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The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma. 耳蜗剂量和放疗年龄可预测髓母细胞瘤患儿接受被动散射质子疗法和顺铂治疗后的严重听力损失。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-03 DOI: 10.1093/neuonc/noae114
Mohammad H Abu-Arja, Austin L Brown, Jack M Su, M Fatih Okcu, Holly B Lindsay, Susan L McGovern, Mary Frances McAleer, David R Grosshans, Murali M Chintagumpala, Arnold C Paulino

Background: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin.

Methods: We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI).

Results: Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range: 3.1-21.1). The mean cochlear dose (Dmc) (±SD) was 31.5 ± 8.5 Gy, and the cumulative cisplatin dose was 295 ± 50 mg/m2. Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range: 4-22) with a median audiogram follow-up of 49 months (range: 6-177). Twenty-seven patients (34%) had grades 3-4 HL. In adjusted Cox models, only higher Dmc (HR = 1.12, 95% CI:1.06-1.18) was associated with grades 3-4 HL. The predicted 3-year incidence of grades 3-4 HL was 40.0% (95% CI: 21.3-66.3) and 66.7% (95% CI: 35.4-93.7) for children with Dmc ≥36 Gy and age at radiotherapy ≥7 and <7 years, respectively (P = .042). It was 8.9% (95% CI: 2.3-31.6) and 15.6% (95% CI: 5.3-41.1) for children with Dmc <36 Gy and age at radiotherapy ≥7 and <7 years, respectively (P = .78).

Conclusions: Children <7 years at radiotherapy with a Dmc ≥36 Gy are at higher risk for HL.

背景:听力损失(HL)与髓母细胞瘤患者较差的神经认知结果有关。我们旨在确定与严重听力损失相关的风险因素,并评估已发表的听力损失计算器在接受被动散射质子疗法(PSPT)和顺铂治疗的患者中的通用性:我们确定了2007-2022年间在本中心接受治疗的3-21岁患者。采用国际儿科肿瘤学会波士顿分级法对听力图进行分级。使用 Kaplan-Meier 模型和多变量 Cox 模型评估 3-4 级 HL 的发生时间,以估计危险比 (HR) 和 95% 置信区间 (CI):79名患者接受了PSPT治疗,中位年龄为7.5岁(3.1-21.1岁)。平均耳蜗剂量(Dmc)(±S.D.)为 31.5±8.5 Gy,累计顺铂剂量为 295±50 mg/m2。59名患者(75%)接受了阿米福星治疗。患者完成的听力检查中位数为 9 次(范围:4-22),听力检查随访中位数为 49 个月(范围:6-177)。27名患者(34%)患有3-4级HL。在调整后的 Cox 模型中,只有较高的 Dmc(HR=1.12,95% CI:1.06-1.18)与 3-4 级 HL 相关。预测3-4级HL的3年发生率为40.0%(95% CI:21.3-66.3),Dmc≥36 Gy且放疗时年龄≥7岁的儿童为66.7%(95% CI:35.4-93.7):儿童
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引用次数: 0
Do we need dosimetry for optimization of theranostics in CNS tumors? 我们需要剂量测定来优化中枢神经系统肿瘤的治疗吗?
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/neuonc/noae200
Francesco Cicone, Silvano Gnesin, Giulia Santo, Caroline Stokke, Mirco Bartolomei, Giuseppe Lucio Cascini, Giuseppe Minniti, Giovanni Paganelli, Antoine Verger, Marta Cremonesi

Radiopharmaceutical theranostic treatments have grown exponentially worldwide, and internal dosimetry has attracted attention and resources. Despite some similarities with chemotherapy, radiopharmaceuticals treatments are essentially radiotherapy treatments, as the release of radiation into tissues is the determinant of the observed clinical effects. Therefore, absorbed dose calculations are key to explain dose-effect correlations and to individualize radiopharmaceutical treatments. The present article introduces the basic principles of internal dosimetry and provides an overview of available locoregional and systemic radiopharmaceutical treatments for CNS tumors. The specific characteristics of dosimetry as applied to these treatments are highlighted, along with their limitations and most relevant results. Dosimetry is performed with higher precision and better reproducibility than in the past, and dosimetric data should be systematically collected, as treatment planning and verification may help exploit the full potential of theranostic of CNS tumors.

放射性药物疗法在全球范围内迅猛发展,其内部剂量测定也吸引了人们的关注和资源的投入。尽管与化疗有一些相似之处,但放射性药物治疗本质上是放射治疗,因为向组织释放辐射是观察到的临床效果的决定因素。因此,吸收剂量计算是解释剂量效应相关性和进行放射性药物个体化治疗的关键。本文介绍了内剂量学的基本原理,并概述了中枢神经系统肿瘤的局部和全身放射性药物治疗方法。文章强调了应用于这些治疗方法的剂量测定的具体特点,以及它们的局限性和最相关的结果。与过去相比,剂量测定的精确度更高,可重复性更好,因此应系统收集剂量测定数据,因为治疗规划和验证有助于充分挖掘中枢神经系统肿瘤放射治疗的潜力。
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引用次数: 0
Quantitative assessment of residual tumor is a strong and independent predictor of survival in methylated glioblastoma following radiochemotherapy with CCNU/TMZ. 残留肿瘤的定量评估是甲基化胶质母细胞瘤患者在接受CCNU/TMZ放化疗后生存期的一个强有力的独立预测指标。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/neuonc/noae205
Thomas Zeyen, Laura Böhm, Daniel Paech, Niklas Schäfer, Theophilos Tzaridis, Cathrina Duffy, Louisa Nitsch, Matthias Schneider, Anna-Laura Potthoff, Javen Lennard Schneider-Rothhaar, Joachim Peter Steinbach, Peter Hau, Thomas Kowalski, Clemens Seidel, Dietmar Krex, Oliver Grauer, Roland Goldbrunner, Pia Susan Zeiner, Ghazaleh Tabatabai, Norbert Galldiks, Walter Stummer, Elke Hattingen, Martin Glas, Eleni Gkika, Hartmut Vatter, Alexander Radbruch, Ulrich Herrlinger, Johannes Weller, Christina Schaub

Background: Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The RANO resect group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol. The purpose of this study was (1) to investigate the prognostic value of EOR in patients receiving combined chemotherapy with lomustine (CCNU)/temozolomide (TMZ), and (2) to analyse the prognostic performance of binary EOR assessment compared to volumetric assessment.

Methods: 78 patients with newly diagnosed MGMT-methylated GBM undergoing tumor resection followed by radiochemotherapy with CCNU/TMZ were included in this study. Residual contrast-enhancing (CE) tumor volume after the first resection was measured and its influence on OS and PFS was analysed using uni- and multivariable Cox regression analysis as well as two-sided log rank test. Patients were divided into RTV ≤1 cm³, >1 cm³ - ≤5 cm³ and >5 cm³ following the proposed criteria of the RANO resect group.

Results: Prolonged OS was associated with age <60 years, low RTV, and gross total resection (GTR). Residual tumor volume (RTV) had a superior prognostic value compared to binary EOR assessment. Patients with total or near total resection of CE tumor (≤1 cm³ RTV) showed prolonged OS (median 54.4 months, 95% CI 46.94-not reached), with a 5-year survival rate of 49%.

Conclusion: Low RTV is associated with increased survival in glioblastoma patients undergoing radiochemotherapy with CCNU/TMZ. This study demonstrates the applicability of the recently proposed RANO resect criteria in this subgroup of patients.

背景:最大程度的肿瘤切除可提高胶质母细胞瘤患者的总生存率(OS)。切除范围(EOR)历来是二分法。最近,RANO resect 小组提出了对按照 Stupp's 方案治疗的患者进行基于容积测量的 EOR 评估标准。本研究的目的是:(1) 探讨EOR在接受洛莫司汀(CCNU)/替莫唑胺(TMZ)联合化疗患者中的预后价值;(2) 分析二元EOR评估与容积评估相比的预后表现。采用单变量和多变量Cox回归分析以及双侧对数秩检验,测量首次切除术后残留的造影剂增强(CE)肿瘤体积,并分析其对OS和PFS的影响。根据RANO切除组提出的标准,将患者分为RTV≤1 cm³、>1 cm³-≤5 cm³和>5 cm³:结果:OS的延长与年龄有关:在接受 CCNU/TMZ 放射化疗的胶质母细胞瘤患者中,低 RTV 与生存期延长有关。这项研究表明,最近提出的 RANO resect 标准适用于这一亚组患者。
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引用次数: 0
Targeted radionuclide therapy for patients with CNS metastasis: overlooked potential? 针对中枢神经系统转移患者的放射性核素靶向治疗:被忽视的潜力?
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/neuonc/noae192
Emilie Le Rhun, Nathalie L Albert, Martin Hüllner, Enrico Franceschi, Norbert Galldiks, Philipp Karschnia, Giuseppe Minniti, Tobias Weiss, Matthias Preusser, Benjamin M Ellingson, Michael Weller

Targeted radionuclide therapy is an emerging therapeutic concept for metastatic cancer that can be considered if a tumor can be delineated by nuclear medicine imaging and also targeted based on expression of a particular target (thera-nostics). This mode of treatment can also compete with or supplement conventional radiotherapy e.g., if MRI does not fully capture the extent of disease, including microscopic metastases. Targeted radionuclide therapy for patients with thyroid cancer, with certain somatostatin receptor 2-expressing tumors and with prostate-specific membrane antigen (PSMA)-expressing prostate cancer are approved, and numerous approaches of targeted radionuclide therapy for patients with metastatic cancer are in development (e.g. using fibroblast activation protein (FAP) as a target). Although brain metastases are rare in the cancers with approved targeted radionuclide therapies, there is no a priori reason to assume that such treatments would not be effective against brain metastases if the targets are expressed and not shielded by the blood brain barrier. Here, we discuss the current state of the art and opportunities of targeted radionuclide therapies for patients with brain and leptomeningeal metastases.

靶向放射性核素疗法是治疗转移性癌症的一种新兴治疗理念,如果肿瘤可以通过核医学成像确定,并根据特定靶点的表达情况进行靶向治疗(thera-nostics),就可以考虑采用这种疗法。如果核磁共振成像不能完全捕捉到包括微小转移灶在内的疾病范围,这种治疗模式也可以与传统放疗竞争或作为补充。针对甲状腺癌、某些表达体生长抑素受体 2 的肿瘤和表达前列腺特异性膜抗原(PSMA)的前列腺癌患者的放射性核素靶向治疗已获得批准,针对转移性癌症患者的多种放射性核素靶向治疗方法(如使用成纤维细胞活化蛋白(FAP)作为靶点)也在开发中。虽然在已获批放射性核素靶向疗法的癌症中,脑转移是罕见的,但没有先验的理由假定,如果靶点表达且未被血脑屏障屏蔽,这种疗法就不会对脑转移有效。在此,我们将讨论针对脑转移瘤和脑膜转移瘤患者的放射性核素靶向疗法的技术现状和机遇。
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引用次数: 0
A targeted gene expression biomarker predicts clinic low-risk meningioma recurrence. 一种靶向基因表达生物标志物可预测临床低风险脑膜瘤复发。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-28 DOI: 10.1093/neuonc/noae198
Minh P Nguyen, Ramin A Morshed, Mark W Youngblood, Haley K Perlow, Calixto-Hope G Lucas, Akash J Patel, Joshua D Palmer, Craig M Horbinski, Stephen T Magill, William C Chen, David R Raleigh

Background: Despite reassuring clinical and histological features, low grade meningiomas can recur after surgery. Targeted gene expression profiling improves risk stratification of meningiomas, but the utility of this approach for clinical low-risk meningiomas is incompletely understood.

Methods: This was a multicenter retrospective cohort study of meningiomas from patients who were treated at 4 institutions from 1992 to 2023. Adult patients with newly diagnosed or recurrent World Health Organization (WHO) grade 1 meningiomas that were treated with gross total resection (GTR) or subtotal resection (STR), or newly diagnosed WHO grade 2 meningiomas that were treated with GTR, were included. A 34-gene expression biomarker and gene expression risk score (continuous from 0 to 1) was evaluated in all samples.

Results: The study cohort was comprised of 723 patients, none of which were used for discovery or training of the gene expression biomarker and 265 of which were previously unreported. There were 626 WHO grade 1 meningiomas, 490 with GTR and 126 with STR, and 97 WHO grade 2 meningiomas with GTR. Targeted gene expression profiling classified 51.3% of clinical low-risk meningiomas as molecular intermediate-risk and 9.5% as molecular high-risk. Combining the gene expression biomarker with extent of resection revealed 19.8% of clinical low-risk meningiomas had unfavorable local freedom from recurrence (LFFR) and overall survival (OS), including 7.1% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR (HR per 0.1 increase in risk score 1.89, 95% CI 1.58-2.25) across all WHO grades, extents of resection, and newly diagnosed or recurrent presentations.

Conclusions: Targeted gene expression profiling can identify clinical low-risk meningiomas that are likely to recur after surgery.

背景:尽管临床和组织学特征令人欣慰,但低级别脑膜瘤术后仍可能复发。靶向基因表达谱分析可改善脑膜瘤的风险分层,但这种方法对临床低风险脑膜瘤的效用尚不完全清楚:这是一项多中心回顾性队列研究,研究对象是1992年至2023年期间在4家医疗机构接受治疗的脑膜瘤患者。研究纳入了新诊断或复发的世界卫生组织(WHO)1级脑膜瘤成人患者,这些患者接受了全切术(GTR)或次全切术(STR)治疗,或新诊断的WHO 2级脑膜瘤患者接受了全切术治疗。在所有样本中评估了34个基因表达生物标志物和基因表达风险评分(从0到1连续评分):研究队列由 723 例患者组成,其中没有一例用于发现或训练基因表达生物标志物,265 例之前未曾报道过。其中626例为WHO 1级脑膜瘤,490例伴有GTR,126例伴有STR;97例为WHO 2级脑膜瘤,伴有GTR。靶向基因表达谱分析将51.3%的临床低危脑膜瘤归类为分子中危,9.5%归类为分子高危。将基因表达生物标志物与切除范围相结合后发现,19.8%的临床低危脑膜瘤的局部无复发率(LFFR)和总生存率(OS)不理想,其中包括7.1%新诊断的WHO 1级脑膜瘤GTR。风险评分是LFFR的预后指标(风险评分每增加0.1,HR为1.89,95% CI为1.58-2.25),适用于所有WHO分级、切除范围、新诊断或复发表现:靶向基因表达谱分析可以识别术后可能复发的临床低风险脑膜瘤。
{"title":"A targeted gene expression biomarker predicts clinic low-risk meningioma recurrence.","authors":"Minh P Nguyen, Ramin A Morshed, Mark W Youngblood, Haley K Perlow, Calixto-Hope G Lucas, Akash J Patel, Joshua D Palmer, Craig M Horbinski, Stephen T Magill, William C Chen, David R Raleigh","doi":"10.1093/neuonc/noae198","DOIUrl":"https://doi.org/10.1093/neuonc/noae198","url":null,"abstract":"<p><strong>Background: </strong>Despite reassuring clinical and histological features, low grade meningiomas can recur after surgery. Targeted gene expression profiling improves risk stratification of meningiomas, but the utility of this approach for clinical low-risk meningiomas is incompletely understood.</p><p><strong>Methods: </strong>This was a multicenter retrospective cohort study of meningiomas from patients who were treated at 4 institutions from 1992 to 2023. Adult patients with newly diagnosed or recurrent World Health Organization (WHO) grade 1 meningiomas that were treated with gross total resection (GTR) or subtotal resection (STR), or newly diagnosed WHO grade 2 meningiomas that were treated with GTR, were included. A 34-gene expression biomarker and gene expression risk score (continuous from 0 to 1) was evaluated in all samples.</p><p><strong>Results: </strong>The study cohort was comprised of 723 patients, none of which were used for discovery or training of the gene expression biomarker and 265 of which were previously unreported. There were 626 WHO grade 1 meningiomas, 490 with GTR and 126 with STR, and 97 WHO grade 2 meningiomas with GTR. Targeted gene expression profiling classified 51.3% of clinical low-risk meningiomas as molecular intermediate-risk and 9.5% as molecular high-risk. Combining the gene expression biomarker with extent of resection revealed 19.8% of clinical low-risk meningiomas had unfavorable local freedom from recurrence (LFFR) and overall survival (OS), including 7.1% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR (HR per 0.1 increase in risk score 1.89, 95% CI 1.58-2.25) across all WHO grades, extents of resection, and newly diagnosed or recurrent presentations.</p><p><strong>Conclusions: </strong>Targeted gene expression profiling can identify clinical low-risk meningiomas that are likely to recur after surgery.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Stereotactic Radiosurgery for 1-10 Brain Metastases to avoid Whole-Brain Radiotherapy - Results of the CYBER-SPACE Randomized Phase 2 Trial. 立体定向放射外科治疗 1-10 例脑转移瘤,避免全脑放疗--CYBER-SPACE 随机 2 期试验结果。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-28 DOI: 10.1093/neuonc/noae201
Rami A El Shafie, Denise Bernhardt, Thomas Welzel, Annabella Schiele, Daniela Schmitt, Paul Thalmann, Sinem Erdem, Angela Paul, Simon Höne, Kristin Lang, Laila König, Fabian Weykamp, Sebastian Adeberg, Adriane Lentz-Hommertgen, Cornelia Jäkel, Farastuk Bozorgmehr, Ursula Nestle, Michael Thomas, Anja Sander, Meinhard Kieser, Jürgen Debus, Stefan Rieken

Background: Stereotactic Radiosurgery (SRS) is an emerging alternative to whole-brain radiotherapy (WBRT) for treating multiple brain metastases (BM), reducing toxicity and improving tumor control. The CYBER-SPACE trial compared SRS based on either SPACE or MPRAGE MRI sequence for avoiding or delaying WBRT in patients with 1-10 BM.

Methods: Patients with 1-10 untreated BM were randomized 1:1 to receive SRS of all lesions based on either SPACE or MPRAGE MRI sequences. If subsequently new BM occurred, SRS was repeated. WBRT was indicated upon occurrence of >10 new BM, leptomeningeal disease or exhausted SRS-radiotolerance. The primary outcome was freedom from WBRT indication (WBRTi). Secondary outcomes included overall survival (OS), safety, and quality of life.

Results: 202 patients were randomized; SPACE n=99, MPRAGE n=103. 12-month WBRTi-free survival was 77.1% (95%-CI: 69.5%-83.1%) overall, 78.5% (95%-CI: 66.7%-86.5%) for SPACE, and 76.0% (95%-CI: 65.2%-83.9%) for MPRAGE (HR=0.84, 95%-CI: 0.43-1.63, p=0.590). Patients with 5-10 BM had shorter WBRTi-free survival (HR=3.13, 95%-CI: 1.53-6.40, p=0.002). Median OS was 13.1 months overall, 10.5 months for SPACE, and 15.2 months for MPRAGE (HR=1.10, 95%-CI: 0.78-1.56, p=0.585). Neurologic death rate was 10.1%. Predictors for longer OS included Karnofsky Performance Status >80% (HR=0.51, 95%-CI: 0.33-0.77, p=0.002) and concurrent immunotherapy (HR=0.34, 95%-CI: 0.23-0.52, p<0.001).

Conclusions: The more sensitive SPACE sequence did not improve outcomes over MPRAGE. SRS with thorough monitoring and immediate re-treatment for new lesions decreases the need for WBRT and achieves low neurologic death rates. SRS should be considered a favorable alternative to WBRT for patients with 1-10 BM.

背景:立体定向放射外科(SRS)是治疗多发性脑转移瘤(BM)的一种新兴的全脑放疗(WBRT)替代疗法,可降低毒性并改善肿瘤控制。CYBER-SPACE试验比较了基于SPACE或MPRAGE MRI序列的SRS,以避免或推迟1-10例脑转移瘤患者的WBRT:根据SPACE或MPRAGE MRI序列对所有病灶进行SRS治疗。如果随后出现新的骨髓瘤,则重复进行 SRS。如果出现>10个新的BM、钩端膜疾病或SRS耐受性衰竭,则需要进行WBRT治疗。主要结果是无WBRT指征(WBRTi)。次要结果包括总生存期(OS)、安全性和生活质量。总生存率为77.1%(95%-CI:69.5%-83.1%),SPACE为78.5%(95%-CI:66.7%-86.5%),MPRAGE为76.0%(95%-CI:65.2%-83.9%)(HR=0.84,95%-CI:0.43-1.63,P=0.590)。有5-10个BM的患者无WBRTi生存期较短(HR=3.13,95%-CI:1.53-6.40,p=0.002)。总的中位OS为13.1个月,SPACE为10.5个月,MPRAGE为15.2个月(HR=1.10,95%-CI:0.78-1.56,P=0.585)。神经系统死亡率为10.1%。延长OS的预测因素包括Karnofsky表现状态>80%(HR=0.51,95%-CI:0.33-0.77,p=0.002)和同时接受免疫治疗(HR=0.34,95%-CI:0.23-0.52,p结论:与MPRAGE相比,灵敏度更高的SPACE序列并未改善疗效。对新病灶进行全面监测和立即再治疗的 SRS 可减少对 WBRT 的需求,并实现较低的神经系统死亡率。对于 1-10 个 BM 的患者,SRS 应被视为 WBRT 的有利替代方案。
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引用次数: 0
Long-term outcome of the Milano-HART strategy for high-risk medulloblastoma, including the impact of molecular subtype. 针对高风险髓母细胞瘤的米兰-HART策略的长期疗效,包括分子亚型的影响。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-27 DOI: 10.1093/neuonc/noae189
Maura Massimino, Francesco Barretta, Chiara Dossena, Simone Minasi, Francesca Romana Buttarelli, Veronica Biassoni, Matilde Oriani, Elisabetta Schiavello, Marica Ficorilli, Olga Nigro, Bianca Pollo, Manila Antonelli, Vittoria Donofrio, Marco Maggioni, Marcel Kool, Emilia Pecori, Sabina Vennarini, Felice Giangaspero, Francesca Gianno, Alessandra Erbetta, Luisa Chiapparini, Roberto Luksch, Elena Barzanò, Cristina Meazza, Marta Podda, Filippo Spreafico, Monica Terenziani, Luca Bergamaschi, Andrea Ferrari, Michela Casanova, Stefano Chiaravalli, Giovanna Gattuso, Piergiorgio Modena, Simon Bailey, Loris De Cecco

Background: We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, MYC/MYCN amplification.

Methods: Patients over 3-years-old received,after surgery,staging and histo-biological analysis,sequential high-dose-methotrexate(HD-MTX),high-dose-etoposide(HD-VP16),high-dose-cyclophosphamide(HD-Cyclo),high-dose-carboplatin(HD-Carbo).Hyperfractionated-accelerated-radiotherapy-craniospinal(HART-CSI),administered in twice daily 1.3 Gy-fractions reached a total dose tailored to the patients' age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease,39 Gy in other/older patients.Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy,respectively,but avoided if metastatic nodules were very big or patients very young.Two courses of high-dose-thiotepa were delivered in case of not CR/PR after pre-radiotherapy(RT) phase and in all M0 patients either - pre/post HART.Subgrouping was performed where tissue was available.

Results: Eighy-nine patients were enrolled,median age 8.8 years,median follow up 136 months.Overall-survival(OS) and event-free-survival(EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively;5/28 fatal events were not related to relapse(three developed secondary malignancies).Sex,age less than 10 years,histological subtype,presence of MYC/MYCN amplification,reduction in CSI dose,omission of RT-boosts,implementation of myeloablative therapy,presence/absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P<0.001).Subgrouping in 66/89 patients' samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) vs. group 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response.

Conclusions: This strategy, partly adopted in the ongoing SIOPE protocol,confirmed improved EFS and OS over previously reported outcomes in all high-risk categories;SHH tumors appeared the most aggressive.

背景:我们将M+髓母细胞瘤的治疗策略应用于所有高风险亚组,包括LC/A组织学、TP53突变、MYC/MYCN扩增:3岁以上患者在接受手术、分期和组织生物学分析后,依次接受大剂量甲氨蝶呤(HD-MTX)、大剂量依托泊苷(HD-VP16)、大剂量环磷酰胺(HD-Cyclo)和大剂量卡铂(HD-Carbo)治疗。根据患者的年龄和放疗前的化疗反应(CT),以每天两次、每次 1.3 Gy 的分次剂量进行超分次加速放疗-颅骨脊髓放疗(HART-CSI),使总剂量达到:31.对后窝/残余转移(M+)病灶分别给予最高达 60 Gy/9 Gy 的总剂量,但如果转移结节非常大或患者非常年轻,则避免使用。在放疗前(RT)阶段未达到CR/PR的患者和所有M0患者在HART前/后接受两个疗程的大剂量噻替派治疗:5/15年的总生存率(OS)和无事件生存率(EFS)分别为75.9%/66.5%和68.2%/65.3%;5/28例死亡事件与复发无关(3例发展为继发性恶性肿瘤)。性别、年龄小于10岁、组织学亚型、MYC/MYCN扩增、CSI剂量减少、不使用RT-boosts、实施髓内消融治疗、有无转移灶等因素均不影响预后:正在进行的SIOPE方案部分采用了这一策略,证实与之前报道的结果相比,该策略改善了所有高危类别患者的EFS和OS;SHH肿瘤似乎最具侵袭性。
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引用次数: 0
The Pediatric Physiatric Posterior Fossa Symptoms scale (3PFSs): Impairments and outcome in pediatric inpatient rehabilitation for posterior fossa brain tumors. 儿科后窝症状量表(3PFSs):后窝脑肿瘤儿科住院康复治疗中的损伤和结果。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-25 DOI: 10.1093/neuonc/noae199
Jennifer Wu, Brian D Wishart, Stephanie E Cohen, Patricia Orme, Susan S Quinn, Donna Nimec

Background: Clinical recognition of the post-operative neurologic sequelae of posterior fossa tumors is inconsistent. This study aimed to characterize functional impairments and recovery trajectories in pediatric patients admitted to inpatient rehabilitation following surgical resection of posterior fossa brain tumors. This study also introduces the Pediatric Physiatric Posterior Fossa Symptom scale (3PFSs) for serial assessment of post-operative symptoms in pediatric posterior fossa brain tumors.

Methods: This retrospective cohort study included 49 patients aged 1.1 to 19.9 years admitted to a pediatric unit of a free-standing rehabilitation hospital following resection of a posterior fossa brain tumor. Functional Independence Measure for Children (WeeFIM) and 3PFSs scores at admission and discharge were the primary outcome measures.

Results: Across the group, WeeFIM score improved from 51.5±23.5 points at admission to 74.2±28.2 points at discharge (t=4.34, p<0.001). The 3PFSs score also showed improvement from 10[IQR=9-12] points at admission to 8[7-10] points at discharge (t=9.3, p<0.0001). While change in both the WeeFIM and 3PFSs captured statistically significant improvement in function, there was low inter-rating correlation (p>0.7). In addition, mortality was correlated with higher discharge 3PFSs score (p=0.007) but not discharge WeeFIM score.

Conclusion: In pediatric patients with post-operative neurologic sequelae due to posterior fossa brain tumors, inpatient rehabilitation resulted in global and domain specific functional improvements. This initial application of the 3PFSs demonstrates potential applicability for stratifying patients to appropriate levels of rehabilitation, capturing functionally relevant response to rehabilitation treatment, and prognosticating long-term outcomes. These initial results are promising but require additional validation in a larger cohort.

背景:临床上对后窝肿瘤术后神经系统后遗症的认识并不一致。本研究旨在描述脑后窝肿瘤手术切除后住院康复治疗的儿童患者的功能障碍和恢复轨迹。本研究还引入了小儿生理学后窝症状量表(3PFSs),用于连续评估小儿脑后窝肿瘤术后症状:这项回顾性队列研究纳入了49名在一家独立康复医院儿科接受后窝脑肿瘤切除术的患者,他们的年龄在1.1岁至19.9岁之间。入院和出院时的儿童功能独立性测量(WeeFIM)和3PFSs评分是主要的结果测量指标:结果:整个组的WeeFIM评分从入院时的51.5±23.5分提高到出院时的74.2±28.2分(t=4.34,P0.7)。此外,死亡率与较高的出院3PFSs评分相关(p=0.007),但与出院WeeFIM评分无关:结论:对于因脑后窝肿瘤导致术后神经系统后遗症的儿科患者,住院康复治疗可改善其整体和特定领域的功能。3PFSs 的这一初步应用证明了其潜在的适用性,可用于将患者分层至适当的康复水平、捕捉康复治疗的功能相关反应以及预测长期结果。这些初步结果很有希望,但还需要在更大的群体中进行进一步验证。
{"title":"The Pediatric Physiatric Posterior Fossa Symptoms scale (3PFSs): Impairments and outcome in pediatric inpatient rehabilitation for posterior fossa brain tumors.","authors":"Jennifer Wu, Brian D Wishart, Stephanie E Cohen, Patricia Orme, Susan S Quinn, Donna Nimec","doi":"10.1093/neuonc/noae199","DOIUrl":"https://doi.org/10.1093/neuonc/noae199","url":null,"abstract":"<p><strong>Background: </strong>Clinical recognition of the post-operative neurologic sequelae of posterior fossa tumors is inconsistent. This study aimed to characterize functional impairments and recovery trajectories in pediatric patients admitted to inpatient rehabilitation following surgical resection of posterior fossa brain tumors. This study also introduces the Pediatric Physiatric Posterior Fossa Symptom scale (3PFSs) for serial assessment of post-operative symptoms in pediatric posterior fossa brain tumors.</p><p><strong>Methods: </strong>This retrospective cohort study included 49 patients aged 1.1 to 19.9 years admitted to a pediatric unit of a free-standing rehabilitation hospital following resection of a posterior fossa brain tumor. Functional Independence Measure for Children (WeeFIM) and 3PFSs scores at admission and discharge were the primary outcome measures.</p><p><strong>Results: </strong>Across the group, WeeFIM score improved from 51.5±23.5 points at admission to 74.2±28.2 points at discharge (t=4.34, p<0.001). The 3PFSs score also showed improvement from 10[IQR=9-12] points at admission to 8[7-10] points at discharge (t=9.3, p<0.0001). While change in both the WeeFIM and 3PFSs captured statistically significant improvement in function, there was low inter-rating correlation (p>0.7). In addition, mortality was correlated with higher discharge 3PFSs score (p=0.007) but not discharge WeeFIM score.</p><p><strong>Conclusion: </strong>In pediatric patients with post-operative neurologic sequelae due to posterior fossa brain tumors, inpatient rehabilitation resulted in global and domain specific functional improvements. This initial application of the 3PFSs demonstrates potential applicability for stratifying patients to appropriate levels of rehabilitation, capturing functionally relevant response to rehabilitation treatment, and prognosticating long-term outcomes. These initial results are promising but require additional validation in a larger cohort.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to: Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer. 更正:美国镭学会表皮生长因子受体突变和 ALK 融合型非小细胞肺癌脑转移适当使用标准执行摘要。
IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-21 DOI: 10.1093/neuonc/noae197
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引用次数: 0
Constitutional mosaicism of pathogenic variants in SMARCB1 in a subset of patients with sporadic rhabdoid tumors 散发性横纹肌瘤患者中SMARCB1致病性变异的宿主镶嵌现象
IF 15.9 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-17 DOI: 10.1093/neuonc/noae188
Lara S Fleischmann, Karolina Nemes, Selina Glaser, Alexandra G Kouroukli, Matej Boros, Susanne Bens, Sonja Dahlum, Helene Kretzmer, Florian Oyen, Joachim Gerss, Martin Hasselblatt, Michael C Frühwald, Reiner Siebert
Background Malignant rhabdoid tumors are aggressive malignancies predominantly affecting very young children. The characteristic genetic alteration is biallelic inactivation of SMARCB1. In approximately 30% of patients one SMARCB1 allele is constitutionally altered conferring a particularly unfavourable prognosis. Constitutional mosaicism for pathogenic SMARCB1 mutations has recently been reported in distinct cases of allegedly sporadic rhabdoid tumors. We aimed to systematically investigate the frequency and clinical impact of constitutional mosaicism in patients with sporadic rhabdoid tumors included in the EU-RHAB registry. Methods We selected 29 patients with rhabdoid tumors displaying at least one pathogenic small variant in SMARCB1 in the tumor DNA and absence of a germline mutation. We re-screened blood-derived patient and control DNA for the respective small variant by PCR with unique molecular identifiers and ultra-deep next generation sequencing. Clinical data in patients with and without mosaicism and 174 EU-RHAB controls were compared. Results Employing an ultra-deep sequencing approach, we detected tumor-associated SMARCB1 variants in blood-derived DNA in 9/29 patients. In 6/29 patients (21%), whose variant allele frequency (VAF) exceeded 2%, constitutional mosaicism was assumed whereas tumor DNA contamination was documented in 1/3 patients with VAF below 1%. No significant differences were observed between 6 mosaic-positive and 20 -negative patients regarding age at diagnosis, presence of metastases, event-free or overall survival. Conclusion Constitutional mosaicism for pathogenic small SMARCB1 variants is recurrent in patients with allegedly sporadic rhabdoid tumors. The clinical implications of such variants need to be determined in larger, prospective cohorts also including detection of structural variants of SMARCB1.
背景 恶性横纹肌瘤是一种侵袭性恶性肿瘤,主要影响年幼儿童。其特征性基因改变是 SMARCB1 的双等位基因失活。约 30% 的患者中,有一个 SMARCB1 等位基因发生了体质性改变,预后特别差。最近有报道称,在不同的所谓散发性横纹肌瘤病例中存在致病性SMARCB1突变的体质镶嵌现象。我们的目的是系统地研究欧盟横纹肌瘤登记处收录的散发性横纹肌瘤患者中出现致病基因嵌合的频率及其临床影响。方法 我们选择了 29 例横纹肌瘤患者,这些患者的肿瘤 DNA 中至少有一个 SMARCB1 致病性小变异,且不存在种系突变。我们通过带有独特分子识别码的 PCR 和超深度新一代测序,重新筛查了患者和对照组血源性 DNA 中的相应小变异。比较了有马赛克和无马赛克患者的临床数据以及 174 例欧盟-RHAB 对照组的临床数据。结果 通过超深度测序方法,我们在 9/29 例患者的血源性 DNA 中检测到了肿瘤相关的 SMARCB1 变异。在变异等位基因频率(VAF)超过 2% 的 6/29 例患者(21%)中,假定存在宪制嵌合,而在 VAF 低于 1% 的 1/3 例患者中,记录到了肿瘤 DNA 污染。在诊断时的年龄、有无转移、无事件生存期或总生存期方面,6 名马赛克阳性患者与 20 名阴性患者之间没有明显差异。结论 在据称是散发性横纹肌瘤的患者中,致病性 SMARCB1 小变体的宪制镶嵌现象反复出现。此类变异的临床影响需要在更大规模的前瞻性队列中确定,其中也包括对SMARCB1结构变异的检测。
{"title":"Constitutional mosaicism of pathogenic variants in SMARCB1 in a subset of patients with sporadic rhabdoid tumors","authors":"Lara S Fleischmann, Karolina Nemes, Selina Glaser, Alexandra G Kouroukli, Matej Boros, Susanne Bens, Sonja Dahlum, Helene Kretzmer, Florian Oyen, Joachim Gerss, Martin Hasselblatt, Michael C Frühwald, Reiner Siebert","doi":"10.1093/neuonc/noae188","DOIUrl":"https://doi.org/10.1093/neuonc/noae188","url":null,"abstract":"Background Malignant rhabdoid tumors are aggressive malignancies predominantly affecting very young children. The characteristic genetic alteration is biallelic inactivation of SMARCB1. In approximately 30% of patients one SMARCB1 allele is constitutionally altered conferring a particularly unfavourable prognosis. Constitutional mosaicism for pathogenic SMARCB1 mutations has recently been reported in distinct cases of allegedly sporadic rhabdoid tumors. We aimed to systematically investigate the frequency and clinical impact of constitutional mosaicism in patients with sporadic rhabdoid tumors included in the EU-RHAB registry. Methods We selected 29 patients with rhabdoid tumors displaying at least one pathogenic small variant in SMARCB1 in the tumor DNA and absence of a germline mutation. We re-screened blood-derived patient and control DNA for the respective small variant by PCR with unique molecular identifiers and ultra-deep next generation sequencing. Clinical data in patients with and without mosaicism and 174 EU-RHAB controls were compared. Results Employing an ultra-deep sequencing approach, we detected tumor-associated SMARCB1 variants in blood-derived DNA in 9/29 patients. In 6/29 patients (21%), whose variant allele frequency (VAF) exceeded 2%, constitutional mosaicism was assumed whereas tumor DNA contamination was documented in 1/3 patients with VAF below 1%. No significant differences were observed between 6 mosaic-positive and 20 -negative patients regarding age at diagnosis, presence of metastases, event-free or overall survival. Conclusion Constitutional mosaicism for pathogenic small SMARCB1 variants is recurrent in patients with allegedly sporadic rhabdoid tumors. The clinical implications of such variants need to be determined in larger, prospective cohorts also including detection of structural variants of SMARCB1.","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":"47 1","pages":""},"PeriodicalIF":15.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Neuro-oncology
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