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1.
Blood ; 143(24): 2464-2473, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38557775

RESUMO

ABSTRACT: Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [median or less] vs high [greater than median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem cell transplantation in patients who had a response). All P values are descriptive. Within high- and low-MTV subgroups, event-free survival (EFS) and progression-free survival (PFS) were superior with axi-cel vs standard care. EFS in patients with high MTV (vs low MTV) was numerically shorter with axi-cel and was significantly shorter with standard care. PFS was shorter in patients with high MTV vs low MTV in both the axi-cel and standard-care arms, and median MTV was lower in patients in ongoing response at data cutoff vs others. Median MTV was higher in patients treated with axi-cel who experienced grade ≥3 neurologic events or cytokine release syndrome (CRS) than in patients with grade 1/2 or no neurologic events or CRS, respectively. Baseline MTV less than or equal to median was associated with better clinical outcomes in patients receiving axi-cel or standard care for second-line LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.


Assuntos
Produtos Biológicos , Linfoma Difuso de Grandes Células B , Padrão de Cuidado , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Produtos Biológicos/uso terapêutico , Produtos Biológicos/administração & dosagem , Idoso , Adulto , Carga Tumoral , Imunoterapia Adotiva/métodos , Resultado do Tratamento , Antígenos CD19/uso terapêutico
2.
Blood ; 143(6): 496-506, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-37879047

RESUMO

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.


Assuntos
Produtos Biológicos , Linfoma de Zona Marginal Tipo Células B , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Humanos , Seguimentos , Recidiva Local de Neoplasia/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Linfoma Folicular/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Antígenos CD19/uso terapêutico
3.
Oncologist ; 29(2): 132-141, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38169017

RESUMO

BACKGROUND: Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated in a phase I study in patients with advanced GI carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose (RP2D). PATIENTS AND METHODS: Patients with refractory GI carcinoma and with measurable disease on CT scan were eligible. The study used a 3 + 3 dose-escalation scheme. Due to neutropenia toxicity, 2 dosing schedules were evaluated to determine the RP2D for future studies. Response was assessed using RECIST 1.1 and Choi criteria. Minnelide and triptolide PK were evaluated. Patients who completed the first 28-day treatment cycle without DLTs continued treatment until disease progression or unacceptable toxicity. RESULTS: Forty-five patients were enrolled (23 pancreatic cancer, 10 colorectal, and the remaining 9 had other GI tumors); 42 patients received at least one dose of Minnelide. Grade ≥ 3 toxicities occurred in 69% of patients, most common neutropenia (38%). 2 patients with severe cerebellar toxicity who had a 2-fold higher triptolide concentration than other participants. ORR was 4%; the disease control rate (DCR) was 54% (15/28). Choi criteria demonstrated a decrease in average tumor density in 57% (16/28) patients. CONCLUSIONS: This first-in-human, phase I clinical study identified a dose and schedule of Minnelide in patients with refractory GI cancers. The primary toxicity experienced was hematologic. Evidence of efficacy of Minnelide treatment in this group of patients was observed. The DCR ranged from ~2 to 6 months in 14/28 (50%) of evaluable patients. Studies in monotherapy and combination treatments are underway.


Assuntos
Antineoplásicos , Diterpenos , Compostos de Epóxi , Neoplasias Gastrointestinais , Neutropenia , Organofosfatos , Fenantrenos , Humanos , Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico
4.
Oncologist ; 25(1): e60-e67, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31391296

RESUMO

BACKGROUND: Molecular analysis has revealed four subtypes of pancreatic ductal adenocarcinoma (PDAC). One subtype identified for the presence of DNA damage repair deficiency can be targeted therapeutically with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. We performed a single institution retrospective analysis of treatment response in patients with PDAC treated with olaparib who have DNA damage repair deficiency mutations. SUBJECTS, MATERIALS, AND METHODS: Patients with germline or somatic mutations involving the DNA repair pathway were identified and treated with olaparib. The primary objective was to examine the objective response rate (ORR). The secondary objectives were assessing tolerability, overall survival, and change in cancer antigen 19-9. Quantitative texture analysis (QTA) was evaluated from CT scans to explore imaging biomarkers. RESULTS: Thirteen individuals with metastatic PDAC were treated with Olaparib. The ORR to Olaparib was 23%. Median overall survival (OS) was 16.47 months. Four of seven patients with BRCA mutations had an effect on RAD51 binding, with a median OS of 24.60 months. Exploratory analysis of index lesions using QTA revealed correlations between lesion texture and OS (hepatic lesion tumor texture correlation coefficient [CC], 0.683, p = .042) and time on olaparib (primary pancreatic lesion tumor texture CC, 0.778, p = .023). CONCLUSION: In individuals with metastatic PDAC who have mutations involved in DNA repair, Olaparib may provide clinical benefit. BRCA mutations affecting RAD51 binding domains translated to improved median OS. QTA of individual tumors may allow for additional information that predicts outcomes to treatment with PARP inhibitors. IMPLICATIONS FOR PRACTICE: Pursuing germline and somatic DNA sequencing in individuals with pancreatic ductal adenocarcinoma may yield abnormalities in DNA repair pathways. These individuals may receive benefit with poly (ADP-ribose) polymerase (PARP) inhibition. Radiomics and deep sequencing analysis may yet uncover additional information that may predict outcome to treatment with PARP inhibitors.


Assuntos
Reparo do DNA/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Estudos Retrospectivos
5.
Invest New Drugs ; 37(4): 636-645, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30264293

RESUMO

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Lactonas/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Lactonas/sangue , Lactonas/farmacocinética , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Camundongos Knockout , Mutação , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Sequenciamento do Exoma
6.
Cancer Treat Res ; 178: 209-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31209847

RESUMO

Pancreas cancer is an aggressive and fatal disease that will become one of the leading causes of cancer mortality by 2030. An all-out effort is underway to better understand the basic biologic mechanisms of this disease ranging from early development to metastatic disease. In order to change the course of this disease, diagnostic radiology imaging may play a vital role in providing a precise, noninvasive method for early diagnosis and assessment of treatment response. Recent progress in combining medical imaging, advanced image analysis and artificial intelligence, termed radiomics, can offer an innovate approach in detecting the earliest changes of tumor development as well as a rapid method for the detection of response. In this chapter, we introduce the principles of radiomics and demonstrate how it can provide additional information into tumor biology, early detection, and response assessments advancing the goals of precision imaging to deliver the right treatment to the right person at the right time.


Assuntos
Neoplasias Pancreáticas , Medicina de Precisão , Radiologia , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Radiografia
7.
Br J Cancer ; 118(2): 153-161, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28949957

RESUMO

BACKGROUND: Hyaluronan accumulation in tumour stroma is associated with reduced survival in preclinical cancer models. PEGPH20 degrades hyaluronan to facilitate tumour access for cancer therapies. Our objective was to assess safety and antitumour activity of PEGPH20 in patients with advanced solid tumours. METHODS: In HALO-109-101 (N=14), PEGPH20 was administered intravenously once or twice weekly (0.5 or 50 µg kg-1) or once every 3 weeks (0.5-1.5 µg kg-1). In HALO-109-102 (N=27), PEGPH20 was administered once or twice weekly (0.5-5.0 µg kg-1), with dexamethasone predose and postdose. RESULTS: Dose-limiting toxicities included grade ⩾3 myalgia, arthralgia, and muscle spasms; the maximum tolerated dose was 3.0 µg kg-1 twice weekly. Plasma hyaluronan increased in a dose-dependent manner, achieving steady state by Day 8 in multidose studies. A decrease in tumour hyaluronan level was observed in 5 of the 6 patients with pretreatment and posttreatment tumour biopsies. Exploratory imaging showed changes in tumour perfusion and decreased tumour metabolic activity, consistent with observations in animal models. CONCLUSIONS: The tumour stroma has emerging importance in the development of cancer therapeutics. PEGPH20 3.0 µg kg-1 administered twice weekly is feasible in patients with advanced cancers; exploratory analyses indicate antitumour activity supporting further evaluation of PEGPH20 in solid tumours.


Assuntos
Hialuronoglucosaminidase/administração & dosagem , Neoplasias/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Ácido Hialurônico/sangue , Hialuronoglucosaminidase/efeitos adversos , Hialuronoglucosaminidase/sangue , Hialuronoglucosaminidase/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico por imagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética
9.
Radiology ; 280(1): 261-70, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27082783

RESUMO

Purpose To investigate whether non-small cell lung cancer (NSCLC) tumors that express high normalized maximum standardized uptake value (SUVmax) are associated with a more epithelial-mesenchymal transition (EMT)-like phenotype. Materials and Methods In this institutional review board-approved study, a public NSCLC data set that contained fluorine 18 ((18)F) fluoro-2-deoxyglucose positron emission tomography (PET) and messenger RNA expression profile data (n = 26) was obtained, and patients were categorized on the basis of measured normalized SUVmax values. Significance analysis of microarrays was then used to create a radiogenomic signature. The prognostic ability of this signature was assessed in a second independent data set that consisted of clinical and messenger RNA expression data (n = 166). Signature concordance with EMT was evaluated by means of validation in a publicly available cell line data set. Finally, by establishing an in vitro EMT lung cancer cell line model, an attempt was made to substantiate the radiogenomic signature with quantitative polymerase chain reaction, and functional assays were performed, including Western blot, cell migration, glucose transporter, and hexokinase assays (paired t test), as well as pharmacologic assays against chemotherapeutic agents (half-maximal effective concentration). Results Differential expression analysis yielded a 14-gene radiogenomic signature (P < .05, false discovery rate [FDR] < 0.20), which was confirmed to have differences in disease-specific survival (log-rank test, P = .01). This signature also significantly overlapped with published EMT cell line gene expression data (P < .05, FDR < 0.20). Finally, an EMT cell line model was established, and cells that had undergone EMT differentially expressed this signature and had significantly different EMT protein expression (P < .05, FDR < 0.20), cell migration, glucose uptake, and hexokinase activity (paired t test, P < .05). Cells that had undergone EMT also had enhanced chemotherapeutic resistance, with a higher half-maximal effective concentration than that of cells that had not undergone EMT (P < .05). Conclusion Integrative radiogenomic analysis demonstrates an association between increased normalized (18)F fluoro-2-deoxyglucose PET SUVmax, outcome, and EMT in NSCLC. (©) RSNA, 2016 Online supplemental material is available for this article.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Transição Epitelial-Mesenquimal/fisiologia , Fluordesoxiglucose F18/farmacocinética , Neoplasias Pulmonares/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Feminino , Genômica/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética
10.
Hepatology ; 62(3): 792-800, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25930992

RESUMO

UNLABELLED: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast-enhanced computed tomography (CECT) biomarker of MVI derived from a 91-gene HCC "venous invasion" gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (κ = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor-node-metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence-free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%). CONCLUSION: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Células Neoplásicas Circulantes/patologia , Intensificação de Imagem Radiográfica/métodos , Análise de Variância , California , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Estudos de Coortes , Estudos Transversais , Intervalo Livre de Doença , Feminino , Hepatectomia/métodos , Hepatectomia/mortalidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Cuidados Pré-Operatórios/métodos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Compostos Radiofarmacêuticos , Estatísticas não Paramétricas , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
11.
Eur Radiol ; 26(8): 2798-807, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26560727

RESUMO

OBJECTIVES: To characterize a radiogenomic risk score (RRS), a previously defined biomarker, and to evaluate its potential for stratifying radiological progression-free survival (rPFS) in patients with metastatic renal cell carcinoma (mRCC) undergoing pre-surgical treatment with bevacizumab. METHODOLOGY: In this IRB-approved study, prospective imaging analysis of the RRS was performed on phase II clinical trial data of mRCC patients (n = 41) evaluating whether patient stratification according to the RRS resulted in groups more or less likely to have a rPFS to pre-surgical bevacizumab prior to cytoreductive nephrectomy. Survival times of RRS subgroups were analyzed using Kaplan-Meier survival analysis. RESULTS: The RRS is enriched in diverse molecular processes including drug response, stress response, protein kinase regulation, and signal transduction pathways (P < 0.05). The RRS successfully stratified rPFS to bevacizumab based on pre-treatment computed tomography imaging with a median progression-free survival of 6 versus >25 months (P = 0.005) and overall survival of 25 versus >37 months in the high and low RRS groups (P = 0.03), respectively. Conventional prognostic predictors including the Motzer and Heng criteria were not predictive in this cohort (P > 0.05). CONCLUSIONS: The RRS stratifies rPFS to bevacizumab in patients from a phase II clinical trial with mRCC undergoing cytoreductive nephrectomy and pre-surgical bevacizumab. KEY POINTS: • The RRS SOMA stratifies patient outcomes in a phase II clinical trial. • RRS stratifies subjects into prognostic groups in a discrete or continuous fashion. • RRS is biologically enriched in diverse processes including drug response programs.


Assuntos
Bevacizumab/uso terapêutico , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Nefrectomia , Medição de Risco/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologia
12.
Radiology ; 277(1): 114-23, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26402495

RESUMO

PURPOSE: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image. MATERIALS AND METHODS: In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis. RESULTS: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001). CONCLUSION: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.


Assuntos
Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Análise em Microsséries , Técnicas de Diagnóstico Molecular , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Estudos de Viabilidade , Feminino , Genômica , Humanos , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco
13.
Radiology ; 272(2): 568-76, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24885982

RESUMO

PURPOSE: To present a radiogenomic computed tomographic (CT) characterization of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) (ALK+). MATERIALS AND METHODS: In this HIPAA-compliant institutional review board-approved retrospective study, CT studies, ALK status, and clinical-pathologic data in 172 patients with NSCLC from three institutions were analyzed. A screen of 24 CT image traits was performed in a training set of 59 patients, followed by random forest variable selection incorporating 24 CT traits plus six clinical-pathologic covariates to identify a radiogenomic predictor of ALK+ status. This predictor was then validated in an independent cohort (n = 113). Test-for-accuracy and subset analyses were performed. A similar analysis was performed to identify a biomarker associated with shorter progression-free survival (PFS) after therapy with the ALK inhibitor crizotinib. RESULTS: ALK+ status was associated with central tumor location, absence of pleural tail, and large pleural effusion. An ALK+ radiogenomic CT status biomarker consisting of these three imaging traits with patient age of younger than 60 years showed strong discriminatory power for ALK+ status, with a sensitivity of 83.3% (15 of 18), a specificity of 77.9% (74 of 95), and an accuracy of 78.8% (89 of 113) in independent testing. The discriminatory power was particularly strong in patients with operable disease (stage IIIA or lower), with a sensitivity of 100.0% (five of five), a specificity of 88.1% (37 of 42), and an accuracy of 89.4% (42 of 47). Tumors with a disorganized vessel pattern had a shorter PFS with crizotinib therapy than tumors without this trait (11.4 vs 20.2 months, P = .041). CONCLUSION: ALK+ NSCLC has distinct characteristics at CT imaging that, when combined with clinical covariates, discriminate ALK+ from non-ALK tumors and can potentially identify patients with a shorter durable response to crizotinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Receptores Proteína Tirosina Quinases/genética , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteínas ras/genética
14.
Sci Rep ; 14(1): 11570, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773189

RESUMO

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10-3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54 s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans < 0.07 min-1 (BA = 72%, p = 0.2), ve < 0.17 (BA = 68%, p < 0.01), and vp < 0.02 (BA = 60%, p < 0.01). A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.


Assuntos
Ácido Hialurônico , Hialuronoglucosaminidase , Imageamento por Ressonância Magnética , Neoplasias , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos
15.
Transl Lung Cancer Res ; 12(7): 1575-1589, 2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37577298

RESUMO

Background and Objective: Radiomics is an emerging field of advanced image analysis that has shown promise as a non-invasive, companion diagnostic in predicting clinical outcomes and response assessments in solid tumors. Radiomics aims to extract high-content information from medical images not visible to the naked eye, especially in early-stage non-small cell lung cancer (NSCLC) patients. Although these patients are being identified by early detection programs, it remains unclear which patients would benefit from adjuvant treatment versus active surveillance. Having a radiomic signature(s) that could predict early recurrence would be beneficial. In this review, an overview of the basic radiomic approaches used to evaluate solid tumors on radiologic scans, including NSCLC is provided followed by a review of relevant literature that supports the use of radiomics to help predict tumor recurrence in early-stage NSCLC patients. Methods: A review of the radiomic literature from 1985 to present focusing on the prediction of disease recurrence in early-stage NSCLC was conducted. PubMed database was searched using key terms for radiomics and NSCLC. A total of 41 articles were identified and 13 studies were considered suitable for inclusion based upon study population, patient number (n>50), use of well described radiomic methodologies, suitable model building features, and well-defined testing/training and validation where feasible. Key Content and Findings: Examples of using radiomics in early-stage NSCLC patients will be presented, where disease free survival is a primary consideration. A summary of the findings demonstrates the importance of both the intratumor and peritumoral radiomic signals as a marker of outcomes. Conclusions: The value of radiomic information for predicting disease recurrence in early-stage NSCLC patients is accumulating. However, overcoming several challenges along with the lack of prospective trials, has inhibited it use as a clinical decision-making support tool in early-stage NSCLC.

16.
Diagnostics (Basel) ; 13(5)2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36900085

RESUMO

Despite a growing number of effective therapeutic options for patients with pancreatic adenocarcinoma, the prognosis remains dismal mostly due to the late-stage presentation and spread of the cancer to other organs. Because a genomic analysis of pancreas tissue revealed that it may take years, if not decades, for pancreatic cancer to develop, we performed radiomics and fat fraction analysis on contrast-enhanced CT (CECT) scans of patients with historical scans showing no evidence of cancer but who subsequently went on to develop pancreas cancer years later, in an attempt to identify specific imaging features of the normal pancreas that may portend the subsequent development of the cancer. In this IRB-exempt, retrospective, single institution study, CECT chest, abdomen, and pelvis (CAP) scans of 22 patients who had evaluable historical imaging data were analyzed. The images from the "healthy" pancreas were obtained between 3.8 and 13.9 years before the diagnosis of pancreas cancer was established. Afterwards, the images were used to divide and draw seven regions of interest (ROIs) around the pancreas (uncinate, head, neck-genu, body (proximal, middle, and distal) and tail). Radiomic analysis on these pancreatic ROIs consisted of first order quantitative texture analysis features such as kurtosis, skewness, and fat quantification. Of all the variables tested, fat fraction in the pancreas tail (p = 0.029) and asymmetry of the histogram frequency curve (skewness) of pancreas tissue (p = 0.038) were identified as the most important imaging signatures for subsequent cancer development. Changes in the texture of the pancreas as measured on the CECT of patients who developed pancreas cancer years later could be identified, confirming the utility of radiomics-based imaging as a potential predictor of oncologic outcomes. Such findings may be potentially useful in the future to screen patients for pancreatic cancer, thereby helping detect pancreas cancer at an early stage and improving survival.

17.
Res Sq ; 2023 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-37720027

RESUMO

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20, HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values that were predictive of pharmacodynamic responses were: ADC > 1.46×10-3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans<0.07min-1 (BA = 72%, p = 0.2), ve<0.17 (BA = 68%, p < 0.01), and vp<0.02 (BA = 60%, p < 0.01). Further, ve<0.39 at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.

18.
Radiol Imaging Cancer ; 5(2): e220022, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36734848

RESUMO

Purpose To investigate ferumoxytol (FMX)-enhanced MRI as a pretreatment predictor of response to liposomal irinotecan (nal-IRI) for thoracoabdominal and brain metastases in women with metastatic breast cancer (mBC). Materials and Methods In this phase 1 expansion trial (ClinicalTrials.gov identifier, NCT01770353; 27 participants), 49 thoracoabdominal (19 participants; mean age, 48 years ± 11 [SD]) and 19 brain (seven participants; mean age, 54 years ± 8) metastases were analyzed on MR images acquired before, 1-4 hours after, and 16-24 hours after FMX administration. In thoracoabdominal metastases, tumor transverse relaxation rate (R*2) was normalized to the mean R*2 in the spleen (rR*2), and the tumor histogram metric rR*2,N, representing the average of rR*2 in voxels above the nth percentile, was computed. In brain metastases, a novel compartmentation index was derived by applying the MRI signal equation to phantom-calibrated coregistered FMX-enhanced MRI brain scans acquired before, 1-4 hours after, and 16-24 hours after FMX administration. The fraction of voxels with an FMX compartmentation index greater than 1 was computed over the whole tumor (FCIGT1) and from voxels above the 90th percentile R*2 (FCIGT1 R*2,90). Results rR*2,90 computed from pretherapy MRI performed 16-24 hours after FMX administration, without reference to calibration phantoms, predicted response to nal-IRI in thoracoabdominal metastases (accuracy, 74%). rR*2,90 performance was robust to the inclusion of some peritumoral tissue within the tumor region of interest. FCIGT1 R*2,90 provided 79% accuracy on cross-validation in prediction of response in brain metastases. Conclusion This first in-human study focused on mBC suggests that FMX-enhanced MRI biologic markers can be useful for pretherapy prediction of response to nal-IRI in patients with mBC. Keywords: MRI Contrast Agent, MRI, Breast, Head/Neck, Tumor Response, Experimental Investigations, Brain/Brain Stem Clinical trial registration no. NCT01770353 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Daldrup-Link in this issue.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Óxido Ferroso-Férrico , Irinotecano/uso terapêutico , Imageamento por Ressonância Magnética/métodos
19.
Cancer ; 118(21): 5310-9, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22511370

RESUMO

BACKGROUND: Inhibition of the hedgehog signaling pathway (HHSP) for the treatment of locally advanced basal cell carcinoma (BCC) and metastatic BCC (mBCC) has produced promising results. Typically, mBCC is not taken into consideration during the workup of a patient with multifocal metastatic disease who has a history of BCC. The objective of the current review, in which the authors evaluated the time from the first BCC diagnosis to metastasis, location of disease, and radiographic features, was to contribute to the general knowledge and awareness among providers, patients, and support groups about mBCC and to provide an outlook for the future of treatments for mBCC. A literature review on mBCC and a review of records from patients with mBCC who presented to Virginia G. Piper Cancer Center Clinical Trials (an oncology clinical trials center) were conducted. The clinical and radiographic findings of 22 patients with mBCC who were evaluated at that center from the initiation of smoothened (SMO) antagonist trials were analyzed along with a review of BCC epidemiology and pathogenesis, the HHSP, and current and future treatments for this rare presentation of the most common malignancy. The results indicated that, in the last 5 years, there has been a plethora of new agents targeting SMO, a key component of the HHSP that, for the majority of patients with mBCC, may be a good match for targeting tumor genetic vulnerability. Like with other targeted therapy for uncommon malignancies, such as chronic myelogenous leukemia and gastrointestinal stromal tumors, the authors anticipate that there will be clinical development of next-generation HHSP inhibitors to combat mBCCs that are nonresponsive to or progress on current SMO antagonists.


Assuntos
Carcinoma Basocelular/secundário , Proteínas Hedgehog/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais , Neoplasias Cutâneas/patologia , Receptor Smoothened , Adulto Jovem
20.
AJR Am J Roentgenol ; 199(3): 654-63, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22915408

RESUMO

OBJECTIVE: Molecular profiling studies have defined the increasing importance of gene expression phenotyping in breast cancer. However, the relationship between global transcriptomic profiles and the information provided by breast MRI remains to be examined. In this pilot study, our aim was to provide a preliminary radiogenomic association map linking MR image phenotypes to underlying global gene expression patterns in breast cancer. MATERIALS AND METHODS: From a multiinstitutional study, a total of 353 patients with a diagnosis of breast cancer were examined for gene expression analysis. Radiogenomic analysis was then performed on a subset of these patients (n = 10) who also underwent breast MRI. Two radiologists evaluated each MRI study across 26 predefined imaging phenotypes. Analyses were performed to correlate the expression and imaging data and to define associations between specific MR image phenotypes and gene sets of interest. RESULTS: High-level analysis revealed 21 imaging traits that were globally correlated (p < 0.05), with 71% of the total genes measured in patients with breast cancer. A significant correlation was identified between heterogeneous enhancement patterns and a previously described interferon breast cancer subtype (p < 0.01). We also identified 12 imaging traits that significantly correlated (false discovery rate < 0.25) with gene sets related to breast cancer and 11 traits correlated (false discovery rate < 0.25) to prognostic gene sets (van't Veer, wound response, and hypoxia metagene signatures) using gene enrichment analysis. CONCLUSION: Radiogenomic analysis of breast cancer with MRI is a novel approach to understanding the underlying molecular biology of breast cancers.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Perfilação da Expressão Gênica , Imageamento por Ressonância Magnética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Humanos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Prognóstico
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