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DNA-incorporated thioguanine to detect potential non-adherence to maintenance therapy in acute lymphoblastic leukemia. dna结合硫鸟嘌呤检测急性淋巴细胞白血病维持治疗的潜在不依从性。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-16 DOI: 10.1007/s00280-025-04784-7
Mathilde Rønne Koch, Anna Sofie Buhl Rasmussen, Bodil Als-Nielsen, Ximo Duarte, Gabriele Escherich, Mats Heyman, Kristi Lepik, Johan Malmros, Jacob Nersting, Inga Johannsdottir, Riitta Niinimäki, Malene Johanne Petersen, Heidi Segers, Inge Margriet van der Sluis, Maria Thastrup, Goda Vaitkeviciene, Kjeld Schmiegelow, Linea Natalie Toksvang

Purpose: Adherence to 6-mercaptopurine (6-MP)/methotrexate maintenance treatment for acute lymphoblastic leukemia (ALL) is pivotal to preventing relapse, and the 6-MP metabolite DNA-incorporated thioguanine (DNA-TG) is associated with relapse risk. In the ALLTogether-1 (A2G1) Maintenance sub-study (EU CT nr 2022-501050-11-01), DNA-TG, thioguanine nucleotides (TGN), and methylated mercaptopurine metabolites (MeMP) are analyzed regularly. Upon levels below preset limits (TGN < 50, or MeMP < 200 or < 100 nmol/mmol hemoglobin for thiopurine S-methyltransferase (TPMT) wild type and heterozygous patients, respectively), the treating physician is informed of potential non-adherence. We investigated the feasibility of using DNA-TG as the primary flagging of potential non-adherence.

Methods: We analyzed 6-MP metabolites in 3,074 blood samples from 368 children enrolled in the A2G1 Maintenance sub-study.

Results: In 6% of samples, TGN (median 212, 95% range 40-642), MeMP (median 4,959, 95% range 135-23,880) or both were below the flagging potential non-adherence limits. DNA-TG was associated with TGN (estimate = 1.72, p < 0.0001), MeMP (estimate = 1.10, p < 0.0001), and prescribed 6-MP dose (estimate = 1.083 and 1.132, p < 0.0001, for TPMT wild type and heterozygous patients) in linear effects models, and the predicted probability of treatment interruption in logistic regression models. DNA-TG was below 200 fmol TG/µg DNA (13th percentile of all measurements, median 569, 95% range 73-1,823) in all samples with both TGN and MeMP below the flagging potential non-adherence limits.

Conclusion: DNA-TG can provide a cost-effective guidance on when to measure TGN and MeMP to determine whether non-adherence should be suspected, which is an additional benefit to monitoring DNA-TG during maintenance therapy.

目的:坚持6-巯基嘌呤(6-MP)/甲氨蝶呤维持治疗是预防急性淋巴细胞白血病(ALL)复发的关键,6-MP代谢物dna结合的硫鸟嘌呤(DNA-TG)与复发风险相关。在ALLTogether-1 (A2G1)维持子研究(EU CT nr 2022-501050-11-01)中,定期分析DNA-TG、硫鸟嘌呤核苷酸(TGN)和甲基化巯基嘌呤代谢物(MeMP)。方法:我们分析了来自368名A2G1维持子研究的儿童的3074份血液样本中的6-MP代谢物。结果:在6%的样本中,TGN(中位数212,95%范围40-642),MeMP(中位数4959,95%范围135-23,880)或两者均低于潜在的不依从限制。结论:DNA-TG可以为何时测量TGN和MeMP以确定是否应怀疑不依从提供具有成本效益的指导,这是维持治疗期间监测DNA-TG的另一个好处。
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引用次数: 0
Unrecognized mutations in DPYD* 2 A wild-type rectal cancer patients receiving postoperative 5-FU-based chemotherapy - do they have a clinical impact? 接受术后5- fu化疗的DPYD* 2a野生型直肠癌患者中未被识别的突变-它们是否具有临床影响?
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-15 DOI: 10.1007/s00280-025-04787-4
P Liersch, S Dierks, R Andag, T Liersch, C de Boer, J Kreutzer, A Hille, H Sülberg, A Leha, Julie Schanz

Purpose: The impact of the unrecognized mutational dihydropyrimidine-dehydrogenase-gene-(DPYD)-status on high-grade CTC-AE-grades ≥ 3 (NCI-Common Terminology Criteria for Adverse Events, vs. 3.0) was assessed in patients with upper rectal cancer (inferior tumor margin ≥ 12 cm above the anal verge) treated with upfront surgery and 5-Fluorouracil (5-FU) based adjuvant chemotherapy (CTx).

Methods: 75 participants of the GAST-05-phase-IIb-trial (ISRCTN35198481) were tested in this single center analysis for DPYD*2A-wildtype (WT) at staging. After surgery, 43 patients (stages II and III, according to the current 8th TNM/UICC-classification, 2017) received FOLFOX-CTx and entered follow-up (median: 101 months). According to recent recommendations of the European Medicines Agency (EMA) and national guidelines, post-hoc genotyping for DPYD*2A (c.1905 + 1G > A; IVS14 + 1G > A; rs3918290), DPYD*13 (c.1679T > G; rs55886062), polymorphism c.2846 A > T (rs67376798) and Haplotype B3 (HapB3) (c.1236G > A; c.1129-5923 C > G) was performed using cryopreserved blood samples and standardized PCR-techniques.

Results: Five patients were found to have a heterozygous (het_) DPYD-HapB3-status. Across all patients, the adherence to CTx-cycles 1 to 4 was 100%, 97.7%, 95.3%, and 93.0%, respectively. Grade ≥ 3 CTC-AEs were observed in 0.9% of both het_HapB3- and WT-patients. The mean administered dose of 5-FU was 68.8% of the target in DPYD-HapB3 carriers, compared to 92.6% in 38 WT patients. Logistic regression analysis revealed that 5-FU dose reductions were significantly associated with DPYD-HapB3 carrier status (odds ratio [OR] 12.55, p = 0.044) and male sex (OR 0.23, p = 0.049). During follow-up het_HapB3-patients had a recurrence rate of 60.0%, compared to 13,6% for WT-patients. The disease-free survival (DFS) for het_HapB3-patients was significantly reduced vs. WT (p = 0.010). Multivariable analysis showed that het_HapB3-patients had an increased risk for reduced DFS (HR 3.774; p = 0.057). Interestingly, 5-FU dose reductions per se were not significantly associated with limited DFS in the total population.

Conclusion: DPYD genotyping revealed a het_HapB3 variant in 11.6% of DPYD*2A-WT patients treated with FOLFOX. While not linked to increased toxicity, HapB3 status was associated with reduced DFS, suggesting an impact on treatment efficacy. These results support DPYD genotyping and highlight the need for adequate 5-FU plasma level assessment followed by subtile dose escalation (therapeutic drug monitoring) to personalize 5-FU dosing more precisely, safely and most effective.

目的:在接受前期手术和基于5-氟尿嘧啶(5-FU)的辅助化疗(CTx)的上直肠癌(下肿瘤边缘≥12 cm)患者中,评估未识别的突变二氢嘧啶脱氢酶基因(DPYD)状态对ctc - ae分级≥3级(nci -不良事件通用术语标准,vs. 3.0)的影响。方法:对gast -05-phase- iib试验(ISRCTN35198481)的75名参与者进行DPYD* 2a野生型(WT)分期单中心分析。术后,43例患者(II期和III期,根据2017年第8期TNM/ uicc分类)接受FOLFOX-CTx治疗并进入随访(中位:101个月)。根据欧洲药品管理局(EMA)最近的建议和国家指南,DPYD*2A (c.1905 + 1G > A;ivs14 + 1g > a;rs3918290), DPYD*13 (c.1679T > G;Rs55886062),多态性c.2846A > T (rs67376798)和单倍型B3 (HapB3) (c.1236G > A;C .1129-5923 C . > G)使用冷冻保存的血液样本和标准化pcr技术进行检测。结果:5例患者存在杂合(het_) dpyd - hapb3状态。在所有患者中,ctx周期1至4的依从性分别为100%,97.7%,95.3%和93.0%。在het_HapB3-和wt -患者中,均有0.9%的患者出现≥3级ctc - ae。在DPYD-HapB3携带者中,5-FU的平均给药剂量为目标的68.8%,而在38例WT患者中为92.6%。Logistic回归分析显示,5-FU剂量减少与DPYD-HapB3携带者状态(比值比[OR] 12.55, p = 0.044)和男性性别(比值比[OR] 0.23, p = 0.049)显著相关。在随访期间,het_hapb3患者的复发率为60.0%,而wt患者的复发率为13.6%。het_hapb3患者的无病生存期(DFS)与WT相比显著降低(p = 0.010)。多变量分析显示,het_hapb3患者DFS降低的风险增加(HR 3.774;p = 0.057)。有趣的是,5-FU剂量减少本身与总体人群的有限DFS没有显著相关。结论:DPYD基因分型显示11.6%接受FOLFOX治疗的DPYD*2A-WT患者存在het_HapB3变异。虽然与毒性增加无关,但HapB3状态与DFS降低相关,表明对治疗效果有影响。这些结果支持DPYD基因分型,并强调需要进行充分的5-FU血浆水平评估,然后进行微妙的剂量递增(治疗药物监测),以更精确、更安全、更有效地个性化5-FU剂量。
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引用次数: 0
Evaluation of the pharmacokinetics of enasidenib in patients with hepatic impairment. enasidenib在肝功能损害患者中的药代动力学评价。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-11 DOI: 10.1007/s00280-025-04797-2
Yiming Cheng, Jian Chen, Carlos Vigil, Shahram Khanzadeh, Anita Rampersad, Thomas Prebet, Yan Li
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引用次数: 0
A case report: capillary leak syndrome in a patient receiving high-dose methotrexate, Tislelizumab and zanubrutinib for CNS lymphoma. 一例报告:接受大剂量甲氨蝶呤、替利单抗和扎鲁替尼治疗中枢神经系统淋巴瘤患者的毛细血管渗漏综合征。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-07 DOI: 10.1007/s00280-025-04796-3
Wenpeng Li, Yuxi Hou

Purpose: The high-dose methotrexate (MTX) regimen is a first-line treatment for primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). However, MTX-related kidney injury is a severe treatment complication. No cases of capillary leak syndrome (CLS) causing delayed MTX metabolism-associated renal failure have been reported.

Case presentation: A 48-year-old female presented to Zibo Central Hospital in April 2024 with headaches. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed a space-occupying lesion in the right occipital lobe. A stereotactic biopsy was performed to determine the nature of the lesion. Postoperative pathology confirmed DLBCL. The patient underwent a TZM regimen, which included Tislelizumab, MTX, and Zanubrutinib. On the first day following MTX, the patient developed generalized edema, shortness of breath, and reduced urine output. Laboratory tests revealed hypoxemia, low albumin levels, and acute kidney injury. Based on these findings, the patient was diagnosed with CLS. To quickly lower the blood MTX concentration, pleural effusion drainage and continuous renal replacement therapy (CRRT) were performed. The treatment was successful, and the patient recovered and was discharged.

Conclusion: CLS is a serious complication for DLBCL patients receiving high-dose MTX therapy.

目的:大剂量甲氨蝶呤(MTX)方案是原发性中枢神经系统弥漫性大b细胞淋巴瘤(PCNS-DLBCL)的一线治疗方案。然而,mtx相关的肾损伤是一种严重的治疗并发症。没有病例毛细血管渗漏综合征(CLS)引起延迟MTX代谢相关肾功能衰竭的报道。病例介绍:一名48岁女性,于2024年4月因头痛入院淄博市中心医院。脑磁共振造影(MRI)显示右侧枕叶占位性病变。进行立体定向活检以确定病变的性质。术后病理证实为DLBCL。患者接受TZM方案,其中包括Tislelizumab, MTX和Zanubrutinib。在甲氨蝶呤治疗后的第一天,患者出现全身性水肿、呼吸急促和尿量减少。实验室检查显示低氧血症、低白蛋白水平和急性肾损伤。基于这些发现,患者被诊断为CLS。为迅速降低血MTX浓度,行胸腔积液引流及持续肾替代治疗(CRRT)。治疗成功,患者康复出院。结论:慢性淋巴细胞白血病是大剂量甲氨蝶呤治疗的严重并发症。
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引用次数: 0
Risk factors and prediction models for cardiotoxicity induced by anthracyclines in malignant chemotherapy. 蒽环类药物致恶性化疗心脏毒性的危险因素及预测模型。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-07 DOI: 10.1007/s00280-025-04795-4
Pengxiang Zhang, Yan Zhang, Zheng Xue, Dongchao Liu, Dongliang Li, Bing Duan, Meina Zhao, Liang Yin, Hongjie Gao, Bulang Gao, Jie Mi
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引用次数: 0
Protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal Cancer. 塞来昔布对卡培他滨诱导的结直肠癌患者手足综合征的保护作用。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-07 DOI: 10.1007/s00280-025-04794-5
Ahmed M Kettana, Tarek M Mostafa, Amr A Ghannam, Dalia R El-Afify

Background: Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine.

Objective: We aimed at evaluating the protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal cancer (CRC).

Methods: In this randomized controlled parallel study, 44 newly diagnosed patients with stage II CRC were randomly allocated into two groups; Group 1(control group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) and group 2 (celecoxib group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) in addition to 200 mg of oral celecoxib twice daily for 14 days of the 3-week cycle. At baseline and after the 6th chemotherapy cycle the patients' quality of life (QOL) was assessed using hand and foot syndrome (HFS) specific QOL questionnaire (HFS-14). Moreover, blood samples were collected in order to evaluate the serum levels of cyclooxygenase-2 (COX-2), tumour necrosis factor-alpha (TNF-α) and malondialdehyde (MDA). Data was analysed using paired and un-paired t-tests.

Results: At the end of the study and as compared to control group, celecoxib treated group showed significantly lower incidence of HFS (P = 0.015). Additionally, celecoxib treated group showed significant decline in the serum levels of TNF-α (P = 0.016) and MDA (P = 0.014) which was associated with non-significant difference in the serum level of COX-2 between the two groups (P = 0.476). Celecoxib was safe and well-tolerated throughout the study period.

Conclusion: Celecoxib may represent a potential protective agent against capecitabine induced hand and foot syndrome in patients with colorectal cancer.

背景:手足综合征(HFS)是卡培他滨最常见的不良反应。目的:评价塞来昔布对卡培他滨诱导的结直肠癌(CRC)患者手足综合征的保护作用。方法:在这项随机对照平行研究中,44例新诊断的II期CRC患者随机分为两组;第一组(对照组;N = 22)组接受6个周期卡培他滨基础化疗(周期为每3周),2组(塞来昔布组;N = 22),接受6个周期卡培他滨化疗(周期为每3周),外加200 mg口服塞来昔布2次,为期14天,3周周期。采用手足综合征(HFS)特异性生活质量问卷(HFS-14)评估患者在基线和第6个化疗周期后的生活质量(QOL)。此外,采集血样评估血清环氧化酶-2 (COX-2)、肿瘤坏死因子-α (TNF-α)和丙二醛(MDA)水平。数据分析采用配对和非配对t检验。结果:研究结束时,与对照组相比,塞来昔布治疗组HFS发生率显著降低(P = 0.015)。塞来昔布治疗组血清TNF-α水平(P = 0.016)和MDA水平(P = 0.014)显著下降,两组血清COX-2水平差异无统计学意义(P = 0.476)。塞来昔布在整个研究期间是安全且耐受性良好的。结论:塞来昔布可能是预防卡培他滨诱导的结直肠癌患者手足综合征的潜在保护剂。
{"title":"Protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal Cancer.","authors":"Ahmed M Kettana, Tarek M Mostafa, Amr A Ghannam, Dalia R El-Afify","doi":"10.1007/s00280-025-04794-5","DOIUrl":"10.1007/s00280-025-04794-5","url":null,"abstract":"<p><strong>Background: </strong>Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine.</p><p><strong>Objective: </strong>We aimed at evaluating the protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal cancer (CRC).</p><p><strong>Methods: </strong>In this randomized controlled parallel study, 44 newly diagnosed patients with stage II CRC were randomly allocated into two groups; Group 1(control group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) and group 2 (celecoxib group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) in addition to 200 mg of oral celecoxib twice daily for 14 days of the 3-week cycle. At baseline and after the 6th chemotherapy cycle the patients' quality of life (QOL) was assessed using hand and foot syndrome (HFS) specific QOL questionnaire (HFS-14). Moreover, blood samples were collected in order to evaluate the serum levels of cyclooxygenase-2 (COX-2), tumour necrosis factor-alpha (TNF-α) and malondialdehyde (MDA). Data was analysed using paired and un-paired t-tests.</p><p><strong>Results: </strong>At the end of the study and as compared to control group, celecoxib treated group showed significantly lower incidence of HFS (P = 0.015). Additionally, celecoxib treated group showed significant decline in the serum levels of TNF-α (P = 0.016) and MDA (P = 0.014) which was associated with non-significant difference in the serum level of COX-2 between the two groups (P = 0.476). Celecoxib was safe and well-tolerated throughout the study period.</p><p><strong>Conclusion: </strong>Celecoxib may represent a potential protective agent against capecitabine induced hand and foot syndrome in patients with colorectal cancer.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"72"},"PeriodicalIF":2.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Impact of altitude on hemoglobin dynamics and prognosis in patients with advanced hepatocellular carcinoma receiving antiangiogenic TKIs: A propensity score matched study. 海拔对接受抗血管生成TKIs治疗的晚期肝癌患者血红蛋白动态和预后的影响:一项倾向评分匹配研究
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-05 DOI: 10.1007/s00280-025-04786-5
Mengyun Zhou, Xiang Zhao, Meng Zhang, Mao Peijing, Chilie Quncuo, Pubu Zhuoga, Bianba Qiongda, Meilang Chutso, Bian Ma Cuo, Bangchao Zhao, Guangfa Wang, Cheng Yuan

Purpose: Antiangiogenic tyrosine kinase inhibitors (TKIs) are associated with elevated hemoglobin [Hb] levels, potentially influencing prognosis in advanced hepatocellular carcinoma (HCC) patients. However, the impact of altitude on Hb dynamics and its prognostic significance remains underexplored. This study aimed to assess altitude-related Hb changes and their relationship with treatment outcomes in patients following TKI treatment.

Methods: In this retrospective cohort study, medical data from two institutions in Tibet and Beijing were analyzed. Between 2016 and 2022, 128 advanced HCC patients treated with antiangiogenic TKIs were divided into high- and low-altitude groups based on their city of residence. Hematological parameters were retrieved at baseline and every 3 months for 9 months post-treatment initiation. Propensity score matching (PSM) was used to adjust for demographic and baseline differences. Hb percentage changes from baseline (no increase, increase < 15%, increase ≥ 15%) were evaluated at each time point as predictors of time to treatment failure (TTTF) using the Cox proportional hazards model.

Results: After PSM, Hb trajectories differed between the altitude groups. The high-altitude patients exhibited progressive increases, while the low-altitude patients experienced a transient rise followed by a decline. We found no significant TTTF differences between the matched altitude groups (P = 0.33). However, in the high-altitude unmatched cohort, a ≥ 15% increase in Hb at 9 months was linked to a significantly lower risk of treatment failure (HR = 0.22 [95% CI = 0.06-0.83]; P = 0.03). Patients with increases < 15% showed a numerical trend toward prolonged TTTF (HR = 0.30 [0.08-1.15]).

Conclusion: Antiangiogenic TKIs induce altitude-dependent Hb changes, with sustained increases at high altitudes and transient reversibility at low altitudes. A ≥ 15% increase in Hb at 9 months after TKI therapy may serve as a potential biomarker for identifying high-altitude populations likely to benefit more from TKI therapy. Future studies should validate these findings in larger cohorts.

目的:抗血管生成酪氨酸激酶抑制剂(TKIs)与血红蛋白[Hb]水平升高相关,可能影响晚期肝细胞癌(HCC)患者的预后。然而,海拔对血红蛋白动力学的影响及其预后意义仍未得到充分探讨。本研究旨在评估TKI治疗后患者与海拔相关的Hb变化及其与治疗结果的关系。方法:采用回顾性队列研究方法,对西藏和北京两所医院的医疗资料进行分析。在2016年至2022年期间,128名接受抗血管生成TKIs治疗的晚期HCC患者根据居住城市分为高海拔组和低海拔组。在治疗开始后9个月内,在基线和每3个月检索一次血液学参数。倾向得分匹配(PSM)用于调整人口统计学和基线差异。结果:PSM后,不同海拔组的Hb变化轨迹不同。高海拔地区患者呈进行性升高,低海拔地区患者呈短暂性上升后下降。我们发现匹配海拔组间TTTF无显著差异(P = 0.33)。然而,在高海拔非匹配队列中,9个月时Hb增加≥15%与治疗失败风险显著降低相关(HR = 0.22 [95% CI = 0.06-0.83];p = 0.03)。结论:抗血管生成TKIs诱导Hb变化高度依赖性,在高海拔地区持续升高,在低海拔地区具有短暂可逆性。TKI治疗后9个月Hb升高≥15%可作为识别高海拔人群可能从TKI治疗中获益更多的潜在生物标志物。未来的研究应该在更大的队列中验证这些发现。
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引用次数: 0
Peptides derived from the POU domain of BRN2 show antitumor activity against murine melanoma model cells in vitro and in vivo. 来源于BRN2 POU结构域的肽在体内和体外均显示出对小鼠黑色素瘤模型细胞的抗肿瘤活性。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-02 DOI: 10.1007/s00280-025-04790-9
Maria Carolina Mariano Cesar, Agnes Kobayashi Calvo de Sant'ana, Renato Arruda Mortara, Victória Santos Souza, Thaysa Paschoalin, Marco Antônio Soufen, Juliana Machado Anastácio, Erenildo F Macedo, Fernanda Fernandes Miranda da Cunha, Dayane Batista Tada, Denise Costa Arruda

The BRN2 transcription factor controls the protein expression involved in cell motility and is overexpressed in melanoma. Gene mutations involved in cell signaling pathways lead to BRN2 overexpression, tumor formation and metastasis. Peptides derived from the DNA binding domain of transcription factors can compete for the transcription binding and regulate protein expression. In this work, the antitumor activity in vitro and in vivo of the peptide E24G, derived from the DNA-binding POU domain of the BRN2 transcription factor was investigated. This peptide was fragmented into two smaller peptides E12F and A12G, their antitumor activities were characterized and compared with E24G. The E24G at 1 mM significantly reduced cell motility in vitro of B16F10-Nex2 melanoma cells. E12F peptide also inhibited cell motility at a concentration eight times smaller than E24G in murine and human melanoma cells. We observed that the antitumor activity of both E24G and E12F peptides depends on the macropinocytosis displayed by tumor cells. Also, the E24G and E12F peptides induced an increase of the CDH13 expression in 50%, however the treatment with E12F increased the expression already after 12 h by 100%. In vivo assays showed that both peptides reduced the development of metastatic lung nodules without presenting toxicity to normal organs. Our results indicate that E12F and E24G peptides can restore normal expression of BRN2 target genes at the molecular level, inhibiting the cell motility. In addition, we confirmed that the peptide binds to the DNA binding site of the BRN2 transcription factor. Further studies will elucidate their mechanisms of antitumor activity, so far our results pointed out the potential application of E12F and E24G peptides as innovative treatments for metastatic melanoma.

BRN2转录因子控制参与细胞运动的蛋白表达,在黑色素瘤中过度表达。参与细胞信号通路的基因突变导致BRN2过表达、肿瘤形成和转移。来自转录因子DNA结合域的肽可以竞争转录结合并调节蛋白质的表达。本文研究了BRN2转录因子dna结合POU结构域衍生的肽E24G在体内和体外的抗肿瘤活性。该肽被分割成两个较小的肽E12F和A12G,它们的抗肿瘤活性被表征并与E24G进行了比较。E24G在1 mM时显著降低B16F10-Nex2黑色素瘤细胞的体外活力。在小鼠和人黑色素瘤细胞中,E12F肽对细胞运动的抑制作用比E24G浓度小8倍。我们观察到E24G和E12F肽的抗肿瘤活性都依赖于肿瘤细胞所显示的巨噬细胞作用。此外,E24G和E12F肽诱导CDH13表达增加50%,而E12F处理在12 h后已使表达增加100%。体内实验表明,这两种肽均可减少转移性肺结节的发展,而不会对正常器官产生毒性。我们的研究结果表明,E12F和E24G肽可以在分子水平上恢复BRN2靶基因的正常表达,抑制细胞运动。此外,我们证实该肽与BRN2转录因子的DNA结合位点结合。进一步的研究将阐明其抗肿瘤活性的机制,目前我们的研究结果指出了E12F和E24G肽作为转移性黑色素瘤的创新治疗方法的潜在应用。
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引用次数: 0
ETV1 genetic polymorphisms as a candidate prognosis biomarker of Gastrointestinal stromal tumor. ETV1基因多态性作为胃肠道间质瘤的候选预后生物标志物。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-02 DOI: 10.1007/s00280-025-04789-2
Wei Zhuang, Minju Jo, Haibo Qiu, Wanlong Lin, Min Huang, Xueding Wang

Purpose: While imatinib is effective for treating Gastrointestinal Stromal Tumors (GISTs), significant variability in patient outcomes exists, highlighting the need for reliable prognostic biomarkers. ETV1, a key transcription factor involved in GIST progression, is implicated in disease biology, but the role of ETV1-related single nucleotide polymorphisms (SNPs) in predicting prognosis remains unclear.

Methods: This study included 75 GIST patients. We focused on identifying tag SNPs in the ETV1 gene and examined their association with clinical outcomes. Patient characteristics, somatic mutations, and imatinib concentration were also analyzed in a multivariate model. ETV1 expression was assessed using immunohistochemistry, and miRNA interactions with ETV1 transcripts were investigated via the dual-luciferase reporter assay system.

Results: We found that the rs3735343 SNP, located in the 3' untranslated region of ETV1, was significantly associated with progression-free survival (PFS) in GIST patients receiving imatinib (P = 0.008). Multivariate analysis identified tumor size (P = 0.032, Hazard Ratio [HR] = 4.173, 95% CI: 1.127-15.454) and rs3735343 (P = 0.009, HR = 8.995, 95% CI: 1.712-47.255) as independent predictors of PFS. The rs3735343 risk allele also correlated with elevated ETV1 expression in GIST tissue (P = 0.04). Additionally, miR-4311 was found to specifically and negatively regulate ETV1 mRNA levels associated with the rs3735343 risk allele in vitro.

Conclusion: This study reported ETV1 rs3735343 as a novel prognostic candidate biomarker for GISTs treated with Imatinib, providing a potential biomarker for risk assessment of GIST. Additionally, our findings suggest that rs3735343 may act as a miRNA-regulated SNP, with miR-4311 playing a key role in its regulation.

目的:虽然伊马替尼对胃肠道间质瘤(gist)有效,但患者预后存在显著差异,强调需要可靠的预后生物标志物。ETV1是参与GIST进展的关键转录因子,与疾病生物学有关,但ETV1相关的单核苷酸多态性(snp)在预测预后中的作用尚不清楚。方法:本研究纳入75例GIST患者。我们专注于识别ETV1基因中的标签snp,并检查它们与临床结果的关系。患者特征、体细胞突变和伊马替尼浓度也在多变量模型中进行了分析。使用免疫组织化学评估ETV1的表达,并通过双荧光素酶报告基因检测系统研究miRNA与ETV1转录物的相互作用。结果:我们发现位于ETV1 3'非翻译区rs3735343 SNP与接受伊马替尼治疗的GIST患者的无进展生存(PFS)显著相关(P = 0.008)。多因素分析发现肿瘤大小(P = 0.032,危险比[HR] = 4.173, 95% CI: 1.127 ~ 15.454)和rs3735343 (P = 0.009, HR = 8.995, 95% CI: 1.712 ~ 47.255)是PFS的独立预测因子。rs3735343风险等位基因也与GIST组织中ETV1表达升高相关(P = 0.04)。此外,miR-4311在体外被发现特异性负向调节与rs3735343风险等位基因相关的ETV1 mRNA水平。结论:本研究报道了ETV1 rs3735343作为伊马替尼治疗GIST的一种新的预后候选生物标志物,为GIST的风险评估提供了潜在的生物标志物。此外,我们的研究结果表明rs3735343可能是mirna调控的SNP, miR-4311在其调控中发挥关键作用。
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引用次数: 0
Pharmacokinetics, safety, and tolerability of fedratinib in adults with moderate and severe hepatic impairment: results from the phase 1 FEDR-CP-001 trial. FEDR-CP-001期临床研究结果:federatinib在中度和重度肝功能损害患者中的药代动力学、安全性和耐受性
IF 2.3 4区 医学 Q3 ONCOLOGY Pub Date : 2025-07-02 DOI: 10.1007/s00280-025-04785-6
Yizhe Chen, Richard A Preston, Thomas Marbury, William B Smith, Massimo Attanasio, Mark Thomas, Michael Thomas, Bing He, Yongjun Xue, Atalanta Ghosh, Gopal Krishna, Ken Ogasawara

Purpose: The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function.

Methods: This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18-75 years and had a BMI of 18-40 kg/m2. HI was determined by Child-Pugh score. Participants were placed into 1 of the following groups: group 1, moderate HI; group 2, healthy participants matched to group 1; group 3, severe HI; and group 4, healthy participants matched to group 3. Participants received a single dose of fedratinib 300 mg (groups 1 and 2) or 200 mg (groups 3 and 4) and were followed for 21 days.

Results: All participants (N = 38; groups 1, 3, and 4 [n = 8 each], group 2 [n = 14]) completed the trial. Peak and total fedratinib exposures (Cmax, AUC0-∞) were similar between moderate HI versus matched healthy participants. In participants with severe HI, there were lower total exposures compared to the matched healthy participants where the ratios of geometric means for Cmax, and AUC0-∞ were 0.897 and 0.660, respectively, and with large inter-participant variability. Ten participants experienced a treatment-emergent adverse event (all were considered mild), which were evenly distributed across groups.

Conclusion: These data indicate that reducing fedratinib starting doses is not necessary for patients with moderate or severe HI, and support clinicians in regular monitoring of patients with HI taking fedratinib.

目的:FEDR-CP-001 (NCT03983161)试验评估了单剂量federatinib在中度或重度肝功能损害(HI)成人中的药代动力学(PK)和安全性,并与匹配的肝功能正常的健康参与者进行了比较。方法:这是一项非随机、开放标签、多中心、1期试验。参与者年龄在18-75岁之间,体重指数为18-40 kg/m2。以Child-Pugh评分确定HI。参与者被分为以下1组:1组,中度HI;第二组,与第一组匹配的健康参与者;3组,重度HI;第四组是与第三组相匹配的健康参与者。参与者接受单剂量的300毫克(1组和2组)或200毫克(3组和4组),并随访21天。结果:所有受试者(N = 38;第1、3、4组[n = 8],第2组[n = 14])完成试验。在中度HI和匹配的健康参与者之间,峰值和总联邦拉替尼暴露(Cmax, AUC0-∞)相似。在重度HI参与者中,与匹配的健康参与者相比,总暴露量较低,其中Cmax和AUC0-∞的几何平均值分别为0.897和0.660,并且参与者间变异性较大。10名参与者经历了治疗中出现的不良事件(都被认为是轻微的),这些不良事件在各组中均匀分布。结论:这些数据表明,对于中度或重度HI患者,减少fedratinib的起始剂量是不必要的,并支持临床医生对服用fedratinib的HI患者进行定期监测。
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Cancer Chemotherapy and Pharmacology
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