In this phase I clinical trial cancer patients suffering from solid tumors or lymphomas, recurring after and/or refractory against standard treatment are treated intravenously (iv) with increasing doses of tTF-NGR(tTF= truncated tissue factor; NGR=Asn-Gly-Arg). The objectives of this trial are to evaluate the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of intravenously (iv) infused daily applications of tTF-NGR for 5 days every 3 weeks in patients with cancer, who had obtained all standard treatment known for their disease entity prior to entry on study. Further objectives are to determine the perfusion and vascular volume fraction of measurable tumor lesions versus normal reference tissue before and after tTF-NGR application by MRI as a biological surrogate parameter for biological activity of the investigational medicinal product (IMP), tTF-NGR, and to obtain pharmacokinetic data.

开始日期2017-03-01

申办/合作机构

Universitätsklinikum Münster

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100 项与 tTF-NGR(University of Münster) 相关的临床结果

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100 项与 tTF-NGR(University of Münster) 相关的转化医学

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100 项与 tTF-NGR(University of Münster) 相关的专利（医药）

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项与 tTF-NGR(University of Münster) 相关的文献（医药）

2023-11-02·Human Reproduction

Impact of low- or moderate-risk gonadotoxic chemotherapy prior to testicular tissue freezing on spermatogonia quantity in human (pre)pubertal testicular tissue

Article

作者: Mirallié, Sophie ; Rondanino, Christine ; Daudin, Myriam ; Feraille, Aurélie ; Rives, Nathalie ; Brugnon, Florence ; Barbotin, Anne-Laure ; Giscard d'Estaing, Sandrine ; Dumont, Ludovic ; Liard, Agnès ; Bubenheim, Michael ; Ancelle, Amélie ; Roux, Christophe ; Schneider, Pascale

AbstractSTUDY QUESTIONWhat is the impact of low- or moderate-risk gonadotoxic chemotherapy received prior to testicular tissue freezing (TTF), and of the cancer itself, on spermatogonia quantity in testicular tissue from (pre)pubertal boys?SUMMARY ANSWERVincristine, when associated with alkylating agents, has an additional adverse effect on spermatogonia quantity, while carboplatin has no individual contribution to spermatogonia quantity, in testicular tissue of (pre)pubertal boys, when compared to patients who have received non-alkylating chemotherapy.WHAT IS KNOWN ALREADYThe improved survival rates after cancer treatment necessitate the inclusion of fertility preservation procedures as part of the comprehensive care for patients, taking into consideration their age. Sperm cryopreservation is an established procedure in post-pubertal males while the TTF proposed for (pre)pubertal boys remains experimental. Several studies exploring testicular tissue of (pre)pubertal boys after TTF have examined the tubular fertility index (TFI, percentage of seminiferous tubule cross-sections containing spermatogonia) and the number of spermatogonia per seminiferous tubule cross-section (S/T). All studies have demonstrated that TFI and S/T always decrease after the introduction of chemotherapeutic agents, especially those which carry high gonadotoxic risks such as alkylating agents.STUDY DESIGN, SIZE, DURATIONTesticular tissue samples from 79 (pre)pubertal boys diagnosed with cancer (from 6 months to 16 years of age) were cryopreserved between May 2009 and June 2014. Their medical diagnoses and previous chemotherapy exposures were recorded. We examined histological sections of (pre)pubertal testicular tissue to elucidate whether the chemotherapy or the primary diagnosis affects mainly TFI and S/T.PARTICIPANTS/MATERIALS, SETTING, METHODS(Pre)pubertal boys with cancer diagnosis who had been offered TTF prior to conditioning treatment for hematopoietic stem cell transplantation were included in the study. All the patients had previously received chemotherapy with low- or moderate-risk for future fertility. We have selected patients for whom the information on the chemotherapy received was complete. The quantity of spermatogonia and quality of testicular tissue were assessed by both morphological and immunohistochemical analyses.MAIN RESULTS AND THE ROLE OF CHANCEA significant reduction in the number of spermatogonia was observed in boys treated with alkylating agents. The mean S/T values in boys exposed to alkylating agents were significantly lower compared to boys exposed to non-alkylating agents (P = 0.018). In contrast, no difference was observed for patients treated with carboplatin as the sole administered alkylating agent compared to the group of patients exposed to non-alkylating agents. We observed an increase of S/T with age in the group of patients who did not receive any alkylating agent and a decrease of S/T with age when patients received alkylating agents included in the cyclophosphamide equivalent dose (CED) formula (r = 0.6166, P = 0.0434; r = −0.3759, P = 0.0036, respectively). The TFI and S/T decreased further in the group of patients who received vincristine in combination with alkylating agents (decrease of 22.4%, P = 0.0049 and P < 0.0001, respectively), but in this group the CED was also increased significantly (P < 0.0001). Multivariate analysis, after CED adjustment, showed the persistence of a decrease in TFI correlated with vincristine administration (P = 0.02).LIMITATIONS, REASONS FOR CAUTIONThis is a descriptive study of testicular tissues obtained from (pre)pubertal boys who were at risk of infertility. The study population is quite heterogeneous, with a small number of patients in each sub-group. Our results are based on comparisons between patients receiving alkylating agents compared to patients receiving non-alkylating agents rather than chemotherapy-naive patients. The French national guidelines for fertility preservation in cancer patients recommend TTF before highly gonadotoxic treatment. Therefore, all the patients had received low- or moderate-risk gonadotoxic chemotherapy before TTF. Access to testicular tissue samples from chemotherapy-naive patients with comparable histological types of cancer was not possible. The functionality of spermatogonia and somatic cells could not be tested by transplantation or in vitro maturation due to limited sample sizes.WIDER IMPLICATIONS OF THE FINDINGSThis study summarizes the spermatogonial quantity of (pre)pubertal boys prior to TTF. We confirmed a negative correlation between the cumulative exposure to alkylating agents and spermatogonial quantity. In addition, the synergistic use of vincristine in combination with alkylating agents showed a cumulative deleterious effect on the TFI. For patients for whom fertility preservation is indicated, TTF should be proposed for chemotherapy with a predicted CED above 4000 mg/m2. However, the data obtained from vincristine and carboplatin use should be confirmed in a subsequent study including more patients.STUDY FUNDING/COMPETING INTEREST(S)This study had financial support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. The sponsors played no role in the study. The authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.

2023-11-01·Journal of Hospital Infection

Bacterial contamination of water used as thermal transfer fluid in fluid-warming devices

Article

作者: Indra, A ; Schnetzinger, M ; Kimberger, O ; Heger, F

INTRODUCTIONRecent reports implicated heater-cooler units (HCUs), which are used for warming infusions, blood or in extracorporeal membrane oxygenation devices, as a possible origin of healthcare-associated infections (HAIs) with potentially pathogenic bacteria, such as non-tuberculous mycobacteria [1]. This represents a source of contamination in a usually sterile setting.AIMTo analyse water from infusion heating devices (IHDs) for bacterial contamination, and to determine if IHDs are a potential source in the transmission of HAIs.METHODSThermal transfer fluid (TTF; 300-500 mL) was collected from the reservoirs of 22 independent IHDs and processed on different selective and non-selective media for colony count and identification of bacteria. Strains of Mycobacterium spp. were analysed by whole-genome sequencing.RESULTSBacterial growth was observed in all 22 TTF samples after cultivation at 22 °C and 36 °C. Pseudomonas aeruginosa was the most frequent pathogen identified, present in 13.64% (3/22) of samples at >100 colony-forming units/100 mL. Colonization with Mycobacterium chimaera, Ralstonia pickettii and Ralstonia mannitolilytica was detectable in 9.09% (2/22) of samples. Primary sequencing of the detected M. chimaera suggests a close relationship with a M. chimaera strain detected in an outbreak in Switzerland which led to the death of two patients.DISCUSSIONContamination of TTF represents a germ reservoir in a sensitive setting. Handling errors of IHDs may lead to the distribution of opportunistic or facultative bacterial pathogens, increasing the risk of transmission of nosocomial infections.

2023-09-27·Molecules (Basel, Switzerland)

A Rapid and Quantitative Method for Determining Seed Viability Using 2,3,5-Triphenyl Tetrazolium Chloride (TTC): With the Example of Wheat Seed.

Article

作者: Wang, Shuonan ; Zhou, Feng ; Qiu, Nianwei ; Zhong, Sunyaxin ; Wu, Mengmeng ; Sun, Jing ; Mao, Xinyue

Current colorimetric methods for quantitative determination of seed viability (SV) with 2,3,5-triphenyl tetrazolium chloride (TTC) have been plagued by issues of being cumbersome and time-consuming during the experimental process, slow in extraction and staining, and exhibiting inconsistent results. In this work, we introduced a new approach that combines TTC-staining with high-temperature extraction using dimethyl sulfoxide (DMSO). The optimization of the germination stage, TTC-staining method, and 1,3,5-triphenylformazan (TTF) extraction method were meticulously carried out as follows: When the majority of wheat seeds had grown the radicle, and the length of radicles was approximately equal to the seed length (24 h-germination), 2 g germinating seeds were placed into a beaker (20 mL) containing 5 mL 10 g·L^-1 TTC solution. The seeds were stained with TTC in the dark at 25 °C for 1 h. Following the staining, 1 mL 1 mol·L^-1 H₂SO₄ was added to stop the reaction for 5 min. The H₂SO₄ solution was then removed, and the seeds were gently rinsed with deionized water. Subsequently, the TTF produced in the seeds was extracted directly with 5 mL DMSO solution at 55 °C for 1 h. The absorbance of the extract was measured at 483 nm, and the index of SV was calculated according to a predetermined TTC calibration curve and expressed by mg TTC·g^-1 (seed)·h^-1. The new method has been demonstrated to be rapid, stable, and highly sensitive, as evidenced by the accurate measurement of seed viability with different aging degrees.

项与 tTF-NGR(University of Münster) 相关的新闻（医药）

2023-09-04

·CPHI制药在线

临床 | 肿瘤电场疗法卵巢癌III期临床失败，前路漫漫亦灿灿

关注并星标CPHI制药在线 8月28日，Novocure宣布，肿瘤电场治疗（TTFields）与紫杉醇联合用于铂类耐药性卵巢癌患者的III期ENGOT-ov50/GOG-3029/INNOVATE-3临床试验在最终分析中没有达到总体生存期（OS）的主要终点。随机接受TTFields加紫杉醇治疗患者（n=280）的中位 OS 为12.2个月，单用紫杉醇治疗患者的中位生存期为11.9个月（n=278）（HR：1.008）。与先前报道的研究一致，TTFields治疗耐受性良好，未增加全身毒性。Novocure股价大跌37%。 ENGOT-ov50/GOG-3029/INNOVATE-3试验招募了最多有五种既往系统治疗线的患者。对探索性亚组的分析表明，以前只接受过一种治疗的患者有潜在的生存益处。鉴于约20%的卵巢癌症患者对一线铂治疗的反应有限，这一信号值得进一步探索。Novocure正在对ENGOT-ov50/GOG-3029/INNOVATE-3试验的数据进行全面评估，包括亚组分析。肿瘤治疗电场及其抗肿瘤机制肿瘤治疗电场（TTFields，Tumor Treating Fields）是一种利用特定电场频率干扰细胞分裂从而抑制肿瘤的疗法。这种由以色列公司Novocure开发的创新疗法，最初以对脑瘤患者治疗的突破性成就闻名，早在2011年时，Novocure的肿瘤电场疗法产品Optune就获得了FDA批准上市，用于治疗复发性胶质母细胞瘤（GBM）。另外，在临床试验中，Optune与化疗药物替莫唑胺TMZ联用表现出了比单药更好的疗效，显著地延长了GBM患者的生存期，这一联合疗法也在2015年获得了FDA批准。再鼎医药于2018年9月从Novocure公司获得了肿瘤电场治疗在大中华区的独家授权许可，并合作开发多个实体肿瘤适应症的临床研究。2020年6月，Optune（爱普盾®）在中国获批上市，再鼎医药的定价约为13万元/月，这个价格与Novocure公司在2015年招股书中披露的每月2.1万美金的Optune使用费用基本一致。根据再鼎医药公布2023年第二季度财报，爱普盾® Q2收入为1370万美元，同比增长18%。加上Q1收入的1330万美元，爱普盾2023H1收入约2700万美元。作为局部区域和非侵入性靶向治疗，TTFields 不像化疗等靶向全身的疗法那样，不会产生全身性的副作用，安全性高，报道的副作用主要为皮肤刺激。同时使用也较为方便，Novocure开发的家用Optune 设备，使GBM患者只用将仪器佩戴在头部就可接受治疗，甚至不影响日常生活活动。肿瘤电场治疗作为一种非侵入性的治疗方法，主要的治疗设备就是一件可以形成电场的可穿戴设备。它基于电生理的原理，通过低强度、中频（200kHz）的交变电场作用于癌细胞增殖所需的微管蛋白，阻碍微管（microtubule）的构建，从而干扰肿瘤细胞的有丝分裂，使受影响的肿瘤细胞凋亡。同时，它也通过电场力作用于癌细胞内各种物体及微小的带电的粒子（例如带极性的隔膜蛋白Septins），趁细胞分裂的时机破坏细胞。近年来，越来越多的证据支持肿瘤电场治疗与其他特定癌症疗法（包括放疗、某些化疗药物和某些免疫疗法）的广泛联用。随着科研人员和医学工作者对肿瘤电场治疗的研究更加深入，也总结出它的更多抗肿瘤机制，具体体现在如下四点：1. 干扰有丝分裂，协同化疗；2. 干扰肿瘤细胞迁移，协同抗血管治疗；3. 增强抗肿瘤免疫活性，协同免疫治疗4. 下调DNA损伤修复，协同放疗。 TTFields 抗肿瘤机制（图片出自：肿瘤资讯）目前电场疗法已被FDA批准用于治疗复发性胶质母细胞瘤、新诊断的胶质母细胞瘤以及恶性胸膜间皮瘤，并且在目前在六大实体肿瘤包括非小细胞肺癌、非小细胞肺癌脑转移、肝癌、胰腺癌、卵巢癌、乳腺癌的临床试验中都取得了惊人的数据，由于其原理是靶向杀灭所有快速有丝分裂的癌细胞，因此理论上适用于所有实体肿瘤。 NSCLCⅢ期临床达主要终点，股价却大跌今年6月，再鼎医药和Novocure在2023年美国临床肿瘤学会年会（ASCO 2023）上，公布了评估肿瘤电场治疗（TTFields）联合标准治疗用于非小细胞肺癌（NSCLC）的III期LUNAR研究阳性结果。数据显示，随机接受肿瘤电场治疗（TTFields）联合标准治疗的患者有137名，中位总生存时间为13.2个月，139名仅接受标准治疗的患者中位总生存时间为9.9个月，中位总生存时间具有显著统计学意义和临床意义的3个月改善，TTFields达到了OS（总生存期）的临床终点。且在免疫疗法的联合治疗中效果更佳，66名患者接受肿瘤电场治疗（TTFields）联合免疫治疗，中位总生存期达到了18.5个月；而仅仅接受免疫治疗的患者中位总生存期是10.8个月，整整提高了近8个月的时间，可将患者死亡风险降低约37%（HR=0.63）。然而，市场并不买账。当天，Novocure股价接近腰斩，其中国合作伙伴再鼎医药股价同样大跌。深究其中根源或许在于LUNAR的临床设计并不完美：该临床试验所选取的对照组主要为化疗，免疫疗法群体占比只有31%，而如今PD-1联合化疗已成为驱动基因阴性NSCLC的一线治疗手段。也就是说，LUNAR并没有充分的数据，证明其作为联用治疗方式，优于最新的标准疗法。另外，还有一个潜在的原因：此前市场对这一临床结果抱有极高的期待。2021年4月13日，美国独立数据监察委员会（DMC）在对研究进行中期分析报告审查后，建议研究样本量减少将近一半并将随访时间缩短至12个月，当天Novocure上涨49%，再鼎医药上涨22%；2023年1月，Novocure和再鼎医药共同宣布LUNAR研究达到了主要终点生存期，OS数据在统计学上具有显著且有临床意义的改善。当天Novocure上涨68%，再鼎上涨41%。LUNAR研究中虽然中位OS达到主要终点，但无进展生存（PFS）数据并不亮眼，两组之间的PFS相差无几（4.8个月 vs. 4.1个月），数据改善显然还是没有达到大家的期望。基于其临床设计瑕疵以及部分结果，市场担忧该产品是否将会获得FDA通过。 LUNAR研究简介（图片出自Novocure官网） TTFields未来路在何方？虽然目前TTFields的适应症拓展之路仍崎岖不平、迷雾重重，但笔者相信只要其找准方向积极探索，终能拨开迷雾见月明。卵巢癌方面，Ш期临床OS虽未达到主要终点，但后续仍有机会通过对该临床试验数据的全面分析，精准筛选出获益人群，得到阳性结果。非小细胞肺癌方面，LUNAR临床研究数据仍有望作为2023年下半年向美国FDA提交上市前批准（PMA）的基础。再鼎医药计划在Novocure向FDA递交申请后，向中国国家药品监督管理局（NMPA）提交上市许可申请（MAA）。2020年，TTF销售额高达5亿美元，主要收入来源胶质母细胞瘤适应症。一直以来肿瘤界便有"得肺癌者得天下"的说法，如果肺癌适应症获批上市，意味着TTF适用人群放大到最大癌种，TTF的天花板将进一步打开，未来市场将成指数级增长，肿瘤电场治疗成为"印钞机"将是必然事件。另外LUNAR临床数据的公布，进一步证实了TTFields具有对PD-1治疗增敏的可能，至于联合免疫究竟疗效如何，还需要更多研究证实。目前已有几项探索TTFields联合免疫疗法的临床试验已在进行中。早在2021年，默沙东就开展了K药联合TTFields一线治疗非小细胞癌的KeyNote-B36研究。如果这一研究能得出积极的结果，对TTFields无异于将是柳暗花明又一村。此外TTFields联合免疫/化疗一线治疗晚期驱动基因阴性NSCLC的LUNAR2研究已经在计划启动中，未来这些研究或许可以给出更多答案。除此之外，TTFields在多种消化道肿瘤中已完成或正在开展多项临床研究。例如，在胰腺癌治疗的PANOVA研究中，TTFields联合化疗可显著延长中位无进展生存（mPFS）和中位总生存（mOS），且具有良好的依从性和安全性，目前，CSCO指南已将TTFields作为局晚期和转移性胰腺癌的治疗选择推荐；此外，PANOVA-3研究（随机、开放标签的全球关键Ⅲ期研究）也已经顺利启动，目前正在入组当中，非常令人期待。在肝癌治疗中，Ⅱ期HEPANOVA研究显示，TTFields联合索拉非尼治疗的ORR约为索拉非尼单药的两倍，安全性可控。目前已有基础研究提示，TTFields联合化疗用于肠癌具有协同增效作用，期待后续临床研究的进展。联合疗法方面，除了联合免疫疗法，TTFields无论联合放疗还是血管靶向治疗都显示出令人鼓舞的初步疗效和可耐受的安全性，值得进一步深入探索。参考来源 1. Novocure Announces Update on Phase 3Pivotal LUNAR Trial of Tumor Treating Fields in Non-Small Cell Lung Cancer.Retrieved April 13, 2021, fromhttps://www.businesswire.com/news/home/20210413005428/en.Gregory F. Guzauskas, Erqi L. Pollom,Volker W. Stieber, Bruce C. 2. Wang, Lou Garrison. Tumor treating fieldstreatment for patients with newly diagnosed glioblastoma: A cost-effectivenessanalysis [abstract]. In: Proceedings of the American Association for CancerResearch Annual Meeting 2018 3. Novocure公司官网智药研习社近期直播报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

财报临床3期上市批准申请上市

100 项与 tTF-NGR(University of Münster) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
淋巴瘤	临床1期	-	University of Münster	-
肿瘤	临床前	德国	University of Münster	2008-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02902237 (CTgov)	临床1期	恶性实体肿瘤 \| 淋巴瘤	24	tTF-NGR	(艱壓構壓蓋齋網衊積築) = 膚積築蓋積醖淵範膚鬱鬱築遞築餘夢壓糧範齋 (鬱廠獵鏇蓋憲鑰範膚餘, 蓋憲獵糧積築壓齋蓋淵 ~ 範鏇憲選餘構餘齋襯醖) 更多	-	2020-12-08
NCT02902237 (ESMO2020)	临床1期	肿瘤	17	tTF-NGR	衊淵襯鏇網壓鏇簾蓋顧(繭網蓋壓積餘鹹繭製醖) = Isolated Troponin T hs elevation occurred as DLT and was interpreted as sensitive early sign for myocardial cell hypoxia, valuable for prevention of clinically relevant side effects. 齋醖齋壓廠簾憲積壓遞 (衊鏇遞餘艱餘壓顧範糧 ) 更多	-	2020-09-17
NCT02902237 (Pubmed \| Cancers (Basel)) 人工标引	临床1期	肿瘤	17	tTF-NGR	(艱鏇艱獵鹽膚觸顧蓋簾) = solated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae 顧鏇繭鏇遞遞壓製夢網 (夢願襯繭網鹹鹽窪窪窪 ) 更多	积极	2020-06-07