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【medical-news】分子学治疗或开创脑胶质瘤患者个体化治疗的新时代
【medical-news】分子学治疗或开创脑胶质瘤患者个体化治疗的新时代
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Molecular characterization leads the wayRogerStupp and Monika E. HegiIn 2012,advances in molecular profiling of primary brain tumours allowed identificationof subgroups of glioma and medulloblastoma that were associated with distinctprognoses and predicted treatment response. Adjuvant chemotherapy is nowestablished for 1p/19q co-deleted anaplastic oligodendrogliomas, and may be thepreferred treatment in elderly patients with glioblastoma with a methylated MGMT promoter.Keyadvances■■ Molecular marker analyses should bepart of the standard diagnostic workup in all 1–3,7 prognostic and predictive markers have direct implications inroutine clinical decision making■■ Long-term follow-up for &11 years demonstratedthat adjuvant chemotherapyprolongssurvival in patients with anaplastic oligodendroglioma harbouring a co-deletionon chromosomes 1p/19q3■■ Systematic profiling ofmedulloblastoma has led to a clinically relevant molecular classification andprognostication, allowing for risk-adapted treatmentstrategiesand novel therapeutic targetsResearch andtreatment of primary brain tumours has unique challenges, such as access totumour tissue, as only small quantities of mostly heterogeneous tumours are availablefor study. Despite these obstacles, important research focused on tumourbiology hasestablished definitively the value of molecular markers in the management of malignantglioma. Co-deletion of 1p/19q and methylation of the methylguanine methyltransferase(MGMT) gene promoter allowsselection of the optimal treatment strategy for patients with glioblastoma and anaplasticoligodendroglial tumours.Two randomizedtrials published in 2012 evaluated the role of temozolomide chemotherapy versusradiotherapy in the management of elderly patients (&60–70 years) with malignant glioma.1,2 In both trials, tumour tissuewas collected, and the methylation status of MGMT was assessed. MGMT is a DNA repair enzyme that blunts thecytotoxic effect of alkylating agents such as temozolomide. Overall, mediansurvival is unsatisfactory (6–10months) with no substantial advantage of chemotherapy over radiotherapy. However,both trials demonstrated that patients with an epigenetically silenced MGMT gene fared betterwhen treated with temozolomide, whereas patients with an unmethylated MGMT promoter had alongersurvival withinitial radiotherapy. These results corroborate earlier findings regarding thevalue of MGMT methylation as a predictive marker for the benefit oftemozolomide chemotherapy in patients with glioblastoma.Oligodendroglialtumours are a distinct entity characterized by a prolonged naturalhistory and anexquisite response to chemotherapy or radiotherapy. So far, however,adjuvantchemotherapy has failed to improve survival in unselected patients withanaplasticoligodendroglial tumours. Long term follow-up in 2012 of two randomizedtrials that wereinitiated almost 18 years ago and that investigated adjuvant PCV (procarbazine,lomustine, vincristine) chemotherapy before or after radiotherapy has now shownan improvement in overall survival with adjuvant treatment.3 Molecular tumour analysisdemonstrated that only patients with a combined deletion of chromosomes 1p and19q, mediated by a translocation [t(1;19)(q10;p10)], benefit from the early introductionof chemotherapy.3Management oflow-grade (grade II) glioma remains controversial. Radiotherapyat initialdiagnosis does not increase overall survival compared with radiationgiven at tumourprogression, and the role of chemotherapy is unclear. In 2012, theRTOG9802randomized Intergroup study evaluated radiotherapy with or without adjuvantPCV-chemotherapy in high-risk patients with low-grade (grade II) glioma.4Between 1998 and patients were randomly assigned to receive radiotherapyalone orradiotherapy followed by adjuvant chemoradiation. Progression-freesurvival improvedwith a however, the primary end pointwas not met—no overall survival benefit was demonstrated. Nevertheless, whenpatients with worst prognosis (16%, defined as patients dying within 2 yearsand thus likely harbouring an unrecognized higher grade tumour) were excludedfrom the analysis, only those patients who remained alive after 2 years seemedto derive a benefit from adjuvant chemotherapy.4 Molecular tumour data are notyet available, and the first results of the EORTC-led Intergroup trial (EORTC/NCIC CE.5) comparingdose-intense temozolomide chemotherapy (21 days of a 28-day cycle) versusradiotherapy are expected in 2013. In this trial, tumour tissue has been prospectivelyanalysed for molecular markers, and patients have been stratified for thepresence of the 1p deletion, a known favourable prognostic factor.Virtually allpatients with malignant glioma will experience tumour recurrence. Inhibition ofVEGF has resulted in impressive radiological responses with an unprecedentedrapid decrease in contrast enhancement and reduction in peritumouraloedema. However,whether this temporary restoration of the blood–brainbarriertranslates intoprolonged survival and a benefit to patients remains the subject of vividcontroversy. The anti-VEGF antibody bevacizumab has finally been investigated ina randomized phase III trial in patients with newly diagnosed glioblastoma.Initial results of the AvaGlio study were presented in abstract form.5 Asexpected, progressionfree s however, this did not translateinto prolonged overall survival at the first interim analysis. Thus, the true valueof bevacizumab remains unclear, and although it seems to be of benefit inselectedpatients withrecurrent glioma, administration of bevacizumab early in the diseasecourse may not bejustified. Unfortunately, biomarkers for the optimal use of bevacizumab havenot been identified yet. Longer term follow-up and the results of a similarly designedRTOG study are awaited (results are expected for ASCO 2013).An entirely novelcancer treatment modality with alternating electrical fields—the so-called tumour treatment fields (TTF)— is being investigated in newly diagnosed and recurrent glioblastoma.Experimental models have shown that rapidly alternating electrical fieldsinterfere with cell division by disturbing mitotic spindle formation and leadto dielectrophoretic movement of intracellular macromolecules and organelles, resultingin cell death. A randomized controlled phase III trial was conducted in heavilypretreated patients with recurrent glioblastoma. Patients were randomly assignedto either physician’s best choiceof chemotherapy(control) or TTF without any chemotherapy.6 This trial demonstratedthe feasibility ofthis approach, with a slightly higher response rate observed forpatients treatedwith TTF (14% versus 10%, P = 0.2), and fewer severe adverse eventsin the TTF arm.However, no significant difference in overall survival was noted(6.6 months versus6.0 months). On the basis of the observed objective responses with this modalityalone, and synergy with chemotherapy in preclinical models, NovoTTF (NovoCureLtd, Haifa, Israel) is currently under investigation in a phase III clinical trialin patients with newly diagnosed glioblastoma, as an addition to adjuvant or maintenancetemozolomide chemotherapy.Mutations of theisocitrate dehydrogenase (IDH) genes have been identified as an early event ingliomagenesis. These mutations are a typical feature of low-grade glioma, secondary(transformed) higher grade glioma and glioblastoma, and are associated with amore-favourable prognosis. Ongoing research is aimed at targeting this enzyme fortherapeutic purposes. IDH mutations result in a neomorphic reaction yielding theoncometabolite 2?hydroxyglutarate (2HG).Subsequent accumulation of this metabolite in the tumour tissue interferes withthe epigenetic machinery and induces a CpG island methylator phenotype. Recent advanceshave shown that magnetic resonance spectroscopy (MRS) is able to detect 2HG ina non-invasive manner.7 MRS may provide an easier molecular characterization andquantification of glioma, and a way to evaluate the response to therapy earlyin the disease course, because typical morphological response often requiresmonths, and MRI evaluation is often ambiguous in these slow-growing tumours.Growth acceleration and malignant transformation might also be identifiedearlier than with conventional imaging techniques.The importance ofmolecular tumour characterization is also well illustrated by recentdevelopments in medulloblastoma. Systematic molecular profiling has allowedidentification ofat least four distinct molecularly defined subgroups that also correspond tosome clinical features and outcome.8 Whole-genome sequencing and analysis of copy-numberaberrations enables further refinement of the disease subgroups and identificationof relevant new genes or epigenetic alterations.9 New findings were published simultaneouslyin four publications in the August issue of Nature. Importantly, these insights into disease pathogenesisopen avenues for novel treatments. About 30% of patients with medulloblastomashave activation of the sonic hedgehog (SHH) signaling pathway, andsmall-molecule inhibitors of Smoothened, a co-activator of SHH, are beingtested in clinical trials. One such agent, vismodegib is currently being testedin patients with medulloblastoma. In 10% of patients with medulloblastoma, theWnt signaling pathway is activated and is associated with a favourableprognosis.8 This allows de-escalation of treatment intensity while maintaining curativeintent. Despite the rarity of medulloblastoma, the strict collection of freshtumour tissue over many years, and the exceptional international collaborationshave provided unprecedented insights into this disease that will haveconsequences on clinical management.The past yearillustrates how molecular tumour characterization has grown beyondthe exclusiveresearch setting. An increasing number of markers have been validated for theirprognostic and predictive power, and have demonstrated great value for everydayclinical decision making. Furthermore, molecular profiling has improved our understandingof pathogenesis and opens novel avenues for therapeutic approaches. Althoughtherapeutic progress has been rather modest, anecdotal evidence suggeststhat some patientsmay derive a true benefit from dose intensification, antiangiogenic agents andnovel treatment modalities. Better tumour characterization will allowidentification of patients most susceptible who arelikely to benefitfrom a specific treatment— personalized strategies are on the horizon.
回复：【medical-news】分子学治疗或开创脑胶质瘤患者个体化治疗的新时代
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Molecular characterization leads the way分子学特征占主导RogerStupp and Monika E. HegiIn 2012,advances in molecular profiling of primary brain tumours allowed identificationof subgroups of glioma and medulloblastoma that were associated with distinctprognoses and predicted treatment response. Adjuvant chemotherapy is nowestablished for 1p/19q co-deleted anaplastic oligodendrogliomas, and may be thepreferred treatment in elderly patients with glioblastoma with a methylated MGMT promoter.在2012年，随着在原发脑部肿瘤中分子生物学机制分析的进步，使得我们可以确定胶质瘤和髓母细胞瘤的具体亚型与患者的预后和其对治疗的反应有关。目前的辅助化疗针对1p/19q共同缺失的间变性少突胶质细胞瘤，或许这对于甲基化MGMT启动子的老年胶质母细胞瘤患者而言也是推荐的治疗方式。Keyadvances重大进展■■ Molecular marker analyses should bepart of the standard diagnostic workup in all 1–3,7 prognostic and predictive markers have direct implications inroutine clinical decision making在所有胶质瘤患者中，分子生物学标记分析应成为标准诊断工作的一部分，与预后和预测因素相关的标记对日常临床决策中有直接提示意义■■ Long-term follow-up for &11 years demonstratedthat adjuvant chemotherapyprolongssurvival in patients with anaplastic oligodendroglioma harbouring a co-deletionon chromosomes 1p/19q3在染色体1p/19q3存在共缺失的间变性少突胶质细胞瘤患者中，对其长达11年的随访结果证实辅助化疗能延长其生存期■■ Systematic profiling ofmedulloblastoma has led to a clinically relevant molecular classification andprognostication, allowing for risk-adapted treatmentstrategiesand novel therapeutic targets对髓母细胞瘤患者的系统分析得出与临床相关的分子生物学分类和预后信息，使得可以根据风险调整患者治疗策略，以及进行新型的靶向治疗Research andtreatment of primary brain tumours has unique challenges, such as access totumour tissue, as only small quantities of mostly heterogeneous tumours are availablefor study. Despite these obstacles, important research focused on tumourbiology hasestablished definitively the value of molecular markers in the management of malignantglioma. Co-deletion of 1p/19q and methylation of the methylguanine methyltransferase(MGMT) gene promoter allowsselection of the optimal treatment strategy for patients with glioblastoma and anaplasticoligodendroglial tumours.针对原发脑肿瘤的研究和治疗面临着独特的挑战，如如何到达肿瘤组织，又如仅有少量的最异质性的肿瘤可供研究。除了上述困难之外，着眼于肿瘤生物学的相关重要研究提示在治疗恶性胶质瘤的过程中分子生物学标记有着明确且重要的价值。在胶质母细胞瘤患者和间变性少突胶质细胞瘤患者中，可以针对1p/19q共缺失和甲基鸟嘌呤甲基转移酶（MGMT）基因启动子的甲基化来制定最优化的治疗方案。Two randomizedtrials published in 2012 evaluated the role of temozolomide chemotherapy versusradiotherapy in the management of elderly patients (&60–70 years) with malignant glioma.1,2 In both trials, tumour tissuewas collected, and the methylation status of MGMT was assessed. MGMT is a DNA repair enzyme that blunts thecytotoxic effect of alkylating agents such as temozolomide. Overall, mediansurvival is unsatisfactory (6–10months) with no substantial advantage of chemotherapy over radiotherapy. However,both trials demonstrated that patients with an epigenetically silenced MGMT gene fared betterwhen treated with temozolomide, whereas patients with an unmethylated MGMT promoter had alongersurvival withinitial radiotherapy. These results corroborate earlier findings regarding thevalue of MGMT methylation as a predictive marker for the benefit oftemozolomide chemotherapy in patients with glioblastoma.在2012年发表了2个随机研究，该研究的受试者为老年恶性胶质瘤患者（年龄在60岁至70岁之间），在研究中研究者评估了以替莫唑胺为基础的化疗和放疗对上述患者的治疗效果。在上述两个研究中，研究者都收集了肿瘤组织，并评估了MGMT的甲基化状态。MGMT是一种DNA修复酶，会削弱诸如替莫唑胺在内的烷化剂的细胞毒作用。总体而言，在上述两个研究者中，受试者的中位生存期不尽如人意，仅为6-10个月，并且研究者观察到化疗并不优于放疗。然而，两个研究都证实具有表观沉默的MGMT基因的患者对替莫唑胺的反应较好，而对于MGMT启动子未发生甲基化的患者而言，如果一开始就接受放疗，那么他们的生存期更长。这些结果证实了早期研究的结果，即在胶质母细胞瘤患者中，MGMT甲基化能作为患者对替莫唑胺治疗反应的极具价值的预测指标。Oligodendroglialtumours are a distinct entity characterized by a prolonged natural history andan exquisite response to chemotherapy or radiotherapy. So far, however,adjuvantchemotherapy has failed to improve survival in unselected patients withanaplasticoligodendroglial tumours. Long term follow-up in 2012 of two randomizedtrials that wereinitiated almost 18 years ago and that investigated adjuvant PCV (procarbazine,lomustine, vincristine) chemotherapy before or after radiotherapy has now shownan improvement in overall survival with adjuvant treatment.3 Molecular tumour analysisdemonstrated that only patients with a combined deletion of chromosomes 1p and19q, mediated by a translocation [t(1;19)(q10;p10)], benefit from the early introductionof chemotherapy.3少突胶质细胞瘤有其独特的特征，即其自然史较长、对化疗或放疗反应较好。然而，至今为止，辅助化疗并不能改善间变性少突胶质细胞瘤患者的生存期。在2012年发表了2个长期随访的研究的结果，这两个研究都开始于18年前，并探究了在放疗前后添加辅助PCV化疗（甲基苄肼、环己亚硝脲和长春新碱）对患者预后的影响，其结果显示经由上述治疗后能改善患者的总体生存期。对肿瘤的分子学分析证实仅在染色体1p和19q存在共同缺失的患者（由t(1;19)(q10;p10)介导的易位），才能从早期化疗中获益。Management of low-grade(grade II) glioma remains controversial. Radiotherapyat initialdiagnosis does not increase overall survival compared with radiationgiven at tumourprogression, and the role of chemotherapy is unclear. In 2012, theRTOG9802randomized Intergroup study evaluated radiotherapy with or without adjuvantPCV-chemotherapy in high-risk patients with low-grade (grade II) glioma.4Between 1998 and patients were randomly assigned to receive radiotherapyalone orradiotherapy followed by adjuvant chemoradiation. Progression-freesurvival improvedwith a however, the primary end pointwas not met—no overall survival benefit was demonstrated. Nevertheless, whenpatients with worst prognosis (16%, defined as patients dying within 2 yearsand thus likely harbouring an unrecognized higher grade tumour) were excludedfrom the analysis, only those patients who remained alive after 2 years seemedto derive a benefit from adjuvant chemotherapy. Molecular tumour data are notyet available, and the first results of the EORTC-led Intergroup trial (EORTC/NCIC CE.5) comparingdose-intense temozolomide chemotherapy (21 days of a 28-day cycle) versusradiotherapy are expected in 2013. In this trial, tumour tissue has been prospectivelyanalysed for molecular markers, and patients have been stratified for thepresence of the 1p deletion, a known favourable prognostic factor.对于低级别（II级）的胶质瘤的治疗方案仍然存在争议。研究发现，在最初确诊时就给予放疗与在肿瘤出现进展时在进行放疗，对患者的总体生存期的增加无明显影响，并且研究也未发现化疗在上述治疗中所起的作用。在2012年，RTOG9802随机组间研究评价了在低级别（II级）胶质瘤高危患者中放疗联合/不联合辅助PCV化疗的治疗效果。在1998年至2002年期间，有251名患者被随机分为2组，一组仅接受放疗，另一组在放疗后继之以放化疗，观察上述两种方案对患者的疗效。研究者发现，无进展生存期在辅助放化疗组有所改善，但是研究结果并未达到研究的主要终点事件，即没有证实在患者中存在整体生存期的改善。然而，当研究者定义了一类预后最差的患者——占所有患者的16%，定义为在2年内死亡的患者，因此其很有可能为存在未经识别的级别较高的肿瘤的患者，并将其从研究的分析中剔除之后，研究者观察到生存期在2年以上的患者可从辅助化疗中获益。但是目前还无法获得肿瘤的分子学数据，预计在2013年可以得到EORTC组间研究（EORTC /NCIC CE.5）的研究结，在该研究中，比较了强化替莫唑胺化疗（28天的疗程内进行21天治疗）和放疗对患者的疗效。在该研究中，研究者在治疗之前就前瞻性的分析了肿瘤组织的生物学标记，并且根据患者是否存在1p缺失（抑制的预后预测因子）对其进行分层。Virtually all patientswith malignant glioma will experience tumour recurrence. Inhibition of VEGF hasresulted in impressive radiological responses with an unprecedented rapiddecrease in contrast enhancement and reduction in peritumouraloedema. However,whether this temporary restoration of the blood–brainbarriertranslates intoprolonged survival and a benefit to patients remains the subject of vividcontroversy. The anti-VEGF antibody bevacizumab has finally been investigated ina randomized phase III trial in patients with newly diagnosed glioblastoma.Initial results of the AvaGlio study were presented in abstract form. Asexpected, progressionfree s however, this did nottranslate into prolonged overall survival at the first interim analysis. Thus,the true value of bevacizumab remains unclear, and although it seems to be ofbenefit in selectedpatients with recurrent glioma, administration ofbevacizumab early in the disease course may not be justified. Unfortunately, biomarkersfor the optimal use of bevacizumab have not been identified yet. Longer termfollow-up and the results of a similarly designed RTOG study are awaited(results are expected for ASCO 2013).事实上，所有具有恶性胶质瘤的患者一般都会出现肿瘤复发。对VEGG的抑制会导致令人震惊的放射反应，表现为对比增强以前所未有的速度降低，以及肿瘤周围组织水肿的消退。然而，这种血脑屏障的暂时重建是否会转化为患者生存期的延长和临床预后的改善，目前对此还存在着诸多争议。最终研究者在一个以新诊断为胶质母细胞瘤的患者中进行了III期随机对照研究以确定抗VEGF抗体贝伐单抗对上述患者的治疗效果。AvaGlio研究的最初结果已经由摘要的形式发表。与我们所预期的一致，患者的无进展生存期得到了改善，然而，中期分析显示无进展生存期的延长并没有转化成患者总体生存期的延长。此外，贝伐单抗的真正治疗价值还属未知，虽然有证据显示在复发的胶质瘤患者能从贝伐单抗治疗中获益，但是无法证实在疾病早期应用贝伐单抗的有益作用。不幸的是，目前还未证实最佳应用贝伐单抗的生物标记。因此我们期望长期随访数据，以及一个和RTOG研究相似的研究的结果（在2013 ASCO上可能发表的结果）。An entirely novelcancer treatment modality with alternating electrical fields—the so-called tumour treatment fields (TTF)— is being investigated in newly diagnosed and recurrent glioblastoma.Experimental models have shown that rapidly alternating electrical fieldsinterfere with cell division by disturbing mitotic spindle formation and leadto dielectrophoretic movement of intracellular macromolecules and organelles, resultingin cell death. A randomized controlled phase III trial was conducted in heavilypretreated patients with recurrent glioblastoma. Patients were randomly assignedto either physician’s best choice of chemotherapy(control) or TTF without any chemotherapy.6 This trial demonstrated thefeasibility of this approach, with a slightly higher response rate observed forpatients treated with TTF (14% versus 10%, P = 0.2), and fewer severe adverse events in the TTF arm.However, no significant difference in overall survival was noted (6.6 monthsversus 6.0 months). On the basis of the observed objective responses with this modalityalone, and synergy with chemotherapy in preclinical models, NovoTTF (NovoCureLtd, Haifa, Israel) is currently under investigation in a phase III clinical trialin patients with newly diagnosed glioblastoma, as an addition to adjuvant or maintenancetemozolomide chemotherapy.一个全新的肿瘤治疗方案是采用交变电场（所谓的肿瘤治疗区域），研究者在新诊断和复发的胶质母细胞瘤的患者中进行研究。研究模型提示交变电场通过干扰有丝分裂纺锤体形成来干预细胞分裂，从而导致细胞内大分子和细胞器的介电电泳运动来造成细胞死亡。研究者已在接受过过度预治疗的复发性胶质母细胞瘤患者中进行一项随机对照III期临床研究。在该研究中，患者被随机分为2组，一组接受医生所认为的最佳的化疗（对照组），另一组接受TTF（不接受任何化疗）。该研究证实了上述治疗方案的可行性，研究者观察到接受TTF治疗的患者的对治疗的反应率略有增高，TTF组和对照组分别为14%和10%，不具有显著统计学意义，研究者也观察到在TTF组的患者中所发生的严重不良反应事件较少。然而，两组的总体生存期并不存在显著统计学差异，分别为6.6月和6.0月。基于在上述研究中所观察到的客观反应率的增高，以及在基础模型中观察到的和化疗的协同模式，目前一个针对新诊断为胶质母细胞瘤的III期临床研究——NovoTTF研究（NovoCureLtd, Haifa, Israel）正在进行之中，该研究主要是观察在TTF的基础上，增加辅助化疗或维持替莫唑胺化疗的治疗效果。Mutations of theisocitrate dehydrogenase (IDH) genes have been identified as an early event ingliomagenesis. These mutations are a typical feature of low-grade glioma, secondary(transformed) higher grade glioma and glioblastoma, and are associated with amore-favourable prognosis. Ongoing research is aimed at targeting this enzyme fortherapeutic purposes. IDH mutations result in a neomorphic reaction yielding theoncometabolite 2?hydroxyglutarate (2HG).Subsequent accumulation of this metabolite in the tumour tissue interferes withthe epigenetic machinery and induces a CpG island methylator phenotype. Recent advanceshave shown that magnetic resonance spectroscopy (MRS) is able to detect 2HG ina non-invasive manner.7 MRS may provide an easier molecular characterization andquantification of glioma, and a way to evaluate the response to therapy earlyin the disease course, because typical morphological response often requiresmonths, and MRI evaluation is often ambiguous in these slow-growing tumours.Growth acceleration and malignant transformation might also be identifiedearlier than with conventional imaging techniques.The importance of moleculartumour characterization is also well illustrated by recent developments inmedulloblastoma. Systematic molecular profiling has allowedidentification ofat least four distinct molecularly defined subgroups that also correspond tosome clinical features and outcome. Whole-genome sequencing and analysis of copy-numberaberrations enables further refinement of the disease subgroups and identificationof relevant new genes or epigenetic alterations. New findings were published simultaneouslyin four publications in the August issue of Nature.既往研究者已经证实在胶质瘤发生的早期就存在异柠檬酸脱氢酶（IDH）基因突变。这些突变的存在是低级别胶质瘤、继发性或转移性高级别的胶质瘤和胶质母细胞瘤的典型的特征，与患者的预后相关。目前正在进行中的研究则靶向针对IDH进行治疗。IDH突变会导致肿瘤代谢物2-羟戊二酸的积聚，从而造成新变体反应。这种代谢产物在肿瘤组织中的积聚会诱导CpG岛状甲基化亚型的出现。最近的进展显示磁共振波谱学（MRS）是一种无创性的监测2HG存在的方法。MRS可提供相关的分子学特征和对胶质瘤进行定量，同时也是一种能在疾病早期评价患者对治疗反应的方法，因为既往根据典型的形态学反应来进行评价需要数月的时间，而MRI评价法在那些生长较缓慢的肿瘤中则显得模棱两可。与其他常规影像学技术相比，MRS能在早期阶段就对肿瘤生长速度和恶变转化情况进行评价。最近，肿瘤分子学特征的重要性也在成髓细胞瘤中显现出来。系统的分子分析能帮助确定至少4个不同特征的分子亚组（对应着不同的临床特征和临床预后）。全基因组测序和分析畸变的拷贝数分析可帮助进一步改善对疾病的亚组分组及确定新的相关基因或表观遗传学变化。在《自然》杂志8月的期刊上同期发表了上述研究的新发现。Importantly, theseinsights into disease pathogenesis open avenues for novel treatments. About 30%of patients with medulloblastomas have activation of the sonic hedgehog (SHH) signalingpathway, and small-molecule inhibitors of Smoothened, a co-activator of SHH, arebeing tested in clinical trials. One such agent, vismodegib is currently beingtested in patients with medulloblastoma. In 10% of patients withmedulloblastoma, the Wnt signaling pathway is activated and is associated witha favourable prognosis. This allows de-escalation of treatment intensity whilemaintaining curative intent. Despite the rarity of medulloblastoma, the strictcollection of fresh tumour tissue over many years, and the exceptionalinternational collaborations have provided unprecedented insights into thisdisease that will have consequences on clinical management.重要的是，这些对疾病发病机制的洞察开拓了新治疗方案。在髓母细胞瘤患者中约有30%的患者存在sonic hedgehog（SHH）信号旁路的激活，所以目前在临床研究中研究者正在测试SHH的辅助激活因子smoothened的小分子抑制剂对疾病的治疗效果。Vismodegib目前正用于髓母细胞瘤患者的治疗。在髓母细胞瘤患者中约有10%的患者存在Wnt信号旁路的激活，该旁路的激活提示患者可能具有较好的预后。这使得在保证治疗效果的同时可降低治疗的强度。虽然髓母细胞瘤在临床上较罕见，多年来研究者一直在收集新鲜的肿瘤组织，并且国际间的合作也为我们提供了前所未有的视角来认识上述疾病，以帮助增加对临床治疗方案的理解。The past yearillustrates how molecular tumour characterization has grown beyondthe exclusiveresearch setting. An increasing number of markers have been validated for theirprognostic and predictive power, and have demonstrated great value for everydayclinical decision making. Furthermore, molecular profiling has improved our understandingof pathogenesis and opens novel avenues for therapeutic approaches. Althoughtherapeutic progress has been rather modest, anecdotal evidence suggests thatsome patients may derive a true benefit from dose intensification, antiangiogenicagents and novel treatment modalities. Better tumour characterization willallow identification of patients most susceptible who arelikely to benefitfrom a specific treatment— personalized strategies are on the horizon.过去的一年见证了肿瘤分子学特征在独特研究设计以外的发展。越来越多的标记物被用来特异性的预测患者的预后，也证实了上述标记物在临床决策制定中所存在的巨大价值。此外，分子分析改善了我们对疾病发病机制的理解，为治疗方案的选择开辟了新的道路。虽然治疗进展比较缓慢，但是有证据提示某些患者可能得益于强化治疗、抗血管生成药物的治疗和新型治疗方案。对肿瘤特征的认识的增加可帮助我们确定最有可能得益于某种治疗的患者人群，个体化治疗方案制定的时代已经到来。编译后（3448）分子学治疗或开创脑胶质瘤患者个体化治疗的新时代在2012年，随着对原发脑肿瘤分子学机制分析的进展，使得我们可以确定胶质瘤和髓母细胞瘤的具体亚型，以探讨不同疾病亚型对患者预后影响，以及其是否影响患者对治疗反应。目前的辅助化疗主要是针对1p/19q共同缺失的间变性少突胶质细胞瘤，或许这对于MGMT启动子甲基化的老年胶质母细胞瘤患者而言也是推荐的治疗方式。重大进展■■在所有胶质瘤患者中，分子生物学标记分析应成为标准诊断流程的一部分，与预后和预测因素相关的标记对日常临床决策中有直接提示意义■■ 在染色体1p/19q3存在共缺失的间变性少突胶质细胞瘤患者中，对其长达11年的随访结果证实辅助化疗能延长其生存期■■ 对髓母细胞瘤患者的系统分析得出与临床相关的分子学分类和预后信息，使得可以根据患者所存在的风险调整其治疗策略，以及进行新型的靶向治疗在针对原发脑肿瘤的研究和治疗选择上我们面临着独特的挑战，比如如何获取肿瘤组织，又如目前仅存在少量的异质性程度最高的肿瘤可供研究。除了存在上述困难之外，着眼于肿瘤生物学的相关重要研究提示在治疗恶性胶质瘤的过程中，分子生物学标记有着明确且重要的价值。在胶质母细胞瘤患者和间变性少突胶质细胞瘤患者中，可以根据1p/19q共同缺失和甲基鸟嘌呤甲基转移酶（MGMT）基因启动子的甲基化的状态来制定最优化的治疗方案。在2012年发表了2个随机研究，在该研究中受试者为老年恶性胶质瘤患者（年龄在60岁至70岁之间），研究者评估了以替莫唑胺为基础的化疗和放疗对上述患者的治疗效果。在上述两个研究中，研究者都收集了肿瘤组织，并评估了肿瘤组织MGMT的甲基化状态。MGMT是一种DNA修复酶，会削弱诸如替莫唑胺在内的烷化剂的细胞毒作用。总体而言，在上述两个研究中，受试者的中位生存期不尽如人意，仅为6-10个月，并且研究者观察到对上述患者而言化疗的效果并不优于放疗。然而，两个研究都证实了具有表观沉默的MGMT基因的患者对替莫唑胺的反应较好，而对于MGMT启动子未发生甲基化的患者而言，如果一开始就接受放疗，那么他们的生存期更长。这些结果证实了早期研究的结果，即在胶质母细胞瘤患者中，MGMT甲基化能作为患者对替莫唑胺治疗反应的极具价值的预测指标。少突胶质细胞瘤有其独特的特征，即其自然史较长、对化疗或放疗反应较好。然而，至今为止，辅助化疗并不能改善间变性少突胶质细胞瘤患者的生存期。同样在2012年发表了2个长期随访的研究的结果，这两个研究都开始于18年前，探究了在放疗前后添加辅助PCV化疗（甲基苄肼、环己亚硝脲和长春新碱）对患者预后的影响，其结果显示经由上述治疗能改善患者的总体生存期。对肿瘤的分子学分析证实只有染色体1p和19q存在共同缺失的患者（由t(1;19)(q10;p10)介导的易位）才能从早期化疗中获益。对于低级别（II级）的胶质瘤的治疗方案仍然存在争议。研究发现，在最初确诊时就给予放疗与在肿瘤出现进展时再进行放疗，对患者的总体生存期的增加无明显影响，并且研究也未发现化疗在上述治疗中所起的作用。在2012年，RTOG9802随机组间研究评价了在低级别（II级）胶质瘤高危患者中放疗联合/不联合辅助PCV化疗的治疗效果。在1998年至2002年期间，有251名患者被随机分为2组，一组仅接受放疗，另一组在放疗后继之以放化疗，观察上述两种方案对患者的疗效。研究者发现，无进展生存期在辅助放化疗组有所改善，但是研究结果并未达到研究者事先设定的主要终点，即没有证实在患者中存在整体生存期的改善。然而，当研究者定义了一类预后最差的患者——占所有患者的16%，定义为在2年内死亡的患者，因此其很有可能为存在未经识别的级别较高的肿瘤的患者，并将其从研究的分析中剔除之后，研究者观察到生存期在2年以上的患者可从辅助化疗中获益。但是目前还无法获得肿瘤的分子学数据，预计在2013年可以得到EORTC组间研究（EORTC /NCIC CE.5）的研究结果，在该研究中，比较了强化替莫唑胺化疗（28天的疗程内进行21天治疗）和放疗对患者的疗效。研究者在治疗开始之前就前瞻性的分析了肿瘤组织的生物学标记，并且根据患者是否存在1p缺失（抑制的预后预测因子）对其进行分层。事实上，所有恶性胶质瘤患者一般都会出现肿瘤复发。对VEGG的抑制会导致令人震惊的放射反应，表现为对比增强以前所未有的速度降低，以及肿瘤周围组织水肿的快速消退。然而，这种血脑屏障的暂时重建是否会转化为患者生存期的延长和临床预后的改善，目前对此还存在着诸多争议。最终研究者在一个以新诊断为胶质母细胞瘤患者群中进行了III期随机对照研究，以确定抗VEGF抗体贝伐单抗对上述患者的治疗效果。AvaGlio研究的最初结果已经由摘要的形式发表。与我们所预期的一致，患者的无进展生存期得到了改善，然而，中期分析显示无进展生存期的延长并没有转化成患者总体生存期的延长。此外，贝伐单抗的真正治疗价值还属未知，虽然有证据显示在复发的胶质瘤患者能从贝伐单抗治疗中获益，但是无法证实在疾病早期应用贝伐单抗是否存在有益作用。不幸的是，目前还未证实可代表最佳应用贝伐单抗的生物标记。因此我们期望长期随访数据，以及一个和RTOG研究相似的研究的结果（在2013 ASCO上可能发表的结果）给我们带来问题的答案。一个全新的肿瘤治疗方案是采用交变电场（所谓的肿瘤治疗区域），研究者在新诊断和复发的胶质母细胞瘤患者中进行了研究。研究模型提示交变电场通过干扰有丝分裂纺锤体形成来干预细胞分裂，从而通过细胞内大分子和细胞器的介电电泳运动来造成细胞死亡。针对接受过过度预治疗的复发性胶质母细胞瘤患者，一项随机对照III期临床研究正在研究中。在该研究中，患者被随机分为2组，一组接受医生所认为的最佳的化疗（对照组），另一组接受TTF（不接受任何化疗）。研究者观察到接受TTF治疗的患者的对治疗的反应率略有增高，TTF组和对照组分别为14%和10%，不具有显著统计学意义，研究者也观察到在TTF组的患者中所发生的严重不良反应事件较少，从而证实了TTF的可行性。然而，两组的总体生存期并不存在显著统计学差异，分别为6.6月和6.0月。基于在上述研究中所观察到的客观反应率的增高，以及在基础模型中观察到的和化疗的协同模式，目前一个针对新诊断为胶质母细胞瘤的III期临床研究——NovoTTF研究（NovoCureLtd, Haifa, Israel）正在进行之中，该研究主要是观察在TTF的基础上，增加辅助化疗或维持替莫唑胺化疗的治疗效果。既往研究者已经证实在胶质瘤发生的早期就存在异柠檬酸脱氢酶（IDH）基因突变。这些突变的存在是低级别胶质瘤、继发性或转移性高级别的胶质瘤和胶质母细胞瘤的典型的特征，与患者的预后相关。目前正在进行中的研究则靶向针对IDH进行治疗。IDH突变会导致肿瘤代谢物2-羟戊二酸的积聚，从而造成新变体反应。这种代谢产物在肿瘤组织中的积聚会诱导CpG岛状甲基化亚型的出现。最近的进展显示磁共振波谱学（MRS）是一种监测2HG存在的无创性方法。MRS可提供相关的分子学特征和对胶质瘤进行定量分析，同时也是一种能在疾病早期就评价患者对治疗反应的方法，因为既往根据典型的形态学反应来进行评价需要数月的时间，而MRI评价法在那些生长较缓慢的肿瘤中则显得模棱两可。与其他常规影像学技术相比，MRS能在早期阶段就对肿瘤生长速度和恶变转化情况进行评价。最近，肿瘤分子学特征的重要性也在成髓细胞瘤中显现出来。系统的分子分析能帮助确定至少4个不同特征的分子亚组（对应着不同的临床特征和临床预后）。全基因组测序和分析畸变的拷贝数分析可帮助进一步改善对疾病的亚组分组及确定新的相关基因或表观遗传学变化。在《自然》杂志8月的期刊上同期发表了上述研究的新发现。重要的是，这些对疾病发病机制的洞察开拓了治疗方案的新领域。在髓母细胞瘤患者中约有30%的患者存在sonic hedgehog（SHH）信号旁路的激活，所以目前在临床研究中研究者正在评估SHH的辅助激活因子smoothened的小分子抑制剂对疾病的治疗效果。Vismodegib目前正用于髓母细胞瘤患者的治疗。在髓母细胞瘤患者中约有10%的患者存在Wnt信号旁路的激活，该旁路的激活提示患者可能具有较好的预后。这使得在保证治疗效果的同时可降低治疗的强度。虽然髓母细胞瘤在临床上较罕见，但是多年来研究者一直在收集新鲜的肿瘤组织，并且国际间的合作也为我们提供了前所未有的视角来认识上述疾病，以帮助增加对临床治疗方案的理解。过去的一年见证了肿瘤分子学特征的发展。越来越多的标记物被用来特异性的预测患者的预后，显示出上述标记物在临床决策制定中的巨大价值。此外，分子分析改善了我们对疾病发病机制的理解，为治疗方案的选择开辟了新的道路。虽然治疗进展比较缓慢，但是有证据提示某些患者可能得益于强化治疗、抗血管生成药物的治疗和新型治疗方案。对肿瘤特征的认识的增加可帮助我们确定最有可能得益于某种治疗的患者人群，个体化治疗方案制定的时代已经到来。
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