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A Real-World Study of Safety, Immunogenicity and Efficacy of Bevacizumab in Patients With Solid Malignancies: A Phase IV, Post-Marketing Study in India. 贝伐单抗在实体恶性肿瘤患者中的安全性、免疫原性和有效性的真实世界研究:印度上市后的IV期研究
IF 2 Q3 Medicine Pub Date : 2023-01-01 DOI: 10.1177/11769351231177277
Shubhadeep D Sinha, Ghanashyam Biswas, Bala Reddy Bheemareddy, Sreenivasa Chary, Pankaj Thakur, Minish Jain, Tanveer Maksud, Suraj Pawar, Koushik Chatterjee, Murali Krishna Voonna, Anil Goel, Krishna Chaitanya Puligundla, Kuntegowdanahalli Chinnagiriyappa Lakshmaiah, Leela Talluri, Ramya Vattipalli, Sheejith Kakkunnath

Objective: The aim of this study was to evaluate the post-marketing safety, tolerability, immunogenicity and efficacy of Bevacizumab (manufactured by Hetero Biopharma) in a broader population of patients with solid tumors.

Patients and methods: This phase IV, prospective, multi-centric clinical study was carried out in Indian patients with solid malignancies (metastatic colorectal cancer, non-squamous non-small-cell lung cancer, metastatic renal cell carcinoma) treated with Bevacizumab between April 2018 and July 2019. This study included 203 patients from 16 tertiary care oncology centers across India for safety assessment, of which a subset of 115 patients who have consented were also evaluated for efficacy and immunogenicity. This study was prospectively registered in the Clinical Trial Registry of India (CTRI), and was commenced only after receiving approval from the competent authority (Central Drugs Standard Control Organization, CDSCO).

Results: Out of the 203 enrolled patients, 121 (59.6%) patients reported 338 adverse events (AEs) during this study. Of 338 reported AEs, 14 serious adverse events (SAEs) were reported by 13 patients including 6 fatal SAEs, assessed as unrelated to the study medication and 7 non-fatal SAEs, 5 assessed as related, and 3 unrelated to Bevacizumab. Most AEs reported in this study (33.9%) were general disorders and administration site conditions, followed by gastrointestinal disorders (29.1%). The most frequently reported AEs were diarrhea (11.3%), asthenia (10.3%), headache (8.9%), pain (7.4%), vomiting (7.9%), and neutropenia (5.9%). At the end of the study, 2 (1.75%) of 69 patients reported antibodies to Bevacizumab without affecting safety and efficacy. However, at the end of 12 months, no patient had reported antibodies to Bevacizumab. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were reported in 18.3%, 22.6%, 9.6%, and 8.7% of patients, respectively. The overall response rate (CR + PR) was reported in 40.9% of patients at the end of the study. Disease control rate (DCR), also known as the clinical benefit rate (CBR) was reported in 50.4% of patients.

Conclusions: Bevacizumab (Cizumab, Hetero Biopharma) was observed to be safe, well tolerated, lacking immunogenicity, and efficacious in the treatment of solid tumors. The findings of this phase IV study of Bevacizumab, primarily as a combination therapy regimen suggest its suitability and rationality for usage in multiple solid malignancies.

Clinical trial registry number: CTRI/2018/4/13371 [Registered on CTRI http://ctri.nic.in/Clinicaltrials/advsearch.php : 19/04/2018]; Trial Registered Prospectively.

目的:本研究的目的是评估贝伐珠单抗(由Hetero Biopharma生产)在更广泛的实体肿瘤患者中的上市后安全性、耐受性、免疫原性和疗效。患者和方法:这项IV期、前瞻性、多中心临床研究在2018年4月至2019年7月期间接受贝伐单抗治疗的印度实体恶性肿瘤(转移性结直肠癌、非鳞状非小细胞肺癌、转移性肾细胞癌)患者中进行。该研究包括来自印度16个三级肿瘤中心的203名患者进行安全性评估,其中115名已同意的患者也进行了疗效和免疫原性评估。本研究在印度临床试验注册中心(CTRI)前瞻性注册,并在获得主管部门(中央药物标准控制组织,CDSCO)的批准后才开始。结果:203例入组患者中,121例(59.6%)患者报告了338例不良事件(ae)。在报告的338例ae中,13例患者报告了14例严重不良事件(SAEs),包括6例致死性SAEs,评估为与研究药物无关;7例非致死性SAEs,评估为与贝伐单抗相关,5例与贝伐单抗无关。本研究中报告的不良事件最多(33.9%)是一般疾病和给药部位情况,其次是胃肠道疾病(29.1%)。最常见的不良反应是腹泻(11.3%)、虚弱(10.3%)、头痛(8.9%)、疼痛(7.4%)、呕吐(7.9%)和中性粒细胞减少(5.9%)。在研究结束时,69例患者中有2例(1.75%)报告了贝伐单抗抗体,但未影响安全性和有效性。然而,在12个月结束时,没有患者报告贝伐单抗抗体。完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)和疾病进展(PD)分别为18.3%、22.6%、9.6%和8.7%。在研究结束时,40.9%的患者报告了总缓解率(CR + PR)。50.4%的患者报告了疾病控制率(DCR),也称为临床获益率(CBR)。结论:贝伐单抗(Cizumab, Hetero Biopharma)治疗实体瘤安全、耐受性好、缺乏免疫原性、有效。贝伐珠单抗的IV期研究结果表明,贝伐珠单抗主要作为联合治疗方案用于多种实体恶性肿瘤的适用性和合理性。临床试验注册号:CTRI/2018/4/13371[在CTRI注册http://ctri.nic.in/Clinicaltrials/advsearch.php: 19/04/2018];前瞻性注册试验。
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引用次数: 0
Chemical Complementarity of Breast Cancer Resident, T-Cell Receptor CDR3 Domains and the Cancer Antigen, ARMC3, is Associated With Higher Levels of Survival and Granzyme Expression. 乳腺癌居民t细胞受体CDR3结构域和癌症抗原ARMC3的化学互补性与更高水平的生存率和颗粒酶表达相关
IF 2 Q3 Medicine Pub Date : 2023-01-01 DOI: 10.1177/11769351231177269
Nagehan Pakasticali, Andrea Chobrutskiy, Dhruv N Patel, Monica Hsiang, Saif Zaman, Konrad J Cios, George Blanck, Boris I Chobrutskiy

Introduction: One of the most pressing goals for cancer immunotherapy at this time is the identification of actionable antigens.

Methods: This study relies on the following considerations and approaches to identify potential breast cancer antigens: (i) the significant role of the adaptive immune receptor, complementarity determining region-3 (CDR3) in antigen binding, and the existence cancer testis antigens (CTAs); (ii) chemical attractiveness; and (iii) informing the relevance of the integration of items (i) and (ii) with patient outcome and tumor gene expression data.

Results: We have assessed CTAs for associations with survival, based on their chemical complementarity with tumor resident T-cell receptor (TCR), CDR3s. Also, we have established gene expression correlations with the high TCR CDR3-CTA chemical complementarities, for Granzyme B, and other immune biomarkers.

Conclusions: Overall, for several independent TCR CDR3 breast cancer datasets, the CTA, ARMC3, stood out as a completely novel, candidate antigen based on multiple algorithms with highly consistent approaches. This conclusion was facilitated by use of the recently constructed Adaptive Match web tool.

目前,癌症免疫治疗最紧迫的目标之一是确定可操作的抗原。方法:本研究基于以下考虑和途径来鉴定潜在的乳腺癌抗原:(1)适应性免疫受体、互补决定区-3 (CDR3)在抗原结合中的重要作用,以及癌睾丸抗原(cta)的存在;(ii)化学吸引力;(iii)告知(i)和(ii)项目整合与患者预后和肿瘤基因表达数据的相关性。结果:基于cta与肿瘤驻留t细胞受体(TCR) CDR3s的化学互补性,我们评估了cta与生存的关系。此外,我们已经建立了基因表达与高TCR CDR3-CTA化学互补性的相关性,用于颗粒酶B和其他免疫生物标志物。结论:总体而言,对于几个独立的TCR CDR3乳腺癌数据集,CTA ARMC3作为一种完全新颖的候选抗原脱颖而出,该抗原基于多种算法,方法高度一致。使用最近构建的Adaptive Match网络工具促进了这一结论。
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引用次数: 1
An Overview: Genetic Tumor Markers for Early Detection and Current Gene Therapy Strategies. 综述:肿瘤基因标志物的早期检测和目前的基因治疗策略。
IF 2 Q3 Medicine Pub Date : 2023-01-01 DOI: 10.1177/11769351221150772
Reeshan Ul Quraish, Tetsuyuki Hirahata, Afraz Ul Quraish, Shahan Ul Quraish

Genomic instability is considered a fundamental factor involved in any neoplastic disease. Consequently, the genetically unstable cells contribute to intratumoral genetic heterogeneity and phenotypic diversity of cancer. These genetic alterations can be detected by several diagnostic techniques of molecular biology and the detection of alteration in genomic integrity may serve as reliable genetic molecular markers for the early detection of cancer or cancer-related abnormal changes in the body cells. These genetic molecular markers can detect cancer earlier than any other method of cancer diagnosis, once a tumor is diagnosed, then replacement or therapeutic manipulation of these cancer-related abnormal genetic changes can be possible, which leads toward effective and target-specific cancer treatment and in many cases, personalized treatment of cancer could be performed without the adverse effects of chemotherapy and radiotherapy. In this review, we describe how these genetic molecular markers can be detected and the possible ways for the application of this gene diagnosis for gene therapy that can attack cancerous cells, directly or indirectly, which lead to overall improved management and quality of life for a cancer patient.

基因组不稳定性被认为是任何肿瘤疾病的基本因素。因此,遗传不稳定的细胞有助于肿瘤内遗传异质性和表型多样性。这些遗传改变可以通过分子生物学的几种诊断技术检测到,基因组完整性改变的检测可以作为早期检测癌症或体细胞中与癌症相关的异常变化的可靠遗传分子标记。这些遗传分子标记可以比任何其他癌症诊断方法更早地检测到癌症,一旦肿瘤被诊断出来,就可以替代或治疗这些与癌症相关的异常基因变化,从而导致有效的和靶向特异性的癌症治疗,在许多情况下,癌症的个性化治疗可以在没有化疗和放疗的不利影响的情况下进行。在这篇综述中,我们描述了如何检测这些遗传分子标记,以及将这些基因诊断应用于基因治疗的可能方法,这些基因治疗可以直接或间接地攻击癌细胞,从而全面改善癌症患者的管理和生活质量。
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引用次数: 0
Antibiotic Treatment in End Stage Cancer Patients; Advantages and Disadvantages. 终末期癌症患者的抗生素治疗优点和缺点。
IF 2 Q3 Medicine Pub Date : 2023-01-01 DOI: 10.1177/11769351231161476
Tahmasebi Mamak, Hosamirudsari Hadiseh, Familrashtian Shirin, Parash Masoud, Salehi Mohammadreza, Abbaszadeh Mahsa

Aim: In this study our aim was to elucidate whether advanced cancer patients benefit from antibiotic treatment in the last days of life in addition to reviewing the relevant costs and effects.

Materials and methods: We reviewed medical records from 100 end-stage cancer patients and their antibiotic use during the hospitalization in Imam Khomeini hospital. Patient's medical records were analyzed retrospectively for cause and periodicity of infections, fever, increase in acute phase proteins, cultures, type and cost of antibiotic.

Results: Microorganisms were found in only 29 patients (29%) and the most microorganism among the patients was E. coli (6%). About 78% of the patients had clinical symptoms. The highest dose of antibiotics was related to Ceftriaxone (40.2%) and in the second place was Metronidazole (34.7%) and the lowest dose was related to Levofloxacin, Gentamycin and Colistin (1.4%). Fifty-one patients (71%) did not have any side effects due to antibiotics. The most common side effect of antibiotics among patients was skin rash (12.5%). The average estimated cost for antibiotic use was 7 935 540 Rials (24.4 dollars).

Conclusion: Prescription of antibiotics was not effective in symptom control in advanced cancer patients. The cost of using antibiotics during hospitalization is very high and also the risk of developing resistant pathogens during admission should be considered. Antibiotic side effects also occur in patients, causing more harm to the patient at the end of life. Therefore, the benefits of antibiotic advice in this time is less than its negative effects.

目的:在本研究中,我们的目的是阐明晚期癌症患者在生命的最后几天是否受益于抗生素治疗,并回顾相关的成本和效果。材料和方法:我们回顾了伊玛目霍梅尼医院100例晚期癌症患者的医疗记录及其住院期间的抗生素使用情况。回顾性分析患者病历中感染的原因和周期性、发热、急性期蛋白升高、培养、抗生素种类和费用。结果:29例患者检出微生物(29%),其中大肠杆菌检出最多(6%)。约78%的患者有临床症状。抗生素使用剂量最高的是头孢曲松(40.2%),其次是甲硝唑(34.7%),最低的是左氧氟沙星、庆大霉素和粘菌素(1.4%)。51例(71%)患者未出现抗生素副作用。抗生素最常见的副作用是皮疹(12.5%)。抗生素使用的平均估计费用为7 935 540里亚尔(24.4美元)。结论:抗生素处方不能有效控制晚期肿瘤患者的症状。住院期间使用抗生素的费用非常高,入院期间发生耐药病原体的风险也应予以考虑。抗生素的副作用也会发生在病人身上,在病人生命的最后阶段对他们造成更大的伤害。因此,在这个时候,抗生素建议的好处小于它的负面影响。
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引用次数: 1
A Comprehensive Analysis of the PI3K/AKT Pathway: Unveiling Key Proteins and Therapeutic Targets for Cancer Treatment. PI3K/AKT通路的综合分析:揭示癌症治疗的关键蛋白和治疗靶点。
IF 2 Q3 Medicine Pub Date : 2023-01-01 DOI: 10.1177/11769351231194273
Emad Fadhal

Background: Cancer development and progression involve a complex network of pathways among which certain pathways play a pivotal role in promoting tumor growth and survival. An important pathway in this context is the PI3K/AKT pathway, which regulates crucial cellular processes including proliferation, viability, and metabolic regulation. Dysregulation of this pathway has been strongly linked to the development of various types of cancers. Consequently, it is imperative to identify the key proteins within this pathway as potential targets for impeding cancer cell proliferation and survival.

Results: One of the key findings of this study was the identification of signaling proteins that dominate various forms of PI3K/Akt pathway. Furthermore, proteins play critical roles in cancer networks, acting as oncogenes that promote cancer development or as tumor suppressor genes that inhibit tumor growth. This study identified several genes, including KIT, ERBB2, PDGFRA, MET, FGFR2, and FGFR3, which are involved in various types of the PI3K/Akt pathways. Additionally, this study identified 55 proteins that are commonly found in various forms of PI3K/Akt, and these proteins play crucial roles in regulating various biological functions.

Conclusions: This study highlights the importance of identifying key proteins involved in the PI3K/AKT pathway. In this study, we identified several genes involved in different pathways that play essential roles in the activation, signaling, and regulation of the pathway. Understanding the proteins participating in the PI3K/AKT pathway is vital for the development of targeted therapies, not only for cancer but also for other related diseases. By elucidating their roles and functions, this study contributes to the advancement of knowledge in the field and paves the way for the development of effective treatments targeting this pathway.

背景:肿瘤的发生和发展涉及一个复杂的通路网络,其中某些通路在促进肿瘤的生长和生存中起着关键作用。在这种情况下,一个重要的途径是PI3K/AKT途径,它调节关键的细胞过程,包括增殖、活力和代谢调节。这一途径的失调与各种癌症的发展密切相关。因此,确定该通路中的关键蛋白作为阻碍癌细胞增殖和存活的潜在靶点是势在必行的。结果:本研究的主要发现之一是鉴定了主导各种形式的PI3K/Akt通路的信号蛋白。此外,蛋白质在癌症网络中起着至关重要的作用,作为促进癌症发展的癌基因或作为抑制肿瘤生长的肿瘤抑制基因。本研究确定了几个基因,包括KIT、ERBB2、PDGFRA、MET、FGFR2和FGFR3,它们参与各种类型的PI3K/Akt通路。此外,本研究还发现了55个在各种形式的PI3K/Akt中常见的蛋白,这些蛋白在调节各种生物功能中起着至关重要的作用。结论:本研究强调了识别参与PI3K/AKT通路的关键蛋白的重要性。在这项研究中,我们确定了几个参与不同途径的基因,这些基因在该途径的激活、信号传导和调节中发挥重要作用。了解参与PI3K/AKT通路的蛋白对于开发靶向治疗至关重要,不仅针对癌症,也针对其他相关疾病。通过阐明它们的作用和功能,本研究有助于该领域知识的进步,并为开发针对该途径的有效治疗方法铺平道路。
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引用次数: 1
In Silico Modeling Demonstrates that User Variability During Tumor Measurement Can Affect In Vivo Therapeutic Efficacy Outcomes. 计算机模拟表明,在肿瘤测量过程中,用户的可变性会影响体内治疗效果的结果。
IF 2 Q3 Medicine Pub Date : 2022-11-29 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221139257
Jake T Murkin, Hope E Amos, Daniel W Brough, Karl D Turley

User measurement bias during subcutaneous tumor measurement is a source of variation in preclinical in vivo studies. We investigated whether this user variability could impact efficacy study outcomes, in the form of the false negative result rate when comparing treated and control groups. Two tumor measurement methods were compared; calipers which rely on manual measurement, and an automatic 3D and thermal imaging device. Tumor growth curve data were used to create an in silico efficacy study with control and treated groups. Before applying user variability, treatment group tumor volumes were statistically different to the control group. Utilizing data collected from 15 different users across 9 in vivo studies, user measurement variability was computed for both methods and simulation was used to investigate its impact on the in silico study outcome. User variability produced a false negative result in 0.7% to 18.5% of simulated studies when using calipers, depending on treatment efficacy. When using an imaging device with lower user variability this was reduced to 0.0% to 2.6%, demonstrating that user variability impacts study outcomes and the ability to detect treatment effect. Reducing variability in efficacy studies can increase confidence in efficacy study outcomes without altering group sizes. By using a measurement device with lower user variability, the chance of missing a therapeutic effect can be reduced and time and resources spent pursuing false results could be saved. This improvement in data quality is of particular interest in discovery and dosing studies, where being able to detect small differences between groups is crucial.

在皮下肿瘤测量中,用户测量偏差是临床前体内研究中差异的一个来源。我们调查了这种使用者可变性是否会影响疗效研究结果,在比较治疗组和对照组时,以假阴性结果率的形式。比较两种肿瘤测量方法;依靠手动测量的卡尺,以及自动3D和热成像装置。肿瘤生长曲线数据用于对照组和治疗组的计算机疗效研究。在应用用户变异性之前,治疗组肿瘤体积与对照组有统计学差异。利用从9个体内研究中收集的15个不同用户的数据,计算了两种方法的用户测量变异性,并使用模拟来研究其对计算机研究结果的影响。当使用卡尺时,根据治疗效果的不同,用户可变性在0.7%至18.5%的模拟研究中产生假阴性结果。当使用用户可变性较低的成像设备时,这一比例降至0.0%至2.6%,这表明用户可变性会影响研究结果和检测治疗效果的能力。减少疗效研究的可变性可以在不改变群体规模的情况下增加疗效研究结果的可信度。通过使用具有较低用户可变性的测量设备,可以减少错过治疗效果的机会,并且可以节省花费在追求错误结果上的时间和资源。数据质量的提高对发现和给药研究特别有意义,因为能够发现各组之间的微小差异是至关重要的。
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引用次数: 1
Integration of Artificial Intelligence and CRISPR/Cas9 System for Vaccine Design. 人工智能与CRISPR/Cas9系统在疫苗设计中的集成
IF 2 Q3 Medicine Pub Date : 2022-11-26 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221140102
Elham Maserat

The CRISPR/Cas9 system offers a new approach to genome editing and cancer treatment. This approach is able to detect drug targets and genomic analysis of cancer. The use of artificial intelligence (AI) capacity to edit genomes through CRISPR/Cas9 enables modification of gene mutations, molecular simulation. AI approaches include knowledge discovery approaches, antigen and epitope prediction approaches, and agent based-model approaches. These methods in combination with CRISPR/Cas9 can be used in vaccine design.

CRISPR/Cas9系统为基因组编辑和癌症治疗提供了一种新方法。这种方法能够检测药物靶点和癌症的基因组分析。利用人工智能(AI)能力编辑基因组,通过CRISPR/Cas9实现基因突变修饰、分子模拟。人工智能方法包括知识发现方法、抗原和表位预测方法以及基于agent的模型方法。这些方法结合CRISPR/Cas9可用于疫苗设计。
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引用次数: 1
Optimizing Drug Response Study Design in Patient-Derived Tumor Xenografts. 优化患者源性肿瘤异种移植的药物反应研究设计。
IF 2 Q3 Medicine Pub Date : 2022-11-22 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221136056
Jessica Weiss, Nhu-An Pham, Melania Pintilie, Ming Li, Geoffrey Liu, Frances A Shepherd, Ming-Sound Tsao, Wei Xu

Patient-derived tumor xenograft (PDX) models were used to evaluate the effectiveness of preclinical anticancer agents. A design using 1 mouse per patient per drug (1 × 1 × 1) was considered practical for large-scale drug efficacy studies. We evaluated modifiable parameters that could increase the statistical power of this design based on our consolidated PDX experiments. Real studies were used as a reference to investigate the relationship between statistical power with treatment effect size, inter-mouse variation, and tumor measurement frequencies. Our results showed that large effect sizes could be detected at a significance level of .2 or .05 under a 1 × 1 × 1 design. We found that the minimum number of mice required to achieve 80% power at an alpha level of .05 under all situations explored was 21 mice per group for a small effect size and 5 mice per group for a medium effect size.

采用患者源性肿瘤异种移植(PDX)模型来评估临床前抗癌药物的有效性。对于大规模的药物疗效研究,采用每名患者1只小鼠(1 × 1 × 1)的设计是可行的。基于我们的综合PDX实验,我们评估了可修改的参数,这些参数可以提高该设计的统计能力。以实际研究为参考,探讨统计效力与治疗效应大小、小鼠间变异和肿瘤测量频率之间的关系。我们的结果显示,在1 × 1 × 1设计下,在显著性水平为0.2或0.05时,可以检测到较大的效应量。我们发现,在所有研究的情况下,在α水平为0.05时达到80%功率所需的最小小鼠数量是,小效应量时每组21只小鼠,中等效应量时每组5只小鼠。
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引用次数: 2
A Random Forest Genomic Classifier for Tumor Agnostic Prediction of Response to Anti-PD1 Immunotherapy. 用于抗 PD1 免疫疗法反应的肿瘤不可知性预测的随机森林基因组分类器。
IF 2 Q3 Medicine Pub Date : 2022-11-22 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221136081
Emma Bigelow, Suchi Saria, Brian Piening, Brendan Curti, Alexa Dowdell, Roshanthi Weerasinghe, Carlo Bifulco, Walter Urba, Noam Finkelstein, Elana J Fertig, Alex Baras, Neeha Zaidi, Elizabeth Jaffee, Mark Yarchoan

Tumor mutational burden (TMB), a surrogate for tumor neoepitope burden, is used as a pan-tumor biomarker to identify patients who may benefit from anti-program cell death 1 (PD1) immunotherapy, but it is an imperfect biomarker. Multiple additional genomic characteristics are associated with anti-PD1 responses, but the combined predictive value of these features and the added informativeness of each respective feature remains unknown. We evaluated whether machine learning (ML) approaches using proposed determinants of anti-PD1 response derived from whole exome sequencing (WES) could improve prediction of anti-PD1 responders over TMB alone. Random forest classifiers were trained on publicly available anti-PD1 data (n = 104), and subsequently tested on an independent anti-PD1 cohort (n = 69). Both the training and test datasets included a range of cancer types such as non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, and smaller numbers of patients from other tumor types. Features used include summaries such as TMB and number of frameshift mutations, as well as more gene-level features such as counts of mutations associated with immune checkpoint response and resistance. Both ML algorithms demonstrated area under the receiver-operator curves (AUC) that exceeded TMB alone (AUC 0.63 "human-guided," 0.64 "cluster," and 0.58 TMB alone). Mutations within oncogenes disproportionately modulate anti-PD1 responses relative to their overall contribution to tumor neoepitope burden. The use of a ML algorithm evaluating multiple proposed genomic determinants of anti-PD1 responses modestly improves performance over TMB alone, highlighting the need to integrate other biomarkers to further improve model performance.

肿瘤突变负荷(TMB)是肿瘤新表位负荷的替代物,它被用作一种泛肿瘤生物标志物,用于识别可能从抗程序性细胞死亡1(PD1)免疫疗法中获益的患者,但它是一种不完善的生物标志物。还有多种基因组特征与抗 PD1 反应相关,但这些特征的综合预测价值以及每个特征的附加信息量仍不清楚。我们评估了使用全外显子组测序(WES)得出的抗 PD1 反应决定因素的机器学习(ML)方法是否能比单独使用 TMB 更好地预测抗 PD1 反应者。随机森林分类器在公开的抗PD1数据(n = 104)上进行了训练,随后在独立的抗PD1队列(n = 69)上进行了测试。训练和测试数据集包括一系列癌症类型,如非小细胞肺癌(NSCLC)、头颈部鳞状细胞癌(HNSCC)、黑色素瘤,以及少量其他肿瘤类型的患者。使用的特征包括 TMB 和换框突变数量等摘要,以及更多基因层面的特征,如与免疫检查点反应和耐药性相关的突变计数。两种 ML 算法的接受者操作曲线下面积(AUC)都超过了单纯的 TMB("人类指导 "算法的 AUC 为 0.63,"群集 "算法的 AUC 为 0.64,单纯的 TMB 算法的 AUC 为 0.58)。相对于其对肿瘤新表位负担的总体贡献,癌基因内的突变不成比例地调节了抗PD1反应。使用 ML 算法评估抗 PD1 反应的多个拟议基因组决定因素,比单独使用 TMB 稍微提高了性能,这突出表明有必要整合其他生物标记物,以进一步提高模型性能。
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引用次数: 0
A transcriptome-Based Deep Neural Network Classifier for Identifying the Site of Origin in Mucinous Cancer. 基于转录组的深层神经网络分类器识别黏液癌起源部位。
IF 2 Q3 Medicine Pub Date : 2022-11-15 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221135141
Taejin Ahn, Kidong Kim, Hyojin Kim, Sarah Kim, Sangick Park, Kyoungbun Lee
Purpose: There is a lack of tools for identifying the site of origin in mucinous cancer. This study aimed to evaluate the performance of a transcriptome-based classifier for identifying the site of origin in mucinous cancer. Materials And Methods: Transcriptomic data of 1878 non-mucinous and 82 mucinous cancer specimens, with 7 sites of origin, namely, the uterine cervix (CESC), colon (COAD), pancreas (PAAD), stomach (STAD), uterine endometrium (UCEC), uterine carcinosarcoma (UCS), and ovary (OV), obtained from The Cancer Genome Atlas, were used as the training and validation sets, respectively. Transcriptomic data of 14 mucinous cancer specimens from a tissue archive were used as the test set. For identifying the site of origin, a set of 100 differentially expressed genes for each site of origin was selected. After removing multiple iterations of the same gene, 427 genes were chosen, and their RNA expression profiles, at each site of origin, were used to train the deep neural network classifier. The performance of the classifier was estimated using the training, validation, and test sets. Results: The accuracy of the model in the training set was 0.998, while that in the validation set was 0.939 (77/82). In the test set which is newly sequenced from a tissue archive, the model showed an accuracy of 0.857 (12/14). t-SNE analysis revealed that samples in the test set were part of the clusters obtained for the training set. Conclusion: Although limited by small sample size, we showed that a transcriptome-based classifier could correctly identify the site of origin of mucinous cancer.
目的:目前缺乏确定黏液癌起源部位的工具。本研究旨在评估基于转录组的分类器在鉴别黏液癌起源部位方面的性能。材料与方法:将来自the cancer Genome Atlas的1878例非黏液性癌和82例黏液性癌的转录组学数据分别作为训练集和验证集,这些样本分别来自宫颈(CESC)、结肠(COAD)、胰腺(PAAD)、胃(STAD)、子宫内膜(UCEC)、子宫癌肉瘤(UCS)和卵巢(OV)等7个起源部位。采用组织档案中14例黏液癌标本的转录组学数据作为测试集。为了确定起源位点,每个起源位点选择了一组100个差异表达基因。在去除同一基因的多次迭代后,选择了427个基因,并使用它们在每个起源位点的RNA表达谱来训练深度神经网络分类器。使用训练集、验证集和测试集来估计分类器的性能。结果:模型在训练集中的准确率为0.998,在验证集中的准确率为0.939(77/82)。在组织档案新测序的测试集中,该模型的准确率为0.857(12/14)。t-SNE分析显示,测试集中的样本是为训练集获得的聚类的一部分。结论:虽然样本量有限,但我们发现基于转录组的分类器可以正确识别黏液癌的起源部位。
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引用次数: 1
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Cancer Informatics
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