1H NMR STUDIES OF NON-HODGKINS LYMPHOMA

非霍奇金淋巴瘤的 1H NMR 研究

• 批准号: 8236871
• 负责人: JERRY D GLICKSON
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236871
• 关键词: Affect; Animals; Area; Biochemical Pathway; Biological Markers; Blood Vessels; CD22 gene; Cell Culture Techniques; Cell Cycle; Chemical Shift Imaging; Choline; Clinic; Clinical; Clinical Research; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Contrast Media; Cyclophosphamide; Deoxyglucose; Detection; Diffusion; Diffusion Magnetic Resonance Imaging; Dimethoate; Doxorubicin; Drug Delivery Systems; Early Diagnosis; Evaluation; Exhibits; Follicular Lymphoma; Funding; Glycolysis; Goals; Grant; Health; Human; Hybrids; Hypoxia; Image; Immunoconjugates; Immunotherapy; Incidence; Individual; Kyocristine; Lactic acid; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Methods; Modeling; Multi-Drug Resistance; Non-Hodgkin' s Lymphoma; Oxygen Consumption; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Physiologic pulse; Positron-Emission Tomography; Prednisone; Production; Proteomics; Protons; Radiation therapy; Regimen; Repression; Resistance; Resolution; Shotguns; Slice; Spectrum Analysis; Staging; Testing; Therapeutic; Therapeutic Agents; Translating; Tumor Angiogenesis; Validation; Variant; Weight; Xenograft Model; bryostatin; chemotherapy; clinically relevant; cofactor; conventional therapy; design; economic impact; extracellular; follow-up; gemcitabine; imaging modality; in vivo; innovation; interstitial; large cell Diffuse non-Hodgkin' s lymphoma; liquid chromatography mass spectrometry; man; network models; novel; pressure; programs; quantum; repair enzyme; response; rituximab; tumor; uptake

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop 1H MRS and MRI methods for prediction and detection of therapeutic response of non-Hodgkin's lymphoma (NHL), a prevalent malignancy whose incidence has increased by more than 90% since 1950 that ranks fourth in overall economic impact. A multi-institutional clinical study in which the PI is participating has already demonstrated that 31P MRS can predict about 2/3 of the tumors that fail to exhibit a complete clinical response, but this method is limited to relatively large superficial tumors. Our approach has been to develop proton imaging and spectroscopy methods that are capable of early detection of response in all patients. During the first funding cycle of this grant we examined a xenograft model, DLCL2, of diffuse large B-cell lymphoma (DLBCL), the most common form of NHL affecting about 1/3 of all patients. We have evaluated the utility of 1H MRS measurements of total choline and lactate and 1H MRI (diffusion-weighted and T2-weighted with dynamic contrast-enhanced and T1A-weighted) in this tumor. We have examined the response to multiple clinically relevant therapies including: combination chemotherapy with Cyclophosphamide, Hydroxydoxorubicin, Oncovin and Prednisone (CHOP), CHOP plus Bryostatin 1 (CHOPB), Rituximab alone, Rituximab plus CHOP and radiation therapy. The most exciting results from these studies are: 1) significant decreases in lactate detected within one cycle of CHOP that correlated with decreased tumor proliferation; 2) regional changes in the apparent diffusion constant and in T2 corresponding to areas of response in the tumor; 3) design and implementation of a novel hybrid pulse sequence for 1H imaging of lactate utilizing multi-slice Hadamard spatial encoding and chemical shift imaging via a selective multi-quantum coherence transfer. This sequence was developed on the animal scanner and has now been translated to a clinical scanner and applied to an NHL patient. The objectives of the current proposal are 1) to define the mechanisms underlying therapy associated decreases in lactic acid, 2) to define the mechanism leading to MRI-detected regional response of the tumor, and 3) to extend the study to more responsive DLBCL xenograft models and to follicular lymphoma, the next most common form of NHL. We will employ a number of sophisticated and innovative methods to achieve these goals including 1) use of a two- compartment model to distinguish between changes in steady-state lactate concentration due to changes in glycolysis and washout, 2) determination if FDG-PET imaging and DCE MRI, which are more readily available in the clinic than 13C MRS, can distinguish between changed in lactate levels due to alterations in glycolytic rate or due to a change in the rate of lactate elimination, 3) 17O imaging methods to image perfusion and oxygen consumption simultaneously and 4) validation of a metabolic network model for 13C NMR by predicted and experimental oxygen consumption rates. We will also explore in depth possible mechanisms that could contribute to regional therapeutic response in the tumor. PUBLIC HEALTH RELEVANCE: This project is directed towards developing NMR methods for prediction and early detection of therapeutic response of individual patients with non-Hodgkin's lymphoma (NHL), one of the prevalent forms of human cancer. A clinical program in which we participate has already developed a 31P NMR method for predicting about 2/3 of the tumors that will fail to respond to conventional treatment. This method, however, is limited to patients with large superficial tumors. Here we are developing much more sensitive 1H NMR methods that can be used for early detection of response in all NHL patients. The same methods should be applicable to other prevalent forms of human cancer.

描述（由申请人提供）：该项目的长期目标是开发用于预测和检测非霍奇金淋巴瘤（NHL）治疗反应的1H MRS和MRI方法，NHL是一种流行的恶性肿瘤，自1950年以来发病率增加了90%以上，在总体经济影响中排名第四。PI参与的一项多机构临床研究已经表明，31P MRS可以预测约2/3的未表现出完全临床反应的肿瘤，但这种方法仅限于相对较大的浅表肿瘤。我们的方法是开发质子成像和光谱方法，能够早期检测所有患者的反应。在该基金的第一个资助周期中，我们研究了弥漫性大b细胞淋巴瘤（DLBCL）的异种移植模型DLCL2， DLBCL是最常见的NHL形式，约占所有患者的1/3。我们评估了总胆碱和乳酸的1H MRS测量和1H MRI（扩散加权和t2加权，动态对比增强和t1a加权）在该肿瘤中的效用。我们研究了多种临床相关治疗的疗效，包括：环磷酰胺、羟多柔比星、Oncovin和强的松联合化疗（CHOP）、CHOP联合苔藓虫素1 （CHOPB）、利妥昔单抗、利妥昔单抗联合CHOP和放疗。这些研究最令人兴奋的结果是：1)在CHOP的一个周期内检测到的乳酸显著减少与肿瘤增殖减少相关；2)肿瘤反应区对应的表观扩散常数和T2的区域性变化；3)利用多层Hadamard空间编码和选择性多量子相干转移的化学位移成像，设计并实现了乳酸盐1H成像的新型混合脉冲序列。该序列是在动物扫描仪上开发的，现在已转化为临床扫描仪并应用于NHL患者。当前提案的目标是1)确定治疗相关的乳酸减少机制，2)确定导致mri检测肿瘤区域反应的机制，以及3)将研究扩展到更反应的DLBCL异种移植模型和滤泡性淋巴瘤（下一种最常见的NHL形式）。我们将采用许多复杂和创新的方法来实现这些目标，包括1)使用双室模型来区分由于糖酵解和洗脱变化引起的稳态乳酸浓度的变化，2)确定FDG-PET成像和DCE MRI（在临床上比13C MRS更容易获得）是否可以区分由于糖酵解速率的改变或由于乳酸消除速率的变化引起的乳酸水平的变化。3)同时成像灌注和耗氧量的17O成像方法；4)通过预测耗氧量和实验耗氧量验证13C核磁共振代谢网络模型。我们还将深入探讨可能有助于肿瘤区域治疗反应的机制。公共卫生相关性：该项目旨在开发核磁共振方法，用于预测和早期检测非霍奇金淋巴瘤（NHL）个体患者的治疗反应，NHL是人类癌症的一种常见形式。我们参与的一个临床项目已经开发出一种31P核磁共振方法，用于预测约三分之二的肿瘤对常规治疗无效。然而，这种方法仅限于有较大浅表肿瘤的患者。在这里，我们正在开发更敏感的1H NMR方法，可用于所有NHL患者的早期反应检测。同样的方法应该适用于其他常见的人类癌症。

项目成果

Monitoring response to chemotherapy of non-Hodgkin's lymphoma xenografts by T(2)-weighted and diffusion-weighted MRI.

• DOI: 10.1002/nbm.1261
• 发表时间: 2008-11
• 期刊: NMR in biomedicine
• 影响因子: 2.9
• 作者: Huang MQ;Pickup S;Nelson DS;Qiao H;Xu HN;Li LZ;Zhou R;Delikatny EJ;Poptani H;Glickson JD
• 通讯作者: Glickson JD

Lactate imaging with Hadamard-encoded slice-selective multiple quantum coherence chemical-shift imaging.

• DOI: 10.1002/mrm.21659
• 发表时间: 2008-08
• 期刊: MAGNETIC RESONANCE IN MEDICINE
• 影响因子: 3.3
• 作者: Pickup, Stephen;Lee, Seung-Cheol;Mancuso, Anthony;Glickson, Jerry D.
• 通讯作者: Glickson, Jerry D.