patients. METHODS: Humanized anti-A33 antibody (10 mg) labeled with the positron-emitting radionuclide (124)I ((124)I-huA33) was injected intravenously in 15 patients with colorectal cancer. Clinical PET/CT was performed approximately 1 wk later, followed by a detailed assay of surgically removed tissue specimens including radioactivity counting, autoradiography, immunohistochemistry, and antigen density determination. RESULTS: PET/CT showed high levels of antibody targeting in tumors and normal bowel. In tissue specimens, the spatial distribution of (124)I-huA33 conformed to that of A33 antigen, and there was a linear relationship between the amount of bound antibody and antigen concentration. Antibody uptake was high in 1- to 2-mm regions of antigen-positive tumor cells (mean, ~0.05 percentage injected dose per gram) and in antigen-positive normal colonic mucosa (mean, ~0.03 percentage injected dose per gram). The estimated binding site occupancy for tumor and normal colon was 20%-50%. CONCLUSION: The in vivo biodistribution of (124)I-huA33 in human patients 1 wk after antibody administration was determined by A33 antigen expression. Our data imply that the optimal strategy for A33-based radioimmunotherapy of colon cancer will consist of a multistep treatment using a radionuclide with short-range (α- or ß-particle) emissions.


Assuntos
Anticorpos Monoclonais Humanizados/metabolismo , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Idoso , Animais , Anticorpos Monoclonais Humanizados/imunologia , Autorradiografia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Transporte Proteico
19.
J Nucl Med ; 52(8): 1173-80, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21764796

RESUMO

UNLABELLED: Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI). METHODS: We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. RESULTS: Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. CONCLUSION: Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.


Assuntos
Neoplasias Colorretais/imunologia , Radioisótopos do Iodo/farmacologia , Glicoproteínas de Membrana/química , Tomografia por Emissão de Pósitrons/métodos , Idoso , Área Sob a Curva , Colo/diagnóstico por imagem , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/terapia , Feminino , Humanos , Imunoglobulinas Intravenosas/metabolismo , Imunoglobulinas Intravenosas/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Radioimunoterapia/métodos , Resultado do Tratamento
20.
Med Chem ; 7(5): 395-412, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21711220

RESUMO

Positron emission tomography (PET) is a powerful molecular imaging technology with the ability to image and monitor molecular events in vivo and in real time. With the increased application of PET radiopharmaceuticals for imaging physiological and pathological processes in vivo, there is a demand for versatile positron emitters with longer physical and biological half-lives. Traditional PET radionuclides, such as carbon-11 ((11)C) and fluorine-18 ((18)F), have relatively short half-lives (20 min and 110 min, respectively). Among the currently available positron emitters, the non-standard radiohalogen iodine-124 ((124)I) has the longest physical half-life at 4.2 d. This, combined with the well characterized radiochemistry of radioiodine, is contributing to the increasing utility of (124)I in investigating slow and complex pharmacokinetic processes in clinical nuclear medicine and small animal PET imaging studies. This review will summarize the progress to date on the potential of (124)I as a positron emitting nuclide for molecular imaging purposes, beginning with the production of (124)I. Particular emphasis will be placed on the basic radiochemistry as it applies to the production of various (124)I-labeled compounds, from small molecules, to biomolecules such as peptides and proteins, and finally to macromolecules like nanoparticles. The review will conclude by highlighting promising future directions in using (124)I as a positron emitter in PET radiochemistry and molecular imaging.


Assuntos
Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Humanos , Radioisótopos do Iodo , Imagem Molecular
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