MR扩散加权成像在进展期胃癌疗效预测与评价中的应用
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摘要
胃癌是最常见的恶性肿瘤之一，在我国，胃癌是第二大常见肿瘤，其发病受地理环境、种族和社会经济等因素的影响。对于进展期胃癌，常通过化疗来减轻症状，提高生存质量及存活率。有效和可靠的评估胃癌治疗疗效对于疾病的临床管理至关重要。
影像医学对于胃癌的诊断起着至关重要的作用，同样，在胃癌疗效评价、肿瘤复发和转移的监测中，影像医学也发挥着重要的作用。当前，评估实体瘤治疗反应的影像学方法主要有X线、计算机断层扫描(computed tomography，CT)或磁共振成像(magnetic resonance imaging，MRI)，通常测量病灶在一个方向上大小的变化。然而，即使病灶大小测量能够反应病灶真实体积的变化，往往也要在治疗数个周期后尚可发现药物对病灶体积的影响。此外，当前和今后一段时间，抗肿瘤药物的设计主要通过高度影响特定肿瘤的特性来抗肿瘤，可能不会立即引起细胞毒性反应，这就需要更敏感、更特异的能够在治疗早期反应肿瘤状态和治疗反应的方法，以便能够可重复、定量、非侵入、可靠地评估肿瘤疗效，这将可以进一步推进肿瘤疗效监测的步伐，对于临床研究非常重要。
近年来，能够定量地测量肿瘤特征的影像学方法已经显著增加。他们包括MRI、光学成像、正电子发射计算机断层扫描(positron emission tomograph，PET)、单光子发射计算机断层扫描(single photon emission computed tomography, SPECT)和超声波。这些技术作为肿瘤分子影像工具已经越来越多地用于评价特定的肿瘤分子学特征，例如肿瘤细胞、血管血液灌注和渗透率、新陈代谢、组织缺氧以及其他特定的细胞和分子过程。此外，由于目前很多抗癌药物的作用机理是改变特定的肿瘤特性，用于报导这一现象的成像方法将有助于改进治疗方法、评估肿瘤疗效。这是一个合理的假设,使用适当的无创的肿瘤分子影像工具来进一步评估肿瘤状态将更进一步提高治疗反应评估的灵敏度和特异度。然而,到目前为止，除了影像学方面的客观进展以及临床前期研究，这些技术很少应用于临床肿瘤疗效预测与评价。
显然，急需先进的影像学方法以描述特定的靶向药物治疗所导致的肿瘤潜在的病理生理变化，这样的方法较肿瘤大小测量有可能更早、更特定地显示肿瘤对治疗反应的变化。目前，MR扩散加权成像技术（diffusion weighted imaging，DWI）以及动态增强MRI(dynamic contrast-enhanced magnetic resonance imaging，DCE-MRI)技术已经成熟，通过测量表观扩散系数（apparent diffusion coefficient,ADC），可以提供组织状态的定量信息，有可能更好地洞察肿瘤特定的生物学以及生理学特征，提供肿瘤状态的更量化更特定的信息。尽管这些技术不直接显示特定分子的变化或活动,他们已经为靶向疗法提供了重要而可靠的直接结果指标。本研究通过与胃镜活组织检查结果及实体瘤疗效评价标准（ResponseEvaluation Criteria In Solid Tumors, RECIST）进行对照，重点探讨MR扩散加权成像在胃癌筛查与诊断、进展期胃癌疗效预测及评价中的应用价值。
材料与方法
目的：
探讨MR扩散加权成像在胃癌筛查与诊断、进展期胃癌疗效早期预测与评价中的应用价值，期望可以将MR扩散加权成像这一技术整合到临床实践中，以便像RECIST标准一样纳入实体瘤疗效评价指导方针。
研究对象：
1.本研究经我院伦理委员会批准，所有患者知情同意并签署知情同意书。选择2008年8月-2013年6月之间疑似胃癌并在我院行常规MRI+DWI扫描(1.5T飞利浦扫描仪)的患者60人（男44人，女16人，年龄41-85岁，平均66.9±10.9岁），与胃镜活组织检查病理学结果进行对照，评价MR扩散加权成像在胃癌筛查与诊断中的应用价值。其中健康对照组20人（男12人，女8人，年龄45-71岁，平均年龄59.5±10.34岁）。
2.对胃镜活检确诊为腺癌、临床资料完整、未行任何抗肿瘤治疗的进展期胃癌患者30人（男23人，女7人，年龄40-85岁，平均年龄71.53±10.64岁）于化疗前、化疗4周期行MRI+DWI扫描，同时记录患者一般资料、化疗前KPS评分、化疗方案、血小板水平、肿瘤生物学标记物、T细胞亚群等检查结果，与最终疗效确认结果进行对照，探讨MR扩散加权成像及胃癌相关因素在进展期胃癌疗效预测中的价值。
3.对胃镜活检确诊为腺癌、临床资料完整、未行任何抗肿瘤治疗的进展期胃癌患者21人（男16人，女5人，年龄54-85岁，平均年龄71.90±9.81岁）于化疗前、化疗2周期、4周期均行MRI+DWI检查，对照实体瘤形态学疗效评价标准——RICIST标准，探讨MR扩散加权成像所测定量指标ADC值在进展期胃癌早期疗效评价中的应用价值。
结果
1.共60例疑似患者最终经胃镜活检确诊胃癌48例。MRI+DWI共诊断胃癌44例，误诊3例，漏诊4例早期胃癌患者（T1期），MRI+DWI诊断胃癌灵敏度91.7%，特异度75%，正确指数66.7%，假阴性率8.3%，假阳性率25%，总符合率88.3%，阳性预测值93.6%，阴性预测值69.2%。胃癌组病灶平均ADC值（1.52±0.63）×10-3mm2/s，最小ADC值（1.21±0.46）×10-3mm2/s，正常胃壁平均ADC值（1.85±0.23）×10-3mm2/s，最小ADC值（1.59±0.17）×10-3mm2/s，胃癌组平均ADC值及最小ADC值均低于正常胃壁，差异具有统计学意义（P<0.05）。
2.30例胃腺癌患者，最终经疗效确认分为有缓解组与无缓解组两组。有缓解组8例，化疗前平均ADC、最小ADC分别为[（1.11±0.43）×10-3mm2/s vs.（0.87±0.32）×10-3mm2/s]；无缓解组22例，化疗前平均ADC、最小ADC分别约[（1.75±0.68）×10-3mm2/s vs.（1.39±0.39）×10-3mm2/s],有缓解组化疗前平均ADC、最小ADC均明显低于无缓解组，差异具有统计学意义（P <0.05）。受试者工作特征曲线（Receiver operating characteristic，ROC）分析结果显示，化疗前平均ADC值ROC曲线下面积（Area Under the Curve，AUC)0.815，取临界点0.98×10-3mm2/s，其诊断胃癌的灵敏度、特异度、阳性似然比、阴性似然比分别是75.0%，90.91%，8.25，0.28；化疗前最小ADC值ROC曲线下面积0.838，临界点取0.80×10-3mm2/s，其诊断胃癌的灵敏度、特异度、阳性似然比、阴性似然比分别是87.5%，90.91%，9.62，0.14。
3.有缓解组与无缓解组间在KPS评分及化疗方案方面具有统计学差异（P<0.05），在血小板、肿瘤生物学标记物及T细胞亚群等方面没有明显统计学差异（P>0.05）。
4.进展期胃癌化疗早期，有缓解组、无缓解组间最小ADC变化率差异显著（P <0.05）。ROC分析显示曲线下面积0.788，取临界点11.3%，化疗早期最小ADC变化率（%△ADCmin2）评价化疗反应有效的灵敏度为87.5%，特异度69.23%，阳性似然比2.84，阴性似然比0.18。两组间在平均ADC变化率、厚度、长径及其变化率方面均没有统计学差异（P>0.05）。
5.化疗4周期后两组间厚度差异具有统计学意义（P<0.05）。
6.化疗4周期两组间最小ADC及平均ADC变化率、厚度及长径变化率均有统计学差异，均可以用于疗效评价（P <0.05）。
7.本组研究对象共21人，至追踪结束生存4人，死亡17人。生存分析显示，有缓解组中位生存期12月，无缓解组13月，二者间没有明显统计学差异（P=0.457）。化疗2周期病灶最小ADC变化率与中位生存期之间没有明显相关性（r=0.017，P=0.942）。
结论
1. MR扩散加权成像可以用于胃癌的诊断。
2.表观扩散系数（平均ADC及最小ADC）可以用于进展期胃癌疗效预测，最小ADC较平均ADC更有优势。
3.最小ADC变化率可以用于进展期胃癌化疗疗效早期评价。
Gastric cancer is one of the most common malignant tumors. It is the secondmost common tumor in our country, and is influenced by geographic, ethnic, andsocioeconomic factors. Chemotherapy has been used as an attempt to controlcancer-related symptoms, improve quality of life and prolong survival in advancedganstric cancer. However，the assesment of tumor response to chemotherapy is stillvery important.
Medical imaging plays a vital role for not only the diagnosis of gastric cancer,but also the evaluation, tumor metastasis and recurrence. Imaging methods, includingX-ray, computed tomography (CT) or magnetic resonance imaging (MRI), can all beused in the evaluation of solid tumor response to treatment. The most commonly usedway is to measure the diameter of the lesions in one direction. However, in general,tumor size only changes at the middle or end of a course of treatment, so it can’t beused in change or adjust the regimen or measure tumor response during the earlyperiod of treatment. In addition, for a period of time, the design of antineoplasticdrugs is to influence the characteristics of specific tumor. Targeted drugs alwaysinduce necrosis and cavitation, which means that effective therapy does notnecessarily result in a reduction of tumour volume. This has increased the interest inapplications of functional imaging techniques such as diffusion-weighted imaging(DWI) and dynamic contrast enhanced MRI (DCE-MRI), which are more sensitive, more specific for tumor response prediction. Early prediction and evaluation oftreatment response might be able to make tumor therapy more efficient and to guideindividual treatment. This is very important for clinical research and is expected tofurther advance the pace of tumor therapy.
Imaging methods that could quantitatively measure the tumor characteristicshave increased significantly in recent years, including magnetic resonance imaging(MRI), optical imaging, positron emission tomography (PET), single photon emissioncomputed tomography (SPECT) and ultrasound. These techniques have beenincreasingly used as the tool of tumor biological marker in the evaluation of specifictumor cells and tumor molecular characteristics, such as blood vessels, perfusion andpermeability, metabolism, hypoxia and other specific cellular and molecularprocesseses. In addition, currently, the mechanism of most antitumor drugs is tochange the specific tumor characteristics. Based on reports of this phenomenon, thekinds of imaging methods will help to improve the method of treatment and assessthe effect of tumor responses. This is a reasonable assumption， using someappropriate and noninvasive imaging methods to assese the theropy response totreatment will further improve the sensitivity and specificity of diagnosis. However,so far, these technologies are seldom applied in the prediction and early assessment oftumor response in addition to the imaging and objective progress in preclinicalstudies.
Obviously，advanced imaging methods that can provide molecular imaging areurgently required to describe the potential pathophysiologic change of tumor inducedby specific targeted drugs. In comparison with tumor size, this way may be morespecific and earlier to provide an earlier indication of tumor response to treatment.Ultimately, these methods will enable earlier cessation of ineffective treatments,minimizing unnecessary toxicity and expenditure. Both DWI and DCE-MRI had beenused in clinical studies at present. By measuring the apparent diffusion coefficient(ADC)，DWI can provide the quantitative information of organization，better insightinto the biological and physiological characteristics of a certain type of cancer. Thepurpose of this study was to investigate the value of DWI in helping diagnosis of gastric tumors and making a comparison with the endoscopic biopsy results, toevaluate the predictive and monitoring role of DWI in tumor response tochemotheropy by means of measuring the ADC values of these lesions. To date, as faras we are concerned, no previous studies that have been reported.
METHODS AND MATERIALS
Objective:
To integrated the technology MR-diffusion weighted imaging into clinicalpractice as soon as possible, to see whether it can be used just like the RECISTcriteria, which might be useful for earlier predictive and assesement of gastric cancer.
Methods:
1. The study was approved by our institutional review board, and informedconsent was obtained from all patients. Between August2008and June2013, MRIand diffusion weighted imaging (Philips Healthcare, Best, The Netherlands,1.5T,Intera scanners) was performed for60patients who was suspected cancer of thestomach(44men and16women; age range41-85years, average66.9±10.9years).For the control group20healthy individuals (male12, female8, age range45-71years, average59.5±10.34years) were included. The purpose of this study was toevaluate the role of MR diffusion weighted imaging in the diagnosis of gastric cancerin comparison with gastroscope biopsy results, to provide the basis for the followingstudies.
2. Routine abdominal MRI and DWI examinations were performed on a1.5-TMRI scanner. Thirty patients with advanced gastric adenocarcinoma (23men and7women, age range40-85years, average71.53±10.64years) who had not received anyanti-tumor treatment before chemotherapy were included in this study. The patients’general information, KPS score, chemotherapy regimens, platelet levels, tumorbiological markers and T cell subgroup test results before chemotherapy were allrecorded. The aim was to evaluate the predictive value of apparent diffusioncoefficient and gastric cancer related factors in gastric cancer according to the resultsof the curative effect.
3. IN order to see whether apparent diffusion coefficient values might be used asa universal biomarker for response evaluation in advanced gastric cancer, weinvestigated the association between apparent diffusion coefficient changes of thelesions and tumor response to chemotherapy. Twenty-one patients with advanced gastric adenocarcinoma (male16, female5, age range54-85years, average71.90±9.81years) who had not received any anti-tumor treatment constituted the case group.MRI including DWI examinations was performed before chemotherapy, after2cyclesand4cycles of chemotherapy.
Results
1. A total of48/60patients were finally confirmed as gastric cancer bygastroscope biopsy.44/60gastric cancers were diagnosed by MRI+DWI. Three caseswere misdiagnosed and four were missed diagnosed（T1stage）. The sensitivity,specificity, Youden’s index, false negative rate, false positive rate, agreement rate,positive predictive value and negative predictive value were respectively91.7%,75%,66.7%,8.3%,25%,88.3%,93.6%and69.2%. Average ADC and minimum ADCwere respectively (1.52±0.63)×10-3mm2/s vs.(1.21±0.46)×10-3mm2/s in gastriccancer group. ADC values in control group (average ADC and minimum ADC) were(1.85±0.23)×10-3mm2/s vs.(1.59±0.17)×10-3mm2/s. The ADC values of gastric cancergroup (both average and minimum ADC) were significantly lower than that of controlgroup, which was statistically significant (P <0.05).
2. A total of thirty gastric adenocarcinoma patients were divided into two groups,in which cases in response group and no-response group were respectively8and22.The average ADC values before chemotherapy in response groupwere (1.11±0.43)×10-3mm2/s which were lower than that in no-responsegroup(1.75±0.66)×10-3mm2/s（P<0.05）. Receiver operating characteristic (ROC)analysis showed an area under the curve (AUC) of0.815at an optimal cutoff value of0.98×10-3mm2/s. This allowed for a prediction of gastric cancer with a sensitivity of75%, a specificity of90.91%, positive likelihood ratio of8.25, andnegative likelihood ratio of0.28.
The minimum ADC values before chemotherapy in response group were lowerthan that in no-response group too [(0.87±0.32)×10-3mm2/s vs.（1.39±0.39）×10-3mm2/s, P <0.05]. ROC analysis showed an AUC of0.838at an optimal cutoffvalue of0.98×10-3mm2/s. This allowed for a prediction of gastric cancer with asensitivity of87.5%, a specificity of90.91%, positive likelihood ratio of9.62, andnegative likelihood ratio of0.14（P <0.05）.
3. There was a statistically significant diffrence between the two groups inchemotherapy regimens and KPS scores（P <0.05）. However, no significant difference was found in platelets, tumor biological markers, T cell subgroup and soon（P>0.05）.
4. There was a statistically significant diffrence between the two groups in rateof minimum ADC change in the earlier period of chemoterapy (after two circles, P <0.05). ROC analysis showed an AUC of0.788at an optimal cutoff value of11.3%.This allowed for a prediction of response group with a sensitivity of87.5%, aspecificity of69.23%, positive likelihood ratio of2.84, and negative likelihood ratioof0.18. However, no significant difference was found in rate of thickness, length andaverage ADC changes（P>0.05）.
5. There was a statistically significant diffrence between the two groups inthinkness at the late period of chemotherapy（after four circles, P <0.05）.
6. There was a statistically significant diffrence between the two groups in rateof thickness, length, verage and minimum ADC change at the late period ofchemotherapy（after four circles, P <0.05）.
7. Survival analysis showed that the difference in median survival between thetwo groups divided by RECIST criteria was not statistically significant（12monthsin response group and13months in no-response group, P=0.457）. There was nosignificant correlation between rate of earlier minimum ADC change and survival（r=0.017，P=0.942）.
Conclusion
1. Diffusion weighted magnetic resonance imaging can be used in the diagnosisof ganstric cancer by the aid of ADC measurements.
2. The apparent diffusion coefficient (both average and minimum ADC values)seemed to be a promising tool for helping predict tumor response to chemotherapy inadvanced ganstric cancer，minimum ADC values was slightly better than the average.
3. Rate of minimum ADC change might be a promising tool for monitoringtherapeutic responses in advanced ganstric cancer at an earlier stage that could bewidely used.
影像医学对于胃癌的诊断起着至关重要的作用，同样，在胃癌疗效评价、肿瘤复发和转移的监测中，影像医学也发挥着重要的作用。当前，评估实体瘤治疗反应的影像学方法主要有X线、计算机断层扫描(computed tomography，CT)或磁共振成像(magnetic resonance imaging，MRI)，通常测量病灶在一个方向上大小的变化。然而，即使病灶大小测量能够反应病灶真实体积的变化，往往也要在治疗数个周期后尚可发现药物对病灶体积的影响。此外，当前和今后一段时间，抗肿瘤药物的设计主要通过高度影响特定肿瘤的特性来抗肿瘤，可能不会立即引起细胞毒性反应，这就需要更敏感、更特异的能够在治疗早期反应肿瘤状态和治疗反应的方法，以便能够可重复、定量、非侵入、可靠地评估肿瘤疗效，这将可以进一步推进肿瘤疗效监测的步伐，对于临床研究非常重要。
近年来，能够定量地测量肿瘤特征的影像学方法已经显著增加。他们包括MRI、光学成像、正电子发射计算机断层扫描(positron emission tomograph，PET)、单光子发射计算机断层扫描(single photon emission computed tomography, SPECT)和超声波。这些技术作为肿瘤分子影像工具已经越来越多地用于评价特定的肿瘤分子学特征，例如肿瘤细胞、血管血液灌注和渗透率、新陈代谢、组织缺氧以及其他特定的细胞和分子过程。此外，由于目前很多抗癌药物的作用机理是改变特定的肿瘤特性，用于报导这一现象的成像方法将有助于改进治疗方法、评估肿瘤疗效。这是一个合理的假设,使用适当的无创的肿瘤分子影像工具来进一步评估肿瘤状态将更进一步提高治疗反应评估的灵敏度和特异度。然而,到目前为止，除了影像学方面的客观进展以及临床前期研究，这些技术很少应用于临床肿瘤疗效预测与评价。
显然，急需先进的影像学方法以描述特定的靶向药物治疗所导致的肿瘤潜在的病理生理变化，这样的方法较肿瘤大小测量有可能更早、更特定地显示肿瘤对治疗反应的变化。目前，MR扩散加权成像技术（diffusion weighted imaging，DWI）以及动态增强MRI(dynamic contrast-enhanced magnetic resonance imaging，DCE-MRI)技术已经成熟，通过测量表观扩散系数（apparent diffusion coefficient,ADC），可以提供组织状态的定量信息，有可能更好地洞察肿瘤特定的生物学以及生理学特征，提供肿瘤状态的更量化更特定的信息。尽管这些技术不直接显示特定分子的变化或活动,他们已经为靶向疗法提供了重要而可靠的直接结果指标。本研究通过与胃镜活组织检查结果及实体瘤疗效评价标准（ResponseEvaluation Criteria In Solid Tumors, RECIST）进行对照，重点探讨MR扩散加权成像在胃癌筛查与诊断、进展期胃癌疗效预测及评价中的应用价值。
材料与方法
目的：
探讨MR扩散加权成像在胃癌筛查与诊断、进展期胃癌疗效早期预测与评价中的应用价值，期望可以将MR扩散加权成像这一技术整合到临床实践中，以便像RECIST标准一样纳入实体瘤疗效评价指导方针。
研究对象：
1.本研究经我院伦理委员会批准，所有患者知情同意并签署知情同意书。选择2008年8月-2013年6月之间疑似胃癌并在我院行常规MRI+DWI扫描(1.5T飞利浦扫描仪)的患者60人（男44人，女16人，年龄41-85岁，平均66.9±10.9岁），与胃镜活组织检查病理学结果进行对照，评价MR扩散加权成像在胃癌筛查与诊断中的应用价值。其中健康对照组20人（男12人，女8人，年龄45-71岁，平均年龄59.5±10.34岁）。
2.对胃镜活检确诊为腺癌、临床资料完整、未行任何抗肿瘤治疗的进展期胃癌患者30人（男23人，女7人，年龄40-85岁，平均年龄71.53±10.64岁）于化疗前、化疗4周期行MRI+DWI扫描，同时记录患者一般资料、化疗前KPS评分、化疗方案、血小板水平、肿瘤生物学标记物、T细胞亚群等检查结果，与最终疗效确认结果进行对照，探讨MR扩散加权成像及胃癌相关因素在进展期胃癌疗效预测中的价值。
3.对胃镜活检确诊为腺癌、临床资料完整、未行任何抗肿瘤治疗的进展期胃癌患者21人（男16人，女5人，年龄54-85岁，平均年龄71.90±9.81岁）于化疗前、化疗2周期、4周期均行MRI+DWI检查，对照实体瘤形态学疗效评价标准——RICIST标准，探讨MR扩散加权成像所测定量指标ADC值在进展期胃癌早期疗效评价中的应用价值。
结果
1.共60例疑似患者最终经胃镜活检确诊胃癌48例。MRI+DWI共诊断胃癌44例，误诊3例，漏诊4例早期胃癌患者（T1期），MRI+DWI诊断胃癌灵敏度91.7%，特异度75%，正确指数66.7%，假阴性率8.3%，假阳性率25%，总符合率88.3%，阳性预测值93.6%，阴性预测值69.2%。胃癌组病灶平均ADC值（1.52±0.63）×10-3mm2/s，最小ADC值（1.21±0.46）×10-3mm2/s，正常胃壁平均ADC值（1.85±0.23）×10-3mm2/s，最小ADC值（1.59±0.17）×10-3mm2/s，胃癌组平均ADC值及最小ADC值均低于正常胃壁，差异具有统计学意义（P<0.05）。
2.30例胃腺癌患者，最终经疗效确认分为有缓解组与无缓解组两组。有缓解组8例，化疗前平均ADC、最小ADC分别为[（1.11±0.43）×10-3mm2/s vs.（0.87±0.32）×10-3mm2/s]；无缓解组22例，化疗前平均ADC、最小ADC分别约[（1.75±0.68）×10-3mm2/s vs.（1.39±0.39）×10-3mm2/s],有缓解组化疗前平均ADC、最小ADC均明显低于无缓解组，差异具有统计学意义（P <0.05）。受试者工作特征曲线（Receiver operating characteristic，ROC）分析结果显示，化疗前平均ADC值ROC曲线下面积（Area Under the Curve，AUC)0.815，取临界点0.98×10-3mm2/s，其诊断胃癌的灵敏度、特异度、阳性似然比、阴性似然比分别是75.0%，90.91%，8.25，0.28；化疗前最小ADC值ROC曲线下面积0.838，临界点取0.80×10-3mm2/s，其诊断胃癌的灵敏度、特异度、阳性似然比、阴性似然比分别是87.5%，90.91%，9.62，0.14。
3.有缓解组与无缓解组间在KPS评分及化疗方案方面具有统计学差异（P<0.05），在血小板、肿瘤生物学标记物及T细胞亚群等方面没有明显统计学差异（P>0.05）。
4.进展期胃癌化疗早期，有缓解组、无缓解组间最小ADC变化率差异显著（P <0.05）。ROC分析显示曲线下面积0.788，取临界点11.3%，化疗早期最小ADC变化率（%△ADCmin2）评价化疗反应有效的灵敏度为87.5%，特异度69.23%，阳性似然比2.84，阴性似然比0.18。两组间在平均ADC变化率、厚度、长径及其变化率方面均没有统计学差异（P>0.05）。
5.化疗4周期后两组间厚度差异具有统计学意义（P<0.05）。
6.化疗4周期两组间最小ADC及平均ADC变化率、厚度及长径变化率均有统计学差异，均可以用于疗效评价（P <0.05）。
7.本组研究对象共21人，至追踪结束生存4人，死亡17人。生存分析显示，有缓解组中位生存期12月，无缓解组13月，二者间没有明显统计学差异（P=0.457）。化疗2周期病灶最小ADC变化率与中位生存期之间没有明显相关性（r=0.017，P=0.942）。
结论
1. MR扩散加权成像可以用于胃癌的诊断。
2.表观扩散系数（平均ADC及最小ADC）可以用于进展期胃癌疗效预测，最小ADC较平均ADC更有优势。
3.最小ADC变化率可以用于进展期胃癌化疗疗效早期评价。
Gastric cancer is one of the most common malignant tumors. It is the secondmost common tumor in our country, and is influenced by geographic, ethnic, andsocioeconomic factors. Chemotherapy has been used as an attempt to controlcancer-related symptoms, improve quality of life and prolong survival in advancedganstric cancer. However，the assesment of tumor response to chemotherapy is stillvery important.
Medical imaging plays a vital role for not only the diagnosis of gastric cancer,but also the evaluation, tumor metastasis and recurrence. Imaging methods, includingX-ray, computed tomography (CT) or magnetic resonance imaging (MRI), can all beused in the evaluation of solid tumor response to treatment. The most commonly usedway is to measure the diameter of the lesions in one direction. However, in general,tumor size only changes at the middle or end of a course of treatment, so it can’t beused in change or adjust the regimen or measure tumor response during the earlyperiod of treatment. In addition, for a period of time, the design of antineoplasticdrugs is to influence the characteristics of specific tumor. Targeted drugs alwaysinduce necrosis and cavitation, which means that effective therapy does notnecessarily result in a reduction of tumour volume. This has increased the interest inapplications of functional imaging techniques such as diffusion-weighted imaging(DWI) and dynamic contrast enhanced MRI (DCE-MRI), which are more sensitive, more specific for tumor response prediction. Early prediction and evaluation oftreatment response might be able to make tumor therapy more efficient and to guideindividual treatment. This is very important for clinical research and is expected tofurther advance the pace of tumor therapy.
Imaging methods that could quantitatively measure the tumor characteristicshave increased significantly in recent years, including magnetic resonance imaging(MRI), optical imaging, positron emission tomography (PET), single photon emissioncomputed tomography (SPECT) and ultrasound. These techniques have beenincreasingly used as the tool of tumor biological marker in the evaluation of specifictumor cells and tumor molecular characteristics, such as blood vessels, perfusion andpermeability, metabolism, hypoxia and other specific cellular and molecularprocesseses. In addition, currently, the mechanism of most antitumor drugs is tochange the specific tumor characteristics. Based on reports of this phenomenon, thekinds of imaging methods will help to improve the method of treatment and assessthe effect of tumor responses. This is a reasonable assumption， using someappropriate and noninvasive imaging methods to assese the theropy response totreatment will further improve the sensitivity and specificity of diagnosis. However,so far, these technologies are seldom applied in the prediction and early assessment oftumor response in addition to the imaging and objective progress in preclinicalstudies.
Obviously，advanced imaging methods that can provide molecular imaging areurgently required to describe the potential pathophysiologic change of tumor inducedby specific targeted drugs. In comparison with tumor size, this way may be morespecific and earlier to provide an earlier indication of tumor response to treatment.Ultimately, these methods will enable earlier cessation of ineffective treatments,minimizing unnecessary toxicity and expenditure. Both DWI and DCE-MRI had beenused in clinical studies at present. By measuring the apparent diffusion coefficient(ADC)，DWI can provide the quantitative information of organization，better insightinto the biological and physiological characteristics of a certain type of cancer. Thepurpose of this study was to investigate the value of DWI in helping diagnosis of gastric tumors and making a comparison with the endoscopic biopsy results, toevaluate the predictive and monitoring role of DWI in tumor response tochemotheropy by means of measuring the ADC values of these lesions. To date, as faras we are concerned, no previous studies that have been reported.
METHODS AND MATERIALS
Objective:
To integrated the technology MR-diffusion weighted imaging into clinicalpractice as soon as possible, to see whether it can be used just like the RECISTcriteria, which might be useful for earlier predictive and assesement of gastric cancer.
Methods:
1. The study was approved by our institutional review board, and informedconsent was obtained from all patients. Between August2008and June2013, MRIand diffusion weighted imaging (Philips Healthcare, Best, The Netherlands,1.5T,Intera scanners) was performed for60patients who was suspected cancer of thestomach(44men and16women; age range41-85years, average66.9±10.9years).For the control group20healthy individuals (male12, female8, age range45-71years, average59.5±10.34years) were included. The purpose of this study was toevaluate the role of MR diffusion weighted imaging in the diagnosis of gastric cancerin comparison with gastroscope biopsy results, to provide the basis for the followingstudies.
2. Routine abdominal MRI and DWI examinations were performed on a1.5-TMRI scanner. Thirty patients with advanced gastric adenocarcinoma (23men and7women, age range40-85years, average71.53±10.64years) who had not received anyanti-tumor treatment before chemotherapy were included in this study. The patients’general information, KPS score, chemotherapy regimens, platelet levels, tumorbiological markers and T cell subgroup test results before chemotherapy were allrecorded. The aim was to evaluate the predictive value of apparent diffusioncoefficient and gastric cancer related factors in gastric cancer according to the resultsof the curative effect.
3. IN order to see whether apparent diffusion coefficient values might be used asa universal biomarker for response evaluation in advanced gastric cancer, weinvestigated the association between apparent diffusion coefficient changes of thelesions and tumor response to chemotherapy. Twenty-one patients with advanced gastric adenocarcinoma (male16, female5, age range54-85years, average71.90±9.81years) who had not received any anti-tumor treatment constituted the case group.MRI including DWI examinations was performed before chemotherapy, after2cyclesand4cycles of chemotherapy.
Results
1. A total of48/60patients were finally confirmed as gastric cancer bygastroscope biopsy.44/60gastric cancers were diagnosed by MRI+DWI. Three caseswere misdiagnosed and four were missed diagnosed（T1stage）. The sensitivity,specificity, Youden’s index, false negative rate, false positive rate, agreement rate,positive predictive value and negative predictive value were respectively91.7%,75%,66.7%,8.3%,25%,88.3%,93.6%and69.2%. Average ADC and minimum ADCwere respectively (1.52±0.63)×10-3mm2/s vs.(1.21±0.46)×10-3mm2/s in gastriccancer group. ADC values in control group (average ADC and minimum ADC) were(1.85±0.23)×10-3mm2/s vs.(1.59±0.17)×10-3mm2/s. The ADC values of gastric cancergroup (both average and minimum ADC) were significantly lower than that of controlgroup, which was statistically significant (P <0.05).
2. A total of thirty gastric adenocarcinoma patients were divided into two groups,in which cases in response group and no-response group were respectively8and22.The average ADC values before chemotherapy in response groupwere (1.11±0.43)×10-3mm2/s which were lower than that in no-responsegroup(1.75±0.66)×10-3mm2/s（P<0.05）. Receiver operating characteristic (ROC)analysis showed an area under the curve (AUC) of0.815at an optimal cutoff value of0.98×10-3mm2/s. This allowed for a prediction of gastric cancer with a sensitivity of75%, a specificity of90.91%, positive likelihood ratio of8.25, andnegative likelihood ratio of0.28.
The minimum ADC values before chemotherapy in response group were lowerthan that in no-response group too [(0.87±0.32)×10-3mm2/s vs.（1.39±0.39）×10-3mm2/s, P <0.05]. ROC analysis showed an AUC of0.838at an optimal cutoffvalue of0.98×10-3mm2/s. This allowed for a prediction of gastric cancer with asensitivity of87.5%, a specificity of90.91%, positive likelihood ratio of9.62, andnegative likelihood ratio of0.14（P <0.05）.
3. There was a statistically significant diffrence between the two groups inchemotherapy regimens and KPS scores（P <0.05）. However, no significant difference was found in platelets, tumor biological markers, T cell subgroup and soon（P>0.05）.
4. There was a statistically significant diffrence between the two groups in rateof minimum ADC change in the earlier period of chemoterapy (after two circles, P <0.05). ROC analysis showed an AUC of0.788at an optimal cutoff value of11.3%.This allowed for a prediction of response group with a sensitivity of87.5%, aspecificity of69.23%, positive likelihood ratio of2.84, and negative likelihood ratioof0.18. However, no significant difference was found in rate of thickness, length andaverage ADC changes（P>0.05）.
5. There was a statistically significant diffrence between the two groups inthinkness at the late period of chemotherapy（after four circles, P <0.05）.
6. There was a statistically significant diffrence between the two groups in rateof thickness, length, verage and minimum ADC change at the late period ofchemotherapy（after four circles, P <0.05）.
7. Survival analysis showed that the difference in median survival between thetwo groups divided by RECIST criteria was not statistically significant（12monthsin response group and13months in no-response group, P=0.457）. There was nosignificant correlation between rate of earlier minimum ADC change and survival（r=0.017，P=0.942）.
Conclusion
1. Diffusion weighted magnetic resonance imaging can be used in the diagnosisof ganstric cancer by the aid of ADC measurements.
2. The apparent diffusion coefficient (both average and minimum ADC values)seemed to be a promising tool for helping predict tumor response to chemotherapy inadvanced ganstric cancer，minimum ADC values was slightly better than the average.
3. Rate of minimum ADC change might be a promising tool for monitoringtherapeutic responses in advanced ganstric cancer at an earlier stage that could bewidely used.
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