1H NMR STUDIES OF NON-HODGKINS LYMPHOMA

非霍奇金淋巴瘤的 1H NMR 研究

• 批准号: 7656108
• 负责人: JERRY D GLICKSON
• 金额: $ 35.74万
• 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/7656108
• 关键词: Affect; Animals; Area; Biochemical Pathway; Biological Markers; Blood Vessels; 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; Human; Hybrids; Hypoxia; Image; Immunotherapy; Incidence; Individual; Kyocristine; Lactic acid; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Methods; Modeling; Multi-Drug Resistance; Non-Hodgkin' s Lymphoma; Oxygen; Oxygen Consumption; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Physiologic pulse; Positron-Emission Tomography; Prednisone; Production; Proteomics; Protons; Radiation therapy; Repression; Resistance; Resolution; Shotguns; Slice; Spectrum Analysis; Staging; Testing; Therapeutic; Therapeutic Agents; Translating; Treatment Protocols; 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; public health relevance; 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）：本项目的长期目标是开发1H MRS和MRI方法，用于预测和检测非霍奇金淋巴瘤（NHL）的治疗反应，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证明，31 P MRS可以预测约2/3未能显示完全临床缓解的肿瘤，但该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。在该资助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DLCL 2，DLBCL是NHL最常见的形式，影响约1/3的患者。我们已经评估了1H MRS测量总胆碱和乳酸和1H MRI（弥散加权和T2加权动态增强和T1 A加权）在这个肿瘤中的效用。我们检查了对多种临床相关疗法的反应，包括：环磷酰胺、羟基阿霉素、长春新碱和泼尼松（CHOP）联合化疗、CHOP加苔藓抑素1（CHOPB）、单用利妥昔单抗、利妥昔单抗加CHOP和放疗。这些研究中最令人兴奋的结果是：1）在CHOP的一个周期内检测到乳酸的显著降低，这与肿瘤增殖的降低相关; 2）表观扩散常数和T2的区域变化对应于肿瘤中的反应区域; 3）设计并实现了一种新的混合脉冲序列，用于利用多个脉冲的乳酸1H成像。切片Hadamard空间编码和通过选择性多量子相干转移的化学位移成像。这个序列是在动物扫描仪上开发的，现在已经被翻译成临床扫描仪并应用于NHL患者。当前提案的目的是：1）确定治疗相关乳酸减少的潜在机制，2）确定导致MRI检测到的肿瘤区域反应的机制，3）将研究扩展到更具反应性的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）使用二室模型来区分由于糖酵解和洗脱的变化引起的稳态乳酸盐浓度的变化，2）确定FDG-PET成像和DCE MRI是否在临床上比13 C MRS更容易获得，可以区分由于糖酵解速率的改变或由于乳酸消除速率的改变而引起的乳酸水平的改变，3）同时成像灌注和氧消耗的17 O成像方法和4）通过预测的和实验的氧消耗速率验证用于13 C NMR的代谢网络模型。我们还将深入探讨可能有助于肿瘤区域治疗反应的可能机制。公共卫生关系：该项目旨在开发NMR方法，用于预测和早期检测患有非霍奇金淋巴瘤（NHL）的个体患者的治疗反应，NHL是人类癌症的流行形式之一。我们参与的一个临床项目已经开发出一种31 P NMR方法，用于预测约2/3的肿瘤对常规治疗无效。然而，这种方法仅限于大的浅表肿瘤患者。在这里，我们正在开发更灵敏的1H NMR方法，可用于早期检测所有NHL患者的反应。同样的方法也适用于其他常见的人类癌症。