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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS1-31-PS1-31
    Abstract: Background: Pathological complete response (pCR) of axillary lymph nodes (ALNs) is frequently achieved in patients with clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC). ALN status is an important prognostic factor for choosing the type of axillary lymph node surgery. Many patients with axillary pCR could replace axillary lymph node dissection (ALND) with sentinel lymph node biopsy (SLNB). Our goal is to develop a new predictive clinical model to detect axillary pCR after NAC and provide clinical clues for avoiding ALND. Methods: A retrospective series of 547 patients who had biopsy-proven positive ALNs at diagnosis from 2007 to 2014 in National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences were involved. We analyzed the clinicopathologic features and developed a nomogram to predict the probability of ALN pCR. Univariate assessment was performed using chi-square test. A multivariate logistic regression stepwise model was used to generate a nomogram to predict ALN pCR in node positive patients. The receiver operating characteristic (ROC) curve was established and the area under the curve (AUC) was calculated to evaluate the accuracy of the model. Internal validation was estimated using 50-50 hold out validation method. Nomogram was validated externally with the prospective cohorts of 167 patients from 2016 to 2018 of Cancer Hospital of Chinese Academy of Medical Sciences and 75 patients from 2018 to 2019 of Beijing Tiantan hospital.Results: In the retrospective study, 172 (31.4%) patients achieved axillary pCR after NAC. Multivariate analysis indicated that clinical nodal (N) stage, hormone receptor (HR) status and clinical response of primary tumor after NAC were significant independent predictors for axillary pCR (P & lt;0.05). The AUCs of the internal validation for the training and test sets were 0.719 and 0.753, respectively. The nomogram was validated in external cohorts with AUCs of 0.862 and 0.766, respectively.Conclusion: We developed a nomogram to predict axillary pCR in node positive breast cancer patients after NAC. The predictive model performed well in prospective external validation. This practical tool could provide information to surgeons about whether to avoid ALND after NAC. Citation Format: Xin Wang, Wenyan Wang, Jiaxiang Liu, Xiangzhi Meng, Jiaqi Liu, Changyuan Guo, Ying Song, Ningyi Cui, Qiao Li, Zeyu Xing, Jie Wang, Menglu Zhang, Kexin Feng, Pilin Wang, Xiang Wang. Nomogram for predicting axillary lymph node pathological response in node-positive breast cancer patients after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-31.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Chinese Medical Journal Vol. 135, No. 3 ( 2021-12-08), p. 333-340
    In: Chinese Medical Journal, Ovid Technologies (Wolters Kluwer Health), Vol. 135, No. 3 ( 2021-12-08), p. 333-340
    Abstract: Pathological complete response (pCR) of axillary lymph nodes (ALNs) is frequently achieved in patients with clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC), and ALN status is an important prognostic factor for breast cancer patients. This study aims to develop a new predictive clinical model to assess the ALN pCR rate after NAC. Methods: This was a retrospective series of 467 patients who had biopsy-proven positive ALNs at diagnosis and underwent ALN dissection from 2007 to 2014 at the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences. We analyzed the clinicopathologic features of the patients and developed a nomogram to predict the probability of ALN pCR. A multivariable logistic regression stepwise model was used to construct a nomogram to predict ALN pCR in node-positive patients. The adjusted area under the receiver operating characteristic curve (AUC) was calculated to quantify the ability to rank patients by risk. Internal validation was performed using the 50/50 hold-out validation method. The nomogram was externally validated with prospective cohorts of 167 patients from 2016 to 2018 at the Cancer Hospital of the Chinese Academy of Medical Sciences and 114 patients from 2018 to 2020 at Beijing Tiantan Hospital. Results: In this retrospective study, 115 (24.6%) patients achieved ALN pCR after NAC. Multivariate analysis showed that clinical tumor stage (Odds ratio [OR]: 0.321, 95% confidence interval [CI] : 0.121–0.856; P  = 0.023); primary tumor response (OR: 0.189; 95% CI: 0.123–0.292; P  〈  0.001), and estrogen receptor status (OR: 0.530, 95% CI: 0.304–0.925; P  = 0.025) were independent predictors of ALN pCR. The nomogram was constructed based on the result of multivariate analysis. In the internal validation of performance of nomogram, the AUCs for the training and test sets were 0.719 and 0.753, respectively. The nomogram was validated in external cohorts with AUCs of 0.720, which demonstrated good discriminatory power in these data sets. Conclusion: We developed a nomogram to predict the likelihood of axillary pCR in node-positive breast cancer patients after NAC. The predictive model performed well in multicenter prospective external validation. This practical tool could provide information to surgeons regarding whether to perform additional ALN dissection after NAC. Trial registration: ChiCTR.org.cn, ChiCTR1800014968.
    Type of Medium: Online Resource
    ISSN: 0366-6999 , 2542-5641
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2108782-9
    SSG: 6,25
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. e15138-e15138
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2017
    In:  Cell Discovery Vol. 3, No. 1 ( 2017-03-07)
    In: Cell Discovery, Springer Science and Business Media LLC, Vol. 3, No. 1 ( 2017-03-07)
    Abstract: The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexed with PD-L1 and free PD-L1, solved here at 1.7 and 2.7 Å resolution, respectively, show that KN035 competes with PD-1 (programmed death protein 1) for the same flat surface on PD-L1, mainly through a single surface loop of 21 amino acids. This loop forms two short helices and develops key hydrophobic and ionic interactions with PD-L1 residues, such as Ile54, Tyr56 and Arg113, which are also involved in PD-1 binding. The detailed mutagenesis study identified the hotspot residues of the PD-L1 surface and provides an explanation for the stronger (~1 000-fold) binding of KN035 to PD-L1 than PD-1 and its lack of binding to PD-L2. Overall, this study reveals how a single immunoglobulin-variable scaffold of KN035 or PD-1 can bind to a flat protein surface through either a single surface loop or beta-sheet strands; and provides a basis for designing new immune checkpoint blockers and generating bi-specific antibodies for combination therapy.
    Type of Medium: Online Resource
    ISSN: 2056-5968
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2842548-0
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 2608-2608
    Abstract: 2608 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc fragment, formulated for subcutaneous (SC) injection. Methods: The escalation phase followed a modified 3+3 design with a 28-day DLT evaluation period and 8 dose levels were planned at 0.1, 0.3, 1.0, 2.5, 5 and 10 mg/kg SC weekly. One patient each was enrolled at 0.1 and 0.3 mg/kg dose levels. Additional dose levels followed traditional 3+3 design. Response was assessed per RECIST 1.1 every 12 weeks. Results: As of 11/2/2018, 17 patients were enrolled in the escalation phase (urothelial carcinoma (n=2), hepatic cell carcinoma (n=2), intrahepatic cholangiocarcinoma (n=2), thymic carcinoma (n=2), colorectal cancer£¨n=2£©£¬renal cell carcinoma (RCC, n=3), Squamous-cell lung carcinoma (n=1) and ovarian cancer (n=1)). The majority of subjects had advanced disease stage, stage IV (15/17) and stage III (2/17). A total of 7 subjects received radiotherapy, 16 subjects received surgery, and 13 subjects received systematic anti-cancer therapies from previous treatment. None had received prior checkpoint inhibitor treatment. Planned maximum dose of 10 mg/kg was reached (n=3) without DLT occurred. There was only one Grade 3 drug related Treatment Emergent Adverse Event (TEAE) occurred at 0.3 mg/kg dose level, which was immune related dermatitis and resolved later. All other drug related TEAEs were either Grade 1 or 2, with the most common events as elevated ALT (5/17) and elevated AST (4/17). Among all enrolled subjects, three subjects had confirmed PR, including one RCC subject at 2.5 mg/kg and one Intrahepatic cholangiocarcinoma subject at 5 mg/kg, and one cholangiocarcinoma subject at 10 mg/kg. Conclusions: KN035 exhibits a favorable safety profile and promising preliminary anti-tumor activity in patients with advanced malignancies. Clinical trial information: NCT03101488.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 2609-2609
    Abstract: 2609 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneous (SC) injection. A phase I safety and pharmacokinetic (PK) study was conducted in Japanese patients. Methods: Patients with advanced solid tumors were treated with KN035 SC once every-7-days (QW) or once every-14-days (Q2W) schedules with the dose limiting toxicities (DLT) evaluation period of 28 days. For the QW schedule, the starting dose was 1 mg/kg (n=3) with escalations to 2.5 (n=4), and 5 (n=3) mg/kg. For the Q2W schedule, 6 patients were planned at the dose levels of 2.5 and 5 mg/kg. Results: No DLT was observed up to the highest dose level of 5 mg/kg QW. No maximum tolerated dose (MTD) was reached. Among evaluable treated subjects (n=14), there were two confirmed partial responses. Preliminary PK analysis suggested that after SC administration, KN035 was slowly absorbed (Tmax ∼ 4 d) and the mean residual time (MRT) was 21 days. Apparent clearance (CL/F) and volume of distribution (Vz/F) were on average 0.58 L/day and 11 L, respectively. Plasma levels generally decreased mono-exponentially with an average terminal elimination half time around 13 days after reaching the peak concentration post SC administration. Exposures of KN035 increased approximately proportionally with dose. Trough concentrations were maintained above 15 µg/mL post administration of 5 mg/kg Q2W. No apparent exposure-body weight relationship was observed. Conclusions: KN035 exhibits a favorable safety profile in patients with advanced malignancies and preliminary results demonstrate encouraging anti-tumor activity. Based on PK data from the Q2W schedule, a fixed dose with less frequent dosing schedule of every 3 or 4 weeks is presently being evaluated. Clinical trial information: NCT03248843.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: Tetrahedron Letters, Elsevier BV, Vol. 78 ( 2021-08), p. 153286-
    Type of Medium: Online Resource
    ISSN: 0040-4039
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2007074-3
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  • 8
    In: Oncotarget, Impact Journals, LLC, Vol. 8, No. 31 ( 2017-08-01), p. 51037-51049
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2560162-3
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3022-3022
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3022-3022
    Abstract: Background: KN026 is a bispecific antibody simultaneously targeting the extracellular domains II and IV of the human HER2. It blocks both ligand-dependent and ligand-independent HER2 signaling pathway. The IgG1 Fc fragment of KN026 binds FcRγIIIa mediates potent ADCC and inhibits tumor cell proliferation. Aim: The goal of the present work is to predict efficacious doses for KN026 using a translational tumor growth inhibition modeling approach based on tumor growth and KN026 exposure data from mouse, followed by a population PK analysis based on KN026 concentration data from patients in a first-in-human (FIH) clinical trial. Methods: A tumor growth inhibition model was developed to fit tumor volume time course data from NCI-N87 and Calu-3 xenografts. A translational tumor growth inhibition model was next developed by adjusting the tumor growth component to more realistically reflect tumor growth dynamics as reported in HER2-positive breast cancer patients. Model parameters intrinsic to KN026 efficacy (Emax, EC50) were assumed constant across species. To determine the target concentration, simulations were performed for different initial tumor volumes and tumor doubling time in humans under different KN026 exposures. Next, intensively sampled pharmacokinetics data from 20 patients in a FIH trial of KN026 were used to develop the human population PK model. KN026 concentration-time profiles in humans were then simulated across a variety of candidate dosing regimens and compared with the projected target concentration from translational tumor growth inhibition modeling. Recommended efficacious doses and dosing schedules were predicted if steady state trough concentration from more than 90% simulated subjects achieve the target concentration. Results: A tumor growth inhibition model adequately described the data from xenograft models. To build the translational tumor growth inhibition model, a literature-documented tumor growth equation more relevant to the observed tumor growth dynamics in breast cancer patients was used to replace the growth component in formula 1 originally fitted to mouse data. Simulation results from the translational tumor growth inhibition model show that tumor stasis can be achieved at the KN026 trough concentration lower than 20 μg/mL. More aggressive tumors will take longer time to achieve tumor stasis under the same given concentration. A two-compartment PK model incorporating body weight as a covariate on both volume of distribution and clearance describes human PK data well. Efficacious steady state dose levels were predicted to be 20 mg/kg Q2W and 30 mg/kg Q3W. Loading doses with a higher frequency were predicted to have the advantage of maximizing initial tumor killing. Conclusions: The use of the modeling and simulation approach to aid decision in drug development has become a popular tool. Here we present a translational PK-PD modeling framework incorporating preclinical tumor growth data and clinical PK data to inform dose selection strategy for KN026 in patients with HER2-positive solid tumors. Furthermore, simulation results suggest that loading doses with higher dosing frequency will likely be beneficial. These model predictions will be further validated by emerging PK and efficacy data from ongoing clinical trials of KN026. Citation Format: Dongmei Ji, Yuan Xiong, Jing Yang, Pilin Wang, Jiarong Wang, Fei Yang, Junfang Xu. Using translational tumor growth inhibition modeling approach and population PK analysis to predict efficacious doses for KN026, a HER2 bispecific antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3022.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    Online Resource
    Online Resource
    S. Karger AG ; 2021
    In:  Breast Care Vol. 16, No. 4 ( 2021), p. 319-327
    In: Breast Care, S. Karger AG, Vol. 16, No. 4 ( 2021), p. 319-327
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 Granulomatous mastitis (GM) is a rare chronic inflammatory disease of the breast. The current therapeutic effects of the antibiotic therapy and surgical or immunomodulatory (steroid) treatment are normally poor due to the unclear etiology. 〈 b 〉 〈 i 〉 Method: 〈 /i 〉 〈 /b 〉 This study aimed to identify the differentially expressed mRNAs in GM tissues using RNA sequencing and further explored the functions of differentially expressed mRNAs resulting in GM. Moreover, we revealed the relationship between GM and breast cancer by shared highly expressed genes in GM tissues and breast cancer tissues. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 A total of 12,115 mRNAs were analyzed in the whole expression profile, and 207 mRNAs (136 upregulated and 71 downregulated mRNAs) were differently expressed between the GM tissues and normal tissues. The enrichment analysis showed that the differentially expressed mRNAs were enriched in the biological processes and played a significant role in the immune system. Besides, the genes expressed significantly highly in breast cancer tissues are found to be enriched with GM genes, which may explain the similar clinical features between breast cancer and GM. We also found that the HSD11B1 gene which was differentially expressed in GM was used as drug target of prednisone, which is a common treatment for GM. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 This study is the first to use sequencing technology to elucidate the genetic mechanisms of GM. The finding of this study may have potential value in GM diagnosis and also provides potential drug targets for GM treatment.
    Type of Medium: Online Resource
    ISSN: 1661-3791 , 1661-3805
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2021
    detail.hit.zdb_id: 2205941-6
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