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Management of head and neck cancer of unknown primary: A phase IV study by DAHANCA 原发不明的头颈癌的治疗:DAHANCA的一项IV期研究。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115211
Signe Bergliot Nielsen , Nina Munk Lyhne , Maria Andersen , Christina Caroline Plaschke , Anita Birgitte Gothelf , Jørgen Johansen , Christian Maare , Mohammad Farhadi , Christian Godballe , Hanne Primdahl , Anne Ivalu Sander Holm , Jan Alsner , Thomas Kjærgaard , Jens Overgaard

Background

Diagnostic and therapeutic management of patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remains a challenge. The aim of the present phase IV study was to assess adherence to the current Danish guidelines and evaluate the treatment outcome in HNSCCUP patients.

Materials and methods

Prospectively collected data in the DAHANCA database from patients treated between 2014 and 2020 was evaluated. The median follow-up was 6.7 years. Treatment included definitive neck dissection (dND), primary (chemo-)radiotherapy ((C-)RT), neck dissection (ND) followed by postoperative (C-)RT (ND + (C-)PORT). Outcome were reported as five-year estimates of loco-regional failure (LRF), ultimate LRF (ULRF), disease specific mortality (DSM), overall survival (OS), and toxicity scores ≥ 3.

Results

A total of 288 patients were treated, of which 254 (88 %) received treatment with curative intent and were eligible for adherence assessment. These were allocated to dND (n = 60), (C-)RT (n = 81) and ND + (C-)PORT (n = 113). The HPV/p16 status was known in 94 % of patients with 109 (43 %) positive cases. The 5-year LRF, DSM, and OS for patients treated with curative intent was 22 %, 15 % and 73 %, and in patients with p16 positive disease 16 %, 5 %, and 85 %. The overall guideline adherence was 76 % (192/254). In the adherent group the LRF, ULRF, DSM, and OS were 22 %, 11 %, 16 %, and 73 %, respectively.

Conclusion

The study revealed good treatment outcome measures in HNSCCUP patients subject to the Danish guidelines, comparable to other head and neck cancer patients. The observed guideline-deviations did not affect outcome.
背景:原发不明的头颈部鳞状细胞癌(HNSCCUP)患者的诊断和治疗管理仍然是一个挑战。目前IV期研究的目的是评估当前丹麦指南的依从性,并评估HNSCCUP患者的治疗结果。材料和方法:对2014年至2020年期间接受治疗的DAHANCA数据库中前瞻性收集的数据进行评估。中位随访时间为6.7年。治疗包括明确的颈部清扫(dND),初始(化疗)放疗((C-)RT),颈部清扫(ND),随后进行术后(C-)RT (ND + (C-)PORT)。结果报告为局部-区域失败(LRF)、最终LRF (ULRF)、疾病特异性死亡率(DSM)、总生存期(OS)和毒性评分≥ 3的五年估计。结果:共治疗288例患者,其中254例(88 %)获得治疗意图,符合依从性评估。这些都是分配给dND (n = 60),(C) RT (n = 81)和ND + (C -)端口(n = 113)。在109例(43 %)阳性病例中,95% %的患者已知HPV/p16状态。有治愈意图的患者的5年LRF、DSM和OS分别为22 %、15 %和73 %,p16阳性患者的5年LRF、DSM和OS分别为16 %、5 %和85 %。总体指南依从性为76 %(192/254)。粘附组LRF、ULRF、DSM、OS分别为22 %、11 %、16 %、73 %。结论:该研究揭示了遵循丹麦指南的HNSCCUP患者的良好治疗结果,与其他头颈癌患者相当。观察到的指南偏差不影响结果。
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引用次数: 0
Sarcomas developed in patients with Lynch Syndrome are enriched in pleomorphic soft-tissue sarcomas and are sensitive to immunotherapy Lynch综合征患者的肉瘤多为多形性软组织肉瘤,对免疫治疗敏感。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115196
F. Poumeaud , T. Valentin , N. Fares , B. Segier , S. Watson , B. Verret , C. Tlemsani , N. Penel , S. Lejeune , N. Firmin , A. Sabouret , J.-C. Thery , S. Bonvalot , E. Cottereau , E. Cauchin , A. Lancon , S. Nambot , H. Zattara , M. Coudert , E. Fourme , R. Guimbaud

Background

Sarcomas do not belong to the Lynch Syndrome (LS)-tumour spectrum. A growing body literature has reported sarcomas in patients with LS. Clinical and tumour characteristics of these patients remain unknown.

Patients and methods

We set up the first national retrospective study, SarcLynch, describing the pathological and clinical characteristics of sarcomas developed in patients with LS. Patients were identified from two national networks and included from 23 centres in France.

Results

Eighty-one patients participated in the SarcLynch study. Sixty-seven (83 %) tumours were soft-tissue sarcomas (STS) and 14 (17 %) bone sarcomas. Among STS, 59 (88 %) showed a pleomorphic component, with undifferentiated pleomorphic sarcoma (UPS) (36 %) and pleomorphic rhabdomyosarcoma (pRMS) (21 %) being the most represented subtypes. Sarcoma was the first neoplastic event in 32 patients (40 %). Thirty-two patients (40 %) were carriers of MSH2 germline pathogenic variants. Among patients who underwent an assessment of deficient mismatch repair (dMMR) by immunohistochemistry and/or molecular biology status, 75 % were dMMR by immunohistochemistry and 45 % were microsatellite instability high (MSI-H). Eight patients received immune checkpoint inhibitors and 4 (50 %) exhibited an objective response with 3 complete radiological response including 1 patient with pathological complete response. Duration of response ranged from 6 to 20 months.

Conclusions

SarcLynch, the largest multicentric series describing sarcomas developed in patients with LS, revealed an enrichment in patients with pleomorphic sarcomas – especially UPS and pRMS. This finding strongly supports screening for MMR status evaluation in these rare histotypes both for oncogenetic screening and therapeutic interest. Considering an objective response rate of 50 %, access to immunotherapy should be considered in these tumours.
背景:肉瘤不属于Lynch综合征(LS)肿瘤谱系。越来越多的身体文献报道了LS患者的肉瘤。这些患者的临床和肿瘤特征尚不清楚。患者和方法:我们建立了第一个全国性的回顾性研究sarlynch,描述了LS患者发生的肉瘤的病理和临床特征。患者从两个国家网络中确定,包括法国的23个中心。结果:81例患者参与了sarlynch研究。67例(83 %)为软组织肉瘤(STS), 14例(17 %)为骨肉瘤。在STS中,59例(88 %)表现出多形性成分,其中未分化多形性肉瘤(UPS)(36 %)和多形性横纹肌肉瘤(pRMS)(21 %)是最具代表性的亚型。32例患者(40% %)中,肉瘤是第一肿瘤事件。32例患者(40 %)为MSH2种系致病变异携带者。在通过免疫组织化学和/或分子生物学状态评估缺陷错配修复(dMMR)的患者中,75% %通过免疫组织化学评估dMMR, 45% %为微卫星不稳定性高(MSI-H)。8例患者接受免疫检查点抑制剂治疗,4例(50% %)表现出客观反应,其中3例放射学完全缓解,1例病理完全缓解。反应持续时间为6至20个月。结论:sarlynch是描述LS患者中肉瘤的最大的多中心系列研究,揭示了多形性肉瘤(尤其是UPS和pRMS)患者中表达丰富。这一发现有力地支持了在这些罕见的组织类型中进行MMR状态评估的筛查,无论是用于癌基因筛查还是治疗目的。考虑到客观应答率为50% %,应考虑对这些肿瘤进行免疫治疗。
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引用次数: 0
Gut microbiome and immune checkpoint inhibitor toxicity 肠道微生物组和免疫检查点抑制剂的毒性。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2025.115221
Rik J. Verheijden , Mick J.M. van Eijs , Fernanda L. Paganelli , Marco C. Viveen , Malbert R.C. Rogers , Janetta Top , Anne M. May , Janneke H.H.M. van de Wijgert , Karijn P.M. Suijkerbuijk , on behalf of the UNICIT-consortium

Background

Multiple studies have suggested that gut microbiome may influence immune checkpoint inhibitor (ICI) efficacy, but its association with immune-related adverse events (irAEs) is less well studied. In this prospective cohort study, we assessed whether gut microbiome composition at start, or changes during ICI, are associated with severe irAEs.

Methods

Stool samples of cancer patients treated with anti-PD-1 ± anti-CTLA-4 were analyzed using 16S rRNA gene sequencing and metagenomic shotgun sequencing. Differences in alpha and beta diversity between patients with and without severe irAE were assessed, as well as differential relative abundance (RA) of taxa, MetaCyc pathways, and seven prespecified literature-based bacterial groups including pathobionts and Ruminococcaceae.

Findings

We analyzed 497 samples of 195 patients before and soon after starting ICI, at severe irAE onset and after starting immunosuppression. Mean RA of the pathobionts group was significantly higher in patients who developed a severe irAE (8.2 %) compared to those who did not (4.8 %; odds ratio 1.40; 95 %CI 1.07–1.87) at baseline, and also early during ICI treatment and at severe irAE onset. A significantly stronger decrease in RA of Ruminococcaceae after starting ICI was observed in patients who developed a severe irAE compared to those who did not. RAs of Ruminococcaceae, the genus Ruminococcus, and the species R. bromii and R. callidus were significantly lower at severe irAE onset compared to other time points.

Interpretation

Gut microbiome dysbiosis signaled by higher RA of pathobionts and decrease in RA of Ruminococcaceae may predispose to severe irAEs.
背景:多项研究表明,肠道微生物组可能影响免疫检查点抑制剂(ICI)的疗效,但其与免疫相关不良事件(irAEs)的关联研究较少。在这项前瞻性队列研究中,我们评估了开始时肠道微生物组组成或ICI期间的变化是否与严重的irae相关。方法:采用16S rRNA基因测序和宏基因组霰弹枪测序技术对经抗pd -1 ± 抗ctla -4治疗的癌症患者粪便样本进行分析。评估了患有和不患有严重irAE的患者之间α和β多样性的差异,以及分类群、MetaCyc途径和七个预先指定的基于文献的细菌群(包括病原体和Ruminococcaceae)的差异相对丰度(RA)。研究结果:我们分析了195例患者的497份样本,这些患者在开始ICI之前和之后不久,在严重irAE发作时和开始免疫抑制后。在发生严重irAE的患者中,病原体组的平均RA(8. %)明显高于未发生严重irAE的患者(4.8% %;优势比1.40;95 %CI 1.07-1.87),以及ICI治疗早期和严重irAE发作时。与没有发生严重irAE的患者相比,在开始ICI后,观察到发生严重irAE的患者的Ruminococcaceae RA的显著下降。Ruminococcaceae、Ruminococcus属以及R. bromii和R. callidus在严重irAE发作时的RAs显著低于其他时间点。解释:由较高的致病菌RA和较低的瘤胃球菌科RA信号的肠道微生物群失调可能导致严重的irae。
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引用次数: 0
Real life data of ONC201 (dordaviprone) in pediatric and adult H3K27-altered recurrent diffuse midline glioma: Results of an international academia-driven compassionate use program ONC201 (dordaviprone)在儿童和成人h3k27改变的复发性弥漫性中线胶质瘤中的现实生活数据:国际学术界驱动的同情使用项目的结果
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115165
D. Di Carlo , M. Annereau , M. Vignes , L. Denis , N. Epaillard , S. Dumont , D. Guyon , A. Rieutord , S. Jacobs , V. Salomon , I. Yoldjian , F. Duperray , L. Brunel , X. Baiao , F. Lemos , E. Vauleon , M. Capra , S. Abbou , M. Touat , M. Sanson , J. Grill

Introduction

H3K27-altered diffuse midline gliomas (DMG) have limited therapeutic options and a very poor prognosis. Encouraging responses were observed in early clinical trials with ONC201. As ONC201 was unavailable in Europe, a compassionate use program supported by the French Authorities was launched for patients at progression after standard of care radiotherapy.

Methods

This program was developed by the French Society of Pediatric Oncology (SFCE) and Association des Neuro-Oncologues d′Expression Française in collaboration with the French National Agency For Medicines and Health Products Safety and Parents Associations.

Results

174 patients (102 children, 72 adults) from 14 countries were treated from November 2021 to August 2023 at Gustave Roussy Institut (Villejuif, France). 37 % received a second course of irradiation at the time of relapse. Median duration of treatment was 57 days or 1,9 months (mo) (range 1–456 days). Median OS since diagnosis for the whole cohort was 466 days or 15,5 mo (112–2612 days); 426 or 14,2 mo (112–2612 days) and 590 or 19,6 mo (range 160–1881) for children and adults, respectively (p = 0.001). Median OS after ONC201 start was 143 days or 4,7 mo (1–711 days) for the whole cohort. Univariate and multivariable analysis identified site (thalamus) and age (older) as favorable prognostic factors. Reirradiation was associated with significantly longer survival after ONC201 start only in children.

Conclusion

While the efficacy of ONC201 needs validation in a controlled randomized clinical trial, our real-life data support a better outcome for patients with thalamic tumors treated with ONC201. We demonstrated furthermore the feasibility of a successful academia-driven compassionate use program
h3k27改变的弥漫性中线胶质瘤(DMG)的治疗选择有限,预后非常差。在ONC201的早期临床试验中观察到令人鼓舞的反应。由于ONC201在欧洲无法获得,由法国当局支持的一项同情使用计划针对标准护理放疗后进展的患者启动。方法:该项目由法国儿科肿瘤学会(SFCE)和法国神经肿瘤表达协会与法国国家药品和健康产品安全局以及家长协会合作开发。结果:来自14个国家的174名患者(102名儿童,72名成人)于2021年11月至2023年8月在Gustave Roussy institute (Villejuif, France)接受了治疗。37%的患者在复发时接受了第二疗程的放疗。治疗中位持续时间为57天或1.9个月(范围1-456天)。自诊断以来,整个队列的中位生存期为466天或15.5个月(112-2612天);儿童和成人分别为426或14.2个月(112-2612天)和590或19.6个月(160-1881天)(p = 0.001)。在整个队列中,ONC201开始后的中位OS为143天或4.7个月(1-711天)。单变量和多变量分析确定部位(丘脑)和年龄(老年)是有利的预后因素。仅在儿童中,ONC201开始后再照射与更长的生存期相关。结论:虽然ONC201的疗效需要在对照随机临床试验中验证,但我们的实际数据支持ONC201治疗丘脑肿瘤患者的更好结果。我们进一步证明了一个成功的学术驱动的同情心使用计划的可行性。
{"title":"Real life data of ONC201 (dordaviprone) in pediatric and adult H3K27-altered recurrent diffuse midline glioma: Results of an international academia-driven compassionate use program","authors":"D. Di Carlo ,&nbsp;M. Annereau ,&nbsp;M. Vignes ,&nbsp;L. Denis ,&nbsp;N. Epaillard ,&nbsp;S. Dumont ,&nbsp;D. Guyon ,&nbsp;A. Rieutord ,&nbsp;S. Jacobs ,&nbsp;V. Salomon ,&nbsp;I. Yoldjian ,&nbsp;F. Duperray ,&nbsp;L. Brunel ,&nbsp;X. Baiao ,&nbsp;F. Lemos ,&nbsp;E. Vauleon ,&nbsp;M. Capra ,&nbsp;S. Abbou ,&nbsp;M. Touat ,&nbsp;M. Sanson ,&nbsp;J. Grill","doi":"10.1016/j.ejca.2024.115165","DOIUrl":"10.1016/j.ejca.2024.115165","url":null,"abstract":"<div><h3>Introduction</h3><div>H3K27-altered diffuse midline gliomas (DMG) have limited therapeutic options and a very poor prognosis. Encouraging responses were observed in early clinical trials with ONC201. As ONC201 was unavailable in Europe, a compassionate use program supported by the French Authorities was launched for patients at progression after standard of care radiotherapy.</div></div><div><h3>Methods</h3><div>This program was developed by the French Society of Pediatric Oncology (SFCE) and Association des Neuro-Oncologues d′Expression Française in collaboration with the French National Agency For Medicines and Health Products Safety and Parents Associations.</div></div><div><h3>Results</h3><div>174 patients (102 children, 72 adults) from 14 countries were treated from November 2021 to August 2023 at Gustave Roussy Institut (Villejuif, France). 37 % received a second course of irradiation at the time of relapse. Median duration of treatment was 57 days or 1,9 months (mo) (range 1–456 days). Median OS since diagnosis for the whole cohort was 466 days or 15,5 mo (112–2612 days); 426 or 14,2 mo (112–2612 days) and 590 or 19,6 mo (range 160–1881) for children and adults, respectively (p = 0.001). Median OS after ONC201 start was 143 days or 4,7 mo (1–711 days) for the whole cohort. Univariate and multivariable analysis identified site (thalamus) and age (older) as favorable prognostic factors. Reirradiation was associated with significantly longer survival after ONC201 start only in children.</div></div><div><h3>Conclusion</h3><div>While the efficacy of ONC201 needs validation in a controlled randomized clinical trial, our real-life data support a better outcome for patients with thalamic tumors treated with ONC201. We demonstrated furthermore the feasibility of a successful academia-driven compassionate use program</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"216 ","pages":"Article 115165"},"PeriodicalIF":7.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Addressing the role of surgery in brain tumour trials: A report from the neurosurgery committee of the EORTC brain tumour group 解决手术在脑肿瘤试验中的作用:EORTC脑肿瘤组神经外科委员会的一份报告。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115198
Johnny Duerinck , Philipp Karschnia , Marike Broekman , Jens Gempt , George E.D. Petrescu , Asgeir S. Jakola , Rachel Grossman , Roland Goldbrunner , Michael D. Jenkinson , Georg Widhalm , Marian Neidert , Thiebaud Picart , Caroline Quoilin , Thierry Gorlia , Emilie Le Rhun , Giuseppe Minniti , Matthias Preusser , Michael Weller
The Brain Tumor Group (BTG) of the European Organization for Research and Treatment of Cancer (EORTC) conducts academic clinical trials and translational research to improve clinical management of patients with primary and secondary brain tumors. The EORTC BTG has traditionally played an important role in providing evidence and thus advancing the field, albeit with a main focus on radiotherapy and pharmacotherapy in gliomas. Although examples of well-designed neuro-oncological surgical trials can be found, evidence in surgical neuro-oncology predominantly includes data from uncontrolled prospective series or retrospective cohorts. By means of a thorough literature and EORTC database review, we demonstrate, firstly, that while the pathway of the neuro-oncology patient most often starts with neurosurgery, its several aspects have traditionally been poorly acknowledged in clinical trials in neuro-oncology. We also show that the definitions and methods of assessment vary greatly between studies, limiting generalizability. The newly established Neurosurgery Committee of the EORTC BTG aims to address this gap by increasing the number of prospective surgical trials, but also the involvement of neurosurgeons in clinical trial design, promoting standardized terminology for description of the surgical aspects, including extent of resection. We will also explore alternative trial designs when randomization is deemed difficult, as well as focus on defining surgical quality indicators that influence outcome. By addressing these challenges, the committee aims to enhance the quality of neurosurgical evidence in neuro-oncology and define optimal surgical methods and standards of care. This should ultimately improve outcomes and quality of life for patients with brain tumors through evidence-based surgical interventions.
欧洲癌症研究和治疗组织(EORTC)的脑肿瘤组(BTG)开展学术临床试验和转化研究,以改善原发性和继发性脑肿瘤患者的临床管理。EORTC BTG传统上在提供证据方面发挥了重要作用,从而推动了该领域的发展,尽管主要侧重于胶质瘤的放疗和药物治疗。虽然可以找到设计良好的神经肿瘤学外科试验的例子,但外科神经肿瘤学的证据主要包括来自非受控前瞻性系列或回顾性队列的数据。通过全面的文献和EORTC数据库回顾,我们首先证明,虽然神经肿瘤患者的途径通常从神经外科开始,但其几个方面传统上在神经肿瘤临床试验中得到的认识很少。我们还表明,评估的定义和方法在研究之间差异很大,限制了通用性。新成立的EORTC BTG神经外科委员会旨在通过增加前瞻性手术试验的数量,以及神经外科医生参与临床试验设计,促进手术方面描述的标准化术语,包括切除程度,来解决这一差距。当随机化被认为是困难的时候,我们还将探讨替代试验设计,并将重点放在确定影响结果的手术质量指标上。通过解决这些挑战,委员会旨在提高神经肿瘤学神经外科证据的质量,并确定最佳的手术方法和护理标准。这将最终通过循证外科干预改善脑肿瘤患者的预后和生活质量。
{"title":"Addressing the role of surgery in brain tumour trials: A report from the neurosurgery committee of the EORTC brain tumour group","authors":"Johnny Duerinck ,&nbsp;Philipp Karschnia ,&nbsp;Marike Broekman ,&nbsp;Jens Gempt ,&nbsp;George E.D. Petrescu ,&nbsp;Asgeir S. Jakola ,&nbsp;Rachel Grossman ,&nbsp;Roland Goldbrunner ,&nbsp;Michael D. Jenkinson ,&nbsp;Georg Widhalm ,&nbsp;Marian Neidert ,&nbsp;Thiebaud Picart ,&nbsp;Caroline Quoilin ,&nbsp;Thierry Gorlia ,&nbsp;Emilie Le Rhun ,&nbsp;Giuseppe Minniti ,&nbsp;Matthias Preusser ,&nbsp;Michael Weller","doi":"10.1016/j.ejca.2024.115198","DOIUrl":"10.1016/j.ejca.2024.115198","url":null,"abstract":"<div><div>The Brain Tumor Group (BTG) of the European Organization for Research and Treatment of Cancer (EORTC) conducts academic clinical trials and translational research to improve clinical management of patients with primary and secondary brain tumors. The EORTC BTG has traditionally played an important role in providing evidence and thus advancing the field, albeit with a main focus on radiotherapy and pharmacotherapy in gliomas. Although examples of well-designed neuro-oncological surgical trials can be found, evidence in surgical neuro-oncology predominantly includes data from uncontrolled prospective series or retrospective cohorts. By means of a thorough literature and EORTC database review, we demonstrate, firstly, that while the pathway of the neuro-oncology patient most often starts with neurosurgery, its several aspects have traditionally been poorly acknowledged in clinical trials in neuro-oncology. We also show that the definitions and methods of assessment vary greatly between studies, limiting generalizability. The newly established Neurosurgery Committee of the EORTC BTG aims to address this gap by increasing the number of prospective surgical trials, but also the involvement of neurosurgeons in clinical trial design, promoting standardized terminology for description of the surgical aspects, including extent of resection. We will also explore alternative trial designs when randomization is deemed difficult, as well as focus on defining surgical quality indicators that influence outcome. By addressing these challenges, the committee aims to enhance the quality of neurosurgical evidence in neuro-oncology and define optimal surgical methods and standards of care. This should ultimately improve outcomes and quality of life for patients with brain tumors through evidence-based surgical interventions.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"216 ","pages":"Article 115198"},"PeriodicalIF":7.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893148","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
Predicting benefit from PARP inhibitors using deep learning on H&E-stained ovarian cancer slides 在h&e染色的卵巢癌载玻片上使用深度学习预测PARP抑制剂的益处。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115199
Frederik Marmé , Eva I. Krieghoff-Henning , Lennard Kiehl , Christoph Wies , Jan Hauke , Eric Hahnen , Philipp Harter , Philip C. Schouten , Tobias Brodkorb , Mohamad Kayali , Florian Heitz , Claudio Zamagni , Antonio González-Martin , Isabelle Treilleux , Stefan Kommoss , Katharina Prieske , Timo Gaiser , Stefan Fröhling , Isabelle Ray-Coquard , Eric Pujade-Lauraine , Titus J. Brinker

Purpose

Ovarian cancer patients with a Homologous Recombination Deficiency (HRD) often benefit from polyadenosine diphosphate–ribose polymerase (PARP) inhibitor maintenance therapy after response to platinum-based chemotherapy. HR status is currently analyzed via complex molecular tests. Predicting benefit from PARP inhibitors directly on histological whole slide images (WSIs) could be a fast and cheap alternative.

Patients and methods

We trained a Deep Learning (DL) model on H&E stained WSIs with “shrunken centroid” (SC) based HRD ground truth using the AGO-TR1 cohort (n = 208: 108 training, 100 test) and tested its ability to predict HRD as evaluated by the Myriad classifier and the benefit from olaparib in the PAOLA-1 cohort (n = 447) in a blinded manner.

Results

In contrast to the HRD prediction AUROC of 72 % on hold-out, our model only yielded an AUROC of 57 % external. Kaplan-Meier analysis showed that progression free survival (PFS) in the PARP inhibitor treated PAOLA-1 patients was significantly improved in the HRD positive group as defined by our model, but not in the HRD negative group. PFS improvement in PARP inhibitor-treated patients was substantially longer in our HRD positive group, hinting at a biologically meaningful prediction of benefit from PARP inhibitors.

Conclusion

Together, our results indicate that it might be possible to generate a predictor of benefit from PARP inhibitors based on the DL-mediated analysis of WSIs. However, further studies with larger cohorts and further methodological improvements will be necessary to generate a predictor with clinically useful accuracy across independent patient cohorts.
目的:同源重组缺乏症(HRD)卵巢癌患者在接受铂类化疗后,通常受益于多腺苷二磷酸核糖聚合酶(PARP)抑制剂维持治疗。目前通过复杂的分子测试来分析HR状态。直接通过组织切片图像(WSIs)预测PARP抑制剂的疗效可能是一种快速而廉价的替代方法。患者和方法:我们使用AGO-TR1队列(n = 208:108训练,100测试)在H&E染色的WSIs上训练了一个基于“萎缩质心”(SC)的HRD ground truth的深度学习(DL)模型,并以盲法测试了其预测HRD的能力,并测试了Myriad分类器评估的能力以及PAOLA-1队列(n = 447)中奥拉帕尼的益处。结果:与HRD预测的AUROC为72 %相比,我们的模型只产生了57 %的外部AUROC。Kaplan-Meier分析显示,在我们的模型定义的HRD阳性组中,PARP抑制剂治疗的PAOLA-1患者的无进展生存期(PFS)显著改善,但在HRD阴性组中没有。在我们的HRD阳性组中,PARP抑制剂治疗患者的PFS改善时间明显更长,这暗示了PARP抑制剂有益的生物学意义预测。结论:总之,我们的研究结果表明,基于dl介导的wsi分析,有可能产生PARP抑制剂获益的预测因子。然而,需要更大规模的研究和进一步的方法学改进,才能在独立患者队列中产生具有临床有用准确性的预测因子。
{"title":"Predicting benefit from PARP inhibitors using deep learning on H&E-stained ovarian cancer slides","authors":"Frederik Marmé ,&nbsp;Eva I. Krieghoff-Henning ,&nbsp;Lennard Kiehl ,&nbsp;Christoph Wies ,&nbsp;Jan Hauke ,&nbsp;Eric Hahnen ,&nbsp;Philipp Harter ,&nbsp;Philip C. Schouten ,&nbsp;Tobias Brodkorb ,&nbsp;Mohamad Kayali ,&nbsp;Florian Heitz ,&nbsp;Claudio Zamagni ,&nbsp;Antonio González-Martin ,&nbsp;Isabelle Treilleux ,&nbsp;Stefan Kommoss ,&nbsp;Katharina Prieske ,&nbsp;Timo Gaiser ,&nbsp;Stefan Fröhling ,&nbsp;Isabelle Ray-Coquard ,&nbsp;Eric Pujade-Lauraine ,&nbsp;Titus J. Brinker","doi":"10.1016/j.ejca.2024.115199","DOIUrl":"10.1016/j.ejca.2024.115199","url":null,"abstract":"<div><h3>Purpose</h3><div>Ovarian cancer patients with a Homologous Recombination Deficiency (HRD) often benefit from polyadenosine diphosphate–ribose polymerase (PARP) inhibitor maintenance therapy after response to platinum-based chemotherapy. HR status is currently analyzed via complex molecular tests. Predicting benefit from PARP inhibitors directly on histological whole slide images (WSIs) could be a fast and cheap alternative.</div></div><div><h3>Patients and methods</h3><div>We trained a Deep Learning (DL) model on H&amp;E stained WSIs with “shrunken centroid” (SC) based HRD ground truth using the AGO-TR1 cohort (n = 208: 108 training, 100 test) and tested its ability to predict HRD as evaluated by the Myriad classifier and the benefit from olaparib in the PAOLA-1 cohort (n = 447) in a blinded manner.</div></div><div><h3>Results</h3><div>In contrast to the HRD prediction AUROC of 72 % on hold-out, our model only yielded an AUROC of 57 % external. Kaplan-Meier analysis showed that progression free survival (PFS) in the PARP inhibitor treated PAOLA-1 patients was significantly improved in the HRD positive group as defined by our model, but not in the HRD negative group. PFS improvement in PARP inhibitor-treated patients was substantially longer in our HRD positive group, hinting at a biologically meaningful prediction of benefit from PARP inhibitors.</div></div><div><h3>Conclusion</h3><div>Together, our results indicate that it might be possible to generate a predictor of benefit from PARP inhibitors based on the DL-mediated analysis of WSIs. However, further studies with larger cohorts and further methodological improvements will be necessary to generate a predictor with clinically useful accuracy across independent patient cohorts.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"216 ","pages":"Article 115199"},"PeriodicalIF":7.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Alectinib for the treatment of papillary thyroid carcinoma harbouring STRN – ALK fusion 阿勒替尼治疗伴有STRN - ALK融合的甲状腺乳头状癌。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115193
Silvia Buriolla , Giulia Zapelloni , Claudia Cipri , Giacomo Pelizzari , Alessandro Follador , Francesco Cortiula

Background

Anaplastic Lymphoma Kinase (ALK) rearrangement is a rare alteration in differentiated thyroid carcinomas (DTCs). Due to its low prevalence, a few evidence are available about the use of ALK inhibitors in advanced DTCs.

Methods

We report the case of a striatin (STRN) - ALK translocated advanced thyroid carcinoma.
STRN – ALK translocation was detected by NGS – RNA analysis.

Results

A 74-year-old woman received first line alectinib for the treatment of a STRN - ALK translocated advanced thyroid carcinoma with symptomatic bilateral lung localizations.
The dose of alectinib was progressively reduced due to the toxicity, but the treatment is still ongoing after 17 months with complete radiological response and clinical benefit.

Conclusion

Here we report the first case in Europe of STRN - ALK translocated advanced thyroid carcinoma successfully treated with alectinib.
背景:间变性淋巴瘤激酶(ALK)重排是分化型甲状腺癌(dtc)中一种罕见的改变。由于ALK的低患病率,在晚期dtc中使用ALK抑制剂的证据很少。方法:我们报告一例纹状蛋白(STRN) - ALK易位的晚期甲状腺癌。通过NGS - RNA分析检测STRN - ALK易位。结果:一名74岁妇女接受一线阿勒替尼治疗STRN - ALK易位晚期甲状腺癌伴双侧肺症状性定位。由于毒性,alectinib的剂量逐渐减少,但治疗在17个月后仍在进行,放射学反应完全,临床获益。结论:我们报告了欧洲首例用阿勒替尼成功治疗STRN - ALK易位晚期甲状腺癌的病例。
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引用次数: 0
Response to Letter Entitled “Elevated serum magnesium levels prompt favourable outcomes in cancer patients treated with immune checkpoint blockers”
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2025.115250
Yingfang Feng, Huilai Zhang, Xianhuo Wang
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引用次数: 0
Glucagon-like Peptide‐1 Agonists Reduce Cardiovascular Events in Cancer Patients on Immune Checkpoint Inhibitors 胰高血糖素样肽-1激动剂可减少使用免疫检查点抑制剂的癌症患者的心血管事件。
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115170
Cho-Han Chiang , Junmin Song , Kuan-Yu Chi , Yu-Cheng Chang , Nutchapon Xanthavanij , Yu Chang , Yuan Ping Hsia , Cho-Hung Chiang , Azin Ghamari , Kerry L. Reynolds , Shuwen Lin , Xiaocao “Haze” Xu , Tomas G. Neilan

Background

Immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE). Glucagon-like peptide-1 agonists (GLP1a), initially developed for type 2 diabetes mellitus (T2DM), have shown promising results in reducing cardiovascular events. We aimed to investigate the effect of GLP1a on cardiovascular events in patients receiving ICIs.

Methods

We conducted a retrospective, propensity score-matched cohort study using the TriNetX database. We identified adults with cancer and T2DM who received ICIs between April 2013 and May 2023. The primary efficacy outcome was incident MACE, defined as a composite of myocardial infarction, need for coronary revascularization, heart failure, ischemic stroke, and cardiac arrest. The secondary efficacy outcomes were the individual components of MACE as well as myocarditis and pericarditis. Safety outcomes included the occurrence of immune-related adverse events, serious adverse events related to GLP1a use, and all-cause mortality.

Results

We identified 7651 patients eligible for inclusion, among which 479 received GLP1a and 7172 received non-GLP1a diabetes medications. After matching (469 patients each), baseline characteristics were well-balanced. Over a median 12-month follow-up, the GLP1a cohort had a significantly lower MACE incidence than the non-GLP1a cohort (9.0 vs. 17.1 events per 100 patient-years) with a 54 % lower risk of MACE (Hazard ratio (HR),0.46 [95 % CI: 0.32–0.67]). There were reductions in myocardial infarction or need for coronary revascularization, heart failure, and all-cause mortality, with no differences in other cardiovascular events. GLP1a use did not increase risk of adverse events, including pancreatitis, biliary disease, bowel obstruction, gastroparesis, and immune-related adverse events.

Conclusion

GLP1a use in cancer patients with T2DM receiving ICIs was associated with reduced MACE and all-cause mortality without an increased risk in serious adverse events.
背景:免疫检查点抑制剂(ICIs)与主要不良心血管事件(MACE)风险增加相关。胰高血糖素样肽-1激动剂(GLP1a)最初是为2型糖尿病(T2DM)开发的,在减少心血管事件方面显示出有希望的结果。我们的目的是研究GLP1a对接受ICIs患者心血管事件的影响。方法:我们使用TriNetX数据库进行回顾性倾向评分匹配队列研究。我们确定了在2013年4月至2023年5月期间接受ICIs治疗的患有癌症和2型糖尿病的成年人。主要疗效指标是MACE的发生率,定义为心肌梗死、冠状动脉血运重建、心力衰竭、缺血性卒中和心脏骤停的综合指标。次要疗效结果是MACE的各个成分以及心肌炎和心包炎。安全性结局包括免疫相关不良事件的发生、与GLP1a使用相关的严重不良事件和全因死亡率。结果:我们确定了7651例符合纳入条件的患者,其中479例接受GLP1a治疗,7172例接受非GLP1a糖尿病药物治疗。匹配后(各469例),基线特征平衡良好。在中位12个月的随访中,GLP1a队列的MACE发生率显著低于非GLP1a队列(9.0 vs. 17.1事件/ 100患者年),MACE风险降低54%(风险比(HR),0.46 [95% CI: 0.32-0.67])。心肌梗死、冠状动脉血运重建术、心力衰竭和全因死亡率均有降低,其他心血管事件无差异。GLP1a的使用不会增加不良事件的风险,包括胰腺炎、胆道疾病、肠梗阻、胃轻瘫和免疫相关不良事件。结论:GLP1a在接受ICIs治疗的T2DM癌症患者中使用与降低MACE和全因死亡率相关,且未增加严重不良事件的风险。
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引用次数: 0
Could intratumoural microbiota be key to unlocking treatment responses in hepatocellular carcinoma? 肿瘤内微生物群可能是开启肝癌治疗反应的关键吗?
IF 7.6 1区 医学 Q1 ONCOLOGY Pub Date : 2025-02-05 DOI: 10.1016/j.ejca.2024.115195
Kin Lam Yu , Sj Shen
Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality worldwide. Current treatments include surgery and immunotherapy with variable response. Despite aggressive treatment, disease progression remains the biggest contributor to mortality. Thus, there is an urgent unmet need to improve current treatments through a better understanding of HCC tumourigenesis. The gut microbiota has been intensively examined in the context of HCC, with evidence showing gut modulation has the potential to modulate tumourigenesis and prognosis. In addition, recent literature suggests the presence of an intratumoural microbiota that may exert significant impacts on the development of solid tumours including HCC. By drawing parallels between the gut and hepatic/tumoural microbiota, we explore in the present review how the hepatic microbiota is established, its impact on tumourigenesis, and how modulation of the gut and hepatic microbiota may be key to improving current treatments of HCC. In particular, we highlight key bacteria that have been discovered in HCC tumours, and how they may affect the tumour immune microenvironment and HCC tumourigenesis. We then explore current therapies that target the intratumoural microbiota. With a deeper understanding of how the intratumoural microbiota is established, how different bacteria may be involved in HCC tumourigenesis, and how they can be targeted, we hope to spark future research in validating intratumoural microbiota as an avenue for improving treatment responses in HCC.
肝细胞癌(HCC)是全球癌症相关死亡的第三大原因。目前的治疗方法包括手术和免疫治疗。尽管进行了积极的治疗,但疾病进展仍然是导致死亡的最大因素。因此,迫切需要通过更好地了解HCC的肿瘤发生来改善目前的治疗方法。在HCC的背景下,肠道微生物群已被深入研究,有证据表明肠道调节具有调节肿瘤发生和预后的潜力。此外,最近的文献表明,肿瘤内微生物群的存在可能对包括HCC在内的实体肿瘤的发展产生重大影响。通过比较肠道和肝脏/肿瘤微生物群之间的相似之处,我们在本综述中探讨了肝脏微生物群是如何建立的,它对肿瘤发生的影响,以及肠道和肝脏微生物群的调节如何可能是改善当前HCC治疗的关键。我们特别强调了在HCC肿瘤中发现的关键细菌,以及它们如何影响肿瘤免疫微环境和HCC肿瘤发生。然后我们探索目前针对肿瘤内微生物群的治疗方法。随着对肿瘤内微生物群如何建立,不同细菌如何参与HCC肿瘤发生以及它们如何被靶向的更深入了解,我们希望激发未来的研究,以验证肿瘤内微生物群作为改善HCC治疗反应的途径。
{"title":"Could intratumoural microbiota be key to unlocking treatment responses in hepatocellular carcinoma?","authors":"Kin Lam Yu ,&nbsp;Sj Shen","doi":"10.1016/j.ejca.2024.115195","DOIUrl":"10.1016/j.ejca.2024.115195","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality worldwide. Current treatments include surgery and immunotherapy with variable response. Despite aggressive treatment, disease progression remains the biggest contributor to mortality. Thus, there is an urgent unmet need to improve current treatments through a better understanding of HCC tumourigenesis. The gut microbiota has been intensively examined in the context of HCC, with evidence showing gut modulation has the potential to modulate tumourigenesis and prognosis. In addition, recent literature suggests the presence of an intratumoural microbiota that may exert significant impacts on the development of solid tumours including HCC. By drawing parallels between the gut and hepatic/tumoural microbiota, we explore in the present review how the hepatic microbiota is established, its impact on tumourigenesis, and how modulation of the gut and hepatic microbiota may be key to improving current treatments of HCC. In particular, we highlight key bacteria that have been discovered in HCC tumours, and how they may affect the tumour immune microenvironment and HCC tumourigenesis. We then explore current therapies that target the intratumoural microbiota. With a deeper understanding of how the intratumoural microbiota is established, how different bacteria may be involved in HCC tumourigenesis, and how they can be targeted, we hope to spark future research in validating intratumoural microbiota as an avenue for improving treatment responses in HCC.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"216 ","pages":"Article 115195"},"PeriodicalIF":7.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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European Journal of Cancer
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