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Identification of Prognostic Biomarkers for Breast Cancer Metastasis Using Penalized Additive Hazards Regression Model. 使用惩罚加性风险回归模型识别乳腺癌转移的预后生物标志物。
IF 2 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1177/11769351231157942
Leili Tapak, Omid Hamidi, Payam Amini, Saeid Afshar, Siamak Salimy, Irina Dinu

Background: Breast cancer (BC) has been reported as one of the most common cancers diagnosed in females throughout the world. Survival rate of BC patients is affected by metastasis. So, exploring its underlying mechanisms and identifying related biomarkers to monitor BC relapse/recurrence using new statistical methods is essential. This study investigated the high-dimensional gene-expression profiles of BC patients using penalized additive hazards regression models.

Methods: A publicly available dataset related to the time to metastasis in BC patients (GSE2034) was used. There was information of 22 283 genes expression profiles related to 286 BC patients. Penalized additive hazards regression models with different penalties, including LASSO, SCAD, SICA, MCP and Elastic net were used to identify metastasis related genes.

Results: Five regression models with penalties were applied in the additive hazards model and jointly found 9 genes including SNU13, CLINT1, MAPK9, ABCC5, NKX3-1, NCOR2, COL2A1, and ZNF219. According the median of the prognostic index calculated using the regression coefficients of the penalized additive hazards model, the patients were labeled as high/low risk groups. A significant difference was detected in the survival curves of the identified groups. The selected genes were examined using validation data and were significantly associated with the hazard of metastasis.

Conclusion: This study showed that MAPK9, NKX3-1, NCOR1, ABCC5, and CD44 are the potential recurrence and metastatic predictors in breast cancer and can be taken into account as candidates for further research in tumorigenesis, invasion, metastasis, and epithelial-mesenchymal transition of breast cancer.

背景:乳腺癌(BC)已被报道为全世界女性最常见的癌症之一。BC患者的生存率受转移的影响。因此,探索其潜在机制和识别相关生物标志物,利用新的统计方法监测BC复发/复发是必要的。本研究使用惩罚加性风险回归模型研究了BC患者的高维基因表达谱。方法:使用与BC患者转移时间相关的公开数据集(GSE2034)。286例BC患者共获得22 283个基因表达谱信息。采用LASSO、SCAD、SICA、MCP和Elastic net等惩罚性加性风险回归模型识别转移相关基因。结果:在加性危害模型中应用了5个带惩罚的回归模型,共发现了SNU13、CLINT1、MAPK9、ABCC5、NKX3-1、NCOR2、COL2A1、ZNF219等9个基因。根据惩罚加性危险模型回归系数计算的预后指数中位数,将患者标记为高/低风险组。鉴定组的生存曲线有显著差异。选择的基因使用验证数据进行检查,并与转移的危险显著相关。结论:本研究显示MAPK9、NKX3-1、NCOR1、ABCC5和CD44是乳腺癌复发和转移的潜在预测因子,可作为进一步研究乳腺癌发生、侵袭、转移和上皮间质转移的候选因子。
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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 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 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
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 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 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
Melanoma and Human Leukocyte Antigen (HLA): Immunogenicity of 69 HLA Class I Alleles With 11 Antigens Expressed in Melanoma Tumors. 黑色素瘤与人类白细胞抗原(HLA):在黑色素瘤肿瘤中表达的69个HLA I类等位基因的免疫原性。
IF 2 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1177/11769351231172604
Apostolos P Georgopoulos, Lisa M James, Spyros A Charonis, Matthew Sanders

Host immunogenetics play a critical role in the human immune response to melanoma, influencing both melanoma prevalence and immunotherapy outcomes. Beneficial outcomes that stimulate T cell response hinge on binding affinity and immunogenicity of human leukocyte antigen (HLA) with melanoma antigen epitopes. Here, we use an in silico approach to characterize binding affinity and immunogenicity of 69 HLA Class I human leukocyte antigen alleles to epitopes of 11 known melanoma antigens. The findings document a significant proportion of positively immunogenic epitope-allele combinations, with the highest proportions of positive immunogenicity found for the Q13072/BAGE1 melanoma antigen and alleles of the HLA B and C genes. The findings are discussed in terms of a personalized precision HLA-mediated adjunct to immune checkpoint blockade immunotherapy to maximize tumor elimination.

宿主免疫遗传学在人类对黑色素瘤的免疫反应中起关键作用,影响黑色素瘤的患病率和免疫治疗结果。刺激T细胞应答的有益结果取决于人白细胞抗原(HLA)与黑色素瘤抗原表位的结合亲和力和免疫原性。在这里,我们使用计算机方法来表征69个HLA I类人白细胞抗原等位基因与11种已知黑色素瘤抗原表位的结合亲和力和免疫原性。研究结果表明,免疫原性阳性的表位-等位基因组合占很大比例,其中Q13072/BAGE1黑色素瘤抗原和HLA B和C基因等位基因的免疫原性阳性比例最高。研究结果在个性化的精确hla介导的辅助免疫检查点阻断免疫治疗方面进行了讨论,以最大限度地消除肿瘤。
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引用次数: 3
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 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 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 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 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 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 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
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 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY 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
Cancer Treatment Data in Central Cancer Registries: When Are Supplemental Data Needed? 中央癌症登记处的癌症治疗数据:何时需要补充数据?
IF 2.4 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2022-07-30 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221112457
Cathy J Bradley, Rifei Liang, Jagar Jasem, Richard C Lindrooth, Lindsay M Sabik, Marcelo C Perraillon

Background: We evaluated treatment concordance between the Colorado All Payer Claims Database (APCD) and the Colorado Central Cancer Registry (CCCR) to explore whether APCDs can augment registry data. We compare treatment concordance for breast cancer, an extensively studied site with an inpatient reporting source and select leukemias that are often diagnosed outpatient.

Methods: We analyzed concordance by cancer type and treatment, patient demographics, reporting source, and health insurance, calculating the sensitivity, specificity, positive predictive values (PPV) and Kappa statistics. We estimated an adjusted logistic regression model to assess whether the APCD statistically significantly reports additional cancer-directed treatments.

Results: Among women with breast cancer, 14% had chemotherapy treatments that were absent from the CCCR. Missing treatments were more common among women younger than age 50 (15%) and patients aged 75 and older (19%), rural residents (17%), and when the reporting source was outpatient (22%). Similar and more pronounced patterns for people with leukemia were observed. Concordance for oral treatments was lower for each cancer. Sensitivity and PPVs were high, with moderate Kappa statistics. The APCD was 5.3 percentage points less likely to identify additional treatments for breast cancer patients and 10 percentage points more likely to identify additional treatments when the reporting source was an outpatient facility.

Conclusion: A robust data infrastructure is needed to investigate research questions that require population-level analyses, particularly for questions seeking to reduce health inequity and comparisons across payers, including Medicare Advantage and fee-for-service. APCD data are a step toward creating an infrastructure for cancer, particularly for patients who reside in rural areas and/or receive care from outpatient centers.

背景:我们评估了科罗拉多州所有支付者索赔数据库(APCD)与科罗拉多州中央癌症登记处(CCCR)之间的治疗一致性,以探讨 APCD 是否能增强登记处数据。我们比较了乳腺癌和白血病的治疗一致性,前者是一个被广泛研究的部位,有住院病人报告来源,而后者通常在门诊确诊:我们按癌症类型和治疗方法、患者人口统计学特征、报告来源和医疗保险分析了一致性,计算了灵敏度、特异性、阳性预测值 (PPV) 和 Kappa 统计量。我们估计了一个调整后的逻辑回归模型,以评估 APCD 是否在统计上显著报告了额外的癌症定向治疗:结果:在乳腺癌女性患者中,有 14% 的化疗疗程在 CCCR 中缺失。在 50 岁以下女性(15%)、75 岁及以上患者(19%)、农村居民(17%)以及报告来源为门诊患者(22%)中,遗漏治疗的情况更为常见。在白血病患者中也观察到类似且更明显的模式。每种癌症的口服治疗一致性都较低。灵敏度和 PPV 均较高,Kappa 统计量适中。当报告来源为门诊机构时,APCD 识别乳腺癌患者额外治疗的可能性要低 5.3 个百分点,识别额外治疗的可能性要高 10 个百分点:调查需要人群水平分析的研究问题需要一个强大的数据基础设施,特别是对于寻求减少医疗不公平的问题以及不同支付者(包括医疗保险优势和付费服务)之间的比较。APCD 数据是创建癌症基础设施的一个步骤,尤其是对于居住在农村地区和/或接受门诊中心治疗的患者而言。
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引用次数: 0
Semi-Automated Computational Assessment of Cancer Organoid Viability Using Rapid Live-Cell Microscopy. 用快速活细胞显微镜对癌症类器官生存能力的半自动计算评估
IF 2 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2022-05-26 eCollection Date: 2022-01-01 DOI: 10.1177/11769351221100754
Joseph D Buehler, Cylaina E Bird, Milan R Savani, Lauren C Gattie, William H Hicks, Michael M Levitt, Mohamad El Shami, Kimmo J Hatanpaa, Timothy E Richardson, Samuel K McBrayer, Kalil G Abdullah

The creation of patient-derived cancer organoids represents a key advance in preclinical modeling and has recently been applied to a variety of human solid tumor types. However, conventional methods used to assess in vivo tumor tissue treatment response are poorly suited for the evaluation of cancer organoids because they are time-intensive and involve tissue destruction. To address this issue, we established a suite of 3-dimensional patient-derived glioma organoids, treated them with chemoradiotherapy, stained organoids with non-toxic cell dyes, and imaged them using a rapid laser scanning confocal microscopy method termed "Apex Imaging." We then developed and tested a fragmentation algorithm to quantify heterogeneity in the topography of the organoids as a potential surrogate marker of viability. This algorithm, SSDquant, provides a 3-dimensional visual representation of the organoid surface and a numerical measurement of the sum-squared distance (SSD) from the derived mass center of the organoid. We tested whether SSD scores correlate with traditional immunohistochemistry-derived cell viability markers (cellularity and cleaved caspase 3 expression) and observed statistically significant associations between them using linear regression analysis. Our work describes a quantitative, non-invasive approach for the serial measurement of patient-derived cancer organoid viability, thus opening new avenues for the application of these models to studies of cancer biology and therapy.

患者来源的癌症类器官的产生代表了临床前建模的关键进展,最近已应用于多种人类实体瘤类型。然而,用于评估体内肿瘤组织治疗反应的传统方法不适合评估癌症类器官,因为它们是时间密集型的,并且涉及组织破坏。为了解决这个问题,我们建立了一套三维患者衍生的神经胶质瘤类器官,用放化疗治疗,用无毒细胞染料对类器官进行染色,并使用名为“Apex Imaging”的快速激光扫描共聚焦显微镜方法对其进行成像。“然后,我们开发并测试了一种碎片算法,以量化类器官拓扑结构的异质性,作为生存能力的潜在替代标记。该算法SSDquant提供了类器官表面的三维视觉表示,并提供了与导出的类器官质心的平方和距离(SSD)的数值测量。我们测试了SSD评分是否与传统的免疫组织化学衍生的细胞活力标记物(细胞数量和裂解的胱天蛋白酶3表达)相关,并使用线性回归分析观察到它们之间的统计学显著相关性。我们的工作描述了一种定量、非侵入性的方法,用于连续测量患者来源的癌症类器官生存能力,从而为这些模型在癌症生物学和治疗研究中的应用开辟了新的途径。
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引用次数: 0
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Cancer Informatics
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