Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction and immune dysregulation. Increasing evidence suggests that dysregulated programmed cell death in keratinocytes and immune cells contributes critically to AD pathogenesis; however, the integrated mechanisms underlying these processes remain poorly understood. Here, we report the construction of a zinc-glycyrrhizic acid supramolecular hydrogel (ZnGA) via metal-ligand coordination and investigate its therapeutic potential and mechanism in AD. ZnGA exhibits excellent injectability, self-healing ability, and biocompatibility, enabling controlled release of Zn2+ and exerting anti-inflammatory activity. In a murine AD model and corresponding in vitro systems, ZnGA significantly alleviates skin inflammation, epidermal hyperplasia, and immune infiltration. Transcriptomic analysis reveals that ZnGA markedly suppresses inflammation-associated programmed cell death pathways, particularly those converging on PANoptosis. Mechanistic studies demonstrate that AD is accompanied by coordinated activation of apoptosis, pyroptosis, and necroptosis in keratinocytes and macrophages. ZnGA simultaneously inhibits these death modalities, thereby exerting a broad-spectrum anti-PANoptotic effect, while exerting an immune protective effect. Further investigation identifies the TLR4/NLRP12 signaling axis as a critical upstream regulator of PANoptosis in AD. ZnGA negatively regulates TLR4 and NLRP12 expression, effectively blocking downstream activation of PANoptosome-associated apoptotic, pyroptotic, and necroptotic pathways. Collectively, this study identifies PANoptosis as a key pathogenic mechanism in AD and presents ZnGA as a novel supramolecular therapeutic that alleviates AD by targeting the TLR4-NLRP12-PANoptosis axis. These findings provide new mechanistic insight and a promising materials-based strategy for the treatment of inflammatory skin diseases.

The transporter associated with antigen processing (TAP) is a key component of the classical HLA I antigen presentation pathway. Our previous studies have demonstrated that the downregulation of TAP1 contributes to tumor progression and is associated with an increased presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. However, it remains unclear whether the elevation of MDSCs leads to immune cell exhaustion in tumors lacking TAP1. In this study, we established mouse models of tumors with TAP1 deficiency, and we employed PMN-MDSC depletion to investigate their impact on the immune microenvironment within the tumors. We found that MDSC depletion significantly altered the immune-suppressive effects of TAP1-deficient tumor when anti-PD-1 treatment was administered. Targeting PMN-MDSC may be a promising therapeutic strategy for the treatment of tumors with TAP1 deficiency during ICB treatment. Immunohistochemistry (IHC) was conducted to assess TAP1 expression in mouse melanoma tissues. Ly6G, F4/80, and NKp46 markers were detected in B16 parental and TAP1 knockout tissues, respectively. To enhance anti-tumor immunity, hyperthermia-treated B16F10 WT cell suspension was injected prior to tumor cell introduction. Subsequently, we established B16F10 TAP1 knockout and WT melanoma mouse models. Tumors were collected, and the immune microenvironment was monitored accordingly. Anti-Ly6G antibody was administered to deplete polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Finally, flow cytometry analysis for immune infiltration, quantitative PCR for cytokine levels, and immunofluorescence assays were performed to analyze the immune response. The level of Ly6G+ cell infiltration was significantly higher in samples exhibiting low TAP1 expression, while no differences were observed in the infiltration of F4/80+ cells or NKp46+ cells. Furthermore, the immune-suppressive effects associated with PMN-MDSCs were reversed following their elimination; this resulted in an increase in CD8+ T cells and a higher ratio of CD8+ T cells to Tregs, while the infiltration of innate immune cells remained unaffected. Functional markers of these immune cells indicated an active anti-tumoral immune response following the removal of PMN-MDSCs. Quantitative PCR analysis indicated elevated levels of TNF-α and IL-6, accompanied by decreased levels of TGF-β in the tumor microenvironment of TAP1. Our data indicate that myeloid-derived suppressor cells (PMN-MDSCs) play an essential role in creating a tumorigenic immune microenvironment in TAP1 knockout tumors. Therefore, targeting PMN-MDSCs may become a promising therapeutic strategy for the treatment of tumors with TAP1 deficiency during ICB treatment.

INTRODUCTION:Garsorasib, a KRAS G12C inhibitor, has previously demonstrated its efficacy and safety in patients with KRAS G12C-mutated non-small-cell lung cancer (NSCLC). Here, we present long-term follow-up data from a pooled analysis of the phase 1/2 study. METHODS:This multicenter, open-label phase 1/2 study enrolled patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC. The primary endpoints for phase 1 were safety and tolerability and for phase 2 objective response rate (ORR) by a blinded independent review committee per RECIST version 1.1. Data was pooled from patients who received garsorasib 600 mg twice daily. RESULTS:This pooled dataset included 189 patients (N = 66 in phase 1 and N = 123 in phase 2). The median pooled follow-up time was 13.0 months (IQR: 6.7-17.5). The objective response rate was 48.1 % (95 %CI: 40.8-55.5), and disease control rate was 87.8 % (95 %CI: 82.3-92.1). The median duration of response was 12.45 months (95 % CI: 8.31, 14.49), the median progression-free survival was 9.07 months (95 %CI: 7.39-9.76), and the median overall survival was 14.19 months (95 %CI: 13.08-17.54). Treatment-related adverse events of any grade occurred in 96.3 % of patients, with grade ≥ 3 in 49.2 % of patients. No new safety findings were observed, and most of the adverse events were controllable. CONCLUSION:This pooled analysis confirmed the robust efficacy and manageable safety of garsorasib in KRAS G12C-mutated NSCLC. CLINICALTRIALS: GOV IDENTIFIER:NCT05383898.

Trichosporon infection is a rare but highly lethal infectious disease. Clinically, Trichosporon asahii is the strain most commonly isolated from patients with Trichosporon infections. T. asahii is an opportunistic pathogen that can cause local or invasive infections in immunocompromised patients. In this article, a case of breakthrough T. asahii infection in an immune thrombocytopenia (ITP) patient during caspofungin and isavuconazole combined therapy is reported. Metagenomic next-generation sequencing (mNGS) played a crucial role in the diagnosis of the breakthrough infection in this patient. Upon receiving combined therapy with intravenous voriconazole and nebulized amphotericin B, the patient demonstrated significant clinical improvement and was subsequently discharged.

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor (ER)-positive advanced breast cancer (BC). D-0502, an orally bioavailable selective estrogen receptor degrader (SERD), has previously demonstrated antitumor activity in various ER-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell lines and xenograft models. The phase Ⅰ open-label study (NCT03471663) evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of D-0502 as monotherapy and in combination with palbociclib in female patients with ER+ and HER2- breast cancer. The dose escalation part of D-0502 monotherapy (phase Ⅰa) has been presented before (SABCS 2021, PS11-26 Abstract #1348). Here, we present the results of D-0502 monotherapy from the dose-expansion stage in phase Ⅰb study. Methods: In the single-agent dose-expansion stage of phase Ⅰb study, patients (n=60) received D-0502 (400 mg QD) in 28-day cycles. Eligible patients included females with confirmed ER+, HER2- locally advanced, or metastatic BC; ECOG 0-1; measurable disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. The primary objectives are to characterize the safety of D-0502. The secondary objectives are to evaluate the preliminary anti-tumor activity and the PK characteristic. Results: As of April 07, 2023, 60 female patients were enrolled and treated with 400mg single-agent D-0502. Median age was 57 (range: 32-82) years, 55.0% had an ECOG PS of 1. Disease progression resulting in treatment discontinuation occurred in 66.7% (40/60) of patients, and 6.7% (4/60) of patients discontinued treatment because of AEs. Treatment-related adverse events (TRAEs) were reported in 57 pts (95.0%), most of which were grade 1-2. No grade 4/5 TRAE has been reported. The incidence of serious adverse events was 6.7% (4/60). The most common (≥ 15%) TRAEs included vomiting, dizziness, nausea, increased aspartate aminotransferase and alanine aminotransferase, anaemia, decreased appetite, diarrhoea, and malaise. In the 51 efficacy evaluable patients, 8 patients had partial response (PR) and 27 had stable disease (SD); objective response rate (ORR) and disease control rate (DCR) were 15.7% (8/51) and 68.6% (35/51), respectively. The clinical benefit rate (CBR: CR + PR + SD ≥24 weeks) was 47.1% (24/51). The median PFS was 5.6 months (95% Cl: 2.0, 10.0). Conclusion: D-0502 monotherapy showed promising antitumor activity and tolerable toxicity in female patients with ER+ and HER2- locally advanced or metastatic BC. Currently this treatment is being evaluated in a phase Ⅲ study for patients with ER+ and HER2- locally advanced or metastatic BC in China. Citation Format: Jiayu Wang, Tao Sun, Qingyuan Zhang, Yanxia Shi, Xu Wang, Yiding Chen, Quchang Ouyang, Kunyan Li, Manojkumar Bupathi, w. Jeffery Edenfield, Andrea L.M. Silber, Hong Zong, Erika Hamilton, Dejan Juric, Kate Lathrop, Yihong Zhang, Kathryn Stazzone, Zhe Shi, Yaolin Wang, Ling Zhang, Binghe Xu. A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-02.

AbstractPurpose: Patients with peripheral T-cell lymphomas (PTCL) in the relapsed or refractory (r/r) setting have only a limited number of therapies available, and the prognosis is extremely poor. SHR2554 is an oral inhibitor against EZH2, a rational therapeutic target for lymphomas. Patients and Methods: This was a multicenter, two-part, phase I study of SHR2554 in r/r mature lymphoid neoplasms. In part I, 350 mg twice daily was established as the recommended phase II dose (RP2D) based on the findings during dose escalation and expansion; subsequently, selected lymphoma subtypes were recruited in clinical expansion cohorts to receive SHR2554 at RP2D. Here, we provide an in-depth assessment of SHR2554 at RP2D in subpopulation with r/r PTCL. Results: Twenty-eight patients were included for analysis (17 angioimmunoblastic T-cell lymphoma and 11 not otherwise specified). Eighteen (64%) patients had received ≥2 lines of previous anticancer therapies. The objective response rate was 61% [95% confidence interval (CI), 41–78]. Responses were still ongoing in 59% (10/17) of the responders; estimated median duration of response was 12.3 months (95% CI, 7.4–not reached). Median progression-free survival was 11.1 months (95% CI, 5.3–22.0), and 12-month overall survival rate was 92% (95% CI, 72–98). The most common grade 3 or 4 treatment-related adverse events were decreased platelet count [nine (32%)] as well as decreased white blood cell count, decreased neutrophil count, and anemia [four (14%) for each]. No treatment-related deaths were reported. Conclusions: This extended follow-up analysis further supports SHR2554 as a therapeutic opportunity for patients with r/r PTCL.

3026 Background: TRS005 is a novel anti-CD20 antibody-drug conjugate targeting CD20 positive tumor cells to deliver MMAE into the cells via receptor-mediated endocytosis. The aim of this study was to evaluate the safety, pharmacokinetics, and anti-tumor activity of TRS005 in relapse/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Methods: This first-in-human, single arm, multicenter, phase I, dose-escalation and expansion study conducted at 28 hospitals in China. The eligible patient had histologically confirmed CD20 positive B-cell lymphoma and had failed ≥2 prior lines of standard treatment. The dose-escalation phase involved 6 dose cohorts (from 0.1mg/kg to 2.1mg/kg) following a 3+3 design. Patients received TRS005 intravenously on day 1 of each 21-day cycle for 6 cycles. The dose cohort in which partial response (PR) or complete response (CR) was observed entered the dose-expansion phase. The safety, tolerability and efficacy of TRS005 were evaluated every two cycles. The primary endpoints were safety and pharmacokinetics. Secondary endpoints were objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) assisted by investigators. Results: From Aug 24 th ,2020 to Oct 23 th ,2023, 130 R/R B-cell NHL patients received treatment. The dose limiting toxicity was observed in the first patient in the 2.1mg/kg dose group during the dose-escalation phase. 70 patients had R/R diffuse large B cell lymphoma (DLBCL). Of the 70 R/R DLBCL patients, the median age was 59 (25-83) years, 82.9% of patients were in stage III-IV and 98.6% of patients received at least 2 lines of treatment (except one patient who only received 1 line of previous treatment). Overall, 88.6% of patients experienced all grades adverse events (AEs). Treatment-emergent adverse events (TEAEs) of ≥grade 3 occurred in 65.7% of patients, hematologic TEAEs were the most common. Two patients withdraw the treatment due to TEAEs and no TEAE related death were observed. At the data cutoff date of Nov 17 th , 2023, the median treatment duration was 4 (1-27) cycles. 58 patients were evaluated for efficacy and confirmed ORR was 46.6%, with a DCR of 75.9%. The highest ORR was seen in 1.8mg/kg dose cohort, with an ORR and DCR of 56.7% and 86.7%, respectively. The PFS was 5.6 (95% CI: 4.2-17.4) months and 12-month PFS was 35.1%. Conclusions: TRS005 is well-tolerated and exhibits encouraging anti-tumor efficacy in the treatment of R/R DLBCL. Clinical trial information: NCT05395533 . [Table: see text]

New drug clinical trials have been considered as a positive way for treating cancer by cancer patients and doctors, and the extended dosing is a special way for patients' withdrawal from antitumor clinical trials to obtain investigational new drugs. However, neither the regulations of expanded dosing nor the detail documents for expanded dosing have been officially published in China. At present, expanded dosing of investigational drugs is still at the exploratory stage in various medical institutions, and a complete management system has not been established to meet patients' urgent needs for drug use. Based on the practical experience of extended dosing in Hunan Cancer Hospital, this paper preliminarily explored the application procedures and ethical review requirements of extended dosing for subjects in antitumor clinical trials. It is necessary to clarify the responsibilities of all patients in the procedure and establish a patient-medical institution-sponsor joint application system. In the process of ethical review, it is recommended that all parties fully consider the risks and benefits of extended dosing for patients, and then the ethics committee makes a comprehensive assessment to decide whether to approve extended dosing.

Background: Clinical trials have been widely recognized as an effective treatment approach by physicians and cancer patients alike. Physicians’ evaluations suggest that many patients are likely to continue experiencing benefits from extended dosing of investigational new drugs even after withdrawing from clinical trials.Objective: Given the uncertainty surrounding the efficacy and safety of investigational new drugs, it is essential to continually assess the benefits of extended dosing for patients.Methods: The trial group for this study comprised patients who requested extended dosing after withdrawing from clinical trials at Hunan Cancer Hospital between 2016 and 2020. The control group consisted of patients who received conventional treatment and were enrolled in a 1:1 ratio. Follow-up assessments were conducted every 3 months for both groups, and included monitoring of patients’ health status, survival time, disease control or remission, treatment modalities received, and medical costs.Results: A total of twenty-three patient pairs were successfully matched for this study. The Ethics Committee approved extended dosing for all patients in the trial group, with an average gap period of 16.48 days between their withdrawal from clinical trials and continuous access to the investigational drugs. The median overall survival for patients after withdrawal from clinical trials was 17.3 months in the extended dosing group and 12.9 months in the control group, with no significant difference observed between the two groups (p > 0.250). The median total cost of treatment after the previous clinical trial was 38,006.76 RMB, of which the median cost of therapeutic drugs for conventional treatment was 15,720 RMB, while extended dosing was provided free of charge.Conclusion: Extended dosing can indeed provide benefits, including survival benefits and economic benefits, to cancer patients after their withdrawal from clinical trials and will clinically present an additional treatment option for patients.

以保障受试者权益为核心,为提高药物临床试验质量,加快早期临床试验成果转化,保障临床试验进程,文章分别从早期药物临床试验中受试者权益保护及质量控制中的受试者管理两个方面探讨受试者的风险管理,并结合药物临床试验质控中受试者风险管理新模式提出受试者风险管理策略,以进一步提高临床试验主体在参与临床试验过程中对受试者的风险管理意识.

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: For patients (pts) with follicular lymphoma (FL) in line 3 or higher, treatment options are limited. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor. Data from previous data cutoffs (primary: Apr 2021; initial update: Dec 2021) showed that parsaclisib demonstrated promising efficacy, and an acceptable safety profile in line 3 or higher FL pts in China. Here, we report updated results from the multicenter, open-label Phase 2 study. Aims: This Phase 2 study is designed to evaluate the safety, tolerability and efficacy of parsaclisib in pts with line 3 or higher Chinese follicular lymphoma. Methods: Key eligibility included, age ≥ 18 years, histologically confirmed FL grade 1, 2, or 3a, ≥ 2 prior systemic therapies, ECOG PS ≤ 2, and ineligible for hematopoietic stem cell transplantation (HSCT). Pts received parsaclisib 20 mg once daily (QD) for 8 weeks followed by 2.5 mg QD, until disease progression (PD), unacceptable toxicity, death or withdrawal of consent. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) according to the Lugano 2014 criteria, secondary endpoints included investigator-assessed ORR according to the Lugano 2014 criteria, duration of response (DoR), PFS, OS, and safety and tolerability. Results: At the data cutoff date (Dec 31, 2022), 61 pts (median age: 50 years; male [n=35, 57.4%]) were enrolled. Thirty-one pts remained on treatment and 30 pts had discontinued study treatment mainly due to PD (n = 21). All 61 pts were evaluated for response by the investigator according to the Lugano 2014 criteria. With a median follow-up time of 22.1 months (range 18.7-32.3), the ORR and complete response rate (CRR) were 90.2% (n=55, 95% CI: 82.7-97.6) and 37.7% (n=23, 95% CI: 25.5-49.9), respectively. Median DOR and PFS were 20.4 months (95% CI: 17.4-NC) and 22.1 months (95% CI: 16.8-NC), respectively. Median OS was not achieved, and the 24-month OS rate was 91.5% (95% CI: 80.7-96.4). All 61 pts were included in the safety analysis. The overall safety profile was consistent with previous reports and no new safety signals were identified. Summary/Conclusion: With longer follow-up, parsaclisib demonstrated a high rate of complete response and durable responses, and had an acceptable safety profile. These results demonstrate that parsaclisib has a favorable benefit-risk profile in patients with line 3 or higher Chinese follicular lymphoma. Clinical trial information: NCT04298879 Keywords: Targeted therapy, Follicular lymphoma, Phase II

目的:建立以护士为主导的抗肿瘤药物Ⅰ期临床试验全程化管理模式,并观察其应用效果.方法:2017年医院建立早期临床研究中心,集中管理全院抗肿瘤药物Ⅰ期临床试验.成立以护士为主导的临床试验专业团队,通过完善病房建设、优化护理流程、明确研究护士岗位职责以及加强病房培训与质量控制,形成集咨询、筛选、预约、住院、给药、随访、健康教育的全程化管理模式.结果:2016年全院Ⅰ期临床试验方案违背率为14.69％,成立早期临床研究中心实施全程化管理模式后方案违背率保持在可控范围内,2022年方案违背率为0.88％.受试者护理不良事件及脱落率逐年降低,受试者满意度逐年提高.结论:以护士为主导的抗肿瘤药物Ⅰ期临床试验全程化管理模式保障了临床试验的高质量实施,体现了研究护士的专业价值,进一步推动临床研究护理向专科领域发展.

8572 Background: Taletrectinib (AB-106 / DS-6051b) is a next-generation, potent, CNS- penetrant, selective ROS1 tyrosine kinase inhibitor. The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are TKI -naïve or crizotinib-pretreated. Here we present the updated efficacy and safety results of the study. Methods: The eligible ROS1-positive NSCLC patients were enrolled into either TKI-naïve or crizotinib-pretreated cohorts, and treated with taletrectinib 600mg once daily. The study endpoints included overall response rate (ORR), duration of response (DOR), disease control rate (DCR), overall intracranial response rate (IC-ORR), progression-free survival (PFS), and safety profile. Results: As of the data cutoff date of September 7, 2021, 61 of the 86 stage IV patients enrolled in the study have at least three postbaseline tumor assessment of which 40 patients in the TKI-naïve cohort, and 21 patients in the crizotinib-pretreated cohort (50% patients having at least one prior chemotherapy). In the TKI -naïve cohort, the confirmed ORR by investigators per RECIST 1.1 was 90.0%: [95%CI: 76.3%; 97.2%] (36/40); and the DCR was 95% [95%CI: 83.1%; 99.4%] (38/40). In the crizotinib-pretreated cohort, the confirmed ORR by investigators was 47.6% [95%CI: 25.7%; 70.2%] (10/21); and DCR was 76.2%: [52.8%; 91.8%] (16/21). The mDOR and mPFS are not reached yet for both cohorts. Of 6 patients having brain metastasis and measurable target brain lesions at baseline, the intracranial ORR and IC-DCR were 83.3% and 100%, respectively. Of 4 patients with ROS1 G2032R mutation, 3 patients achieved partial response (PR), and 1 patient achieved stable disease (SD). The most common treatment-related adverse events (TRAEs) include diarrhea, nausea, vomiting, transaminase elevation, anemia, neutrophil count decrease, etc. were Grade 1 or 2, and the most common AEs (below 10%) were ALT/AST increased but reversible. Conclusions: Taletrectinib demonstrated meaningful clinical efficacy in both TKI-naïve and crizotinib-pretreated ROS1 positive NSCLC patients. In particular, taletrectinib showed clinical effectiveness in patients with ROS1 secondary G2032 mutations and patients with brain metastasis. Taletrectinib was well tolerated in this patient population. Clinical trial information: NCT04395677.

目的 总结湖南省肿瘤医院构建肿瘤专科特色I期临床研究病房的实践经验,为正在建设I期临床研究病房的医疗机构提供参考和借鉴.方法 我院I期临床研究病房以肿瘤受试者为中心,以多学科团队协作模式进行肿瘤受试者的全病程管理,建立高效的管理体系来保障I期临床研究病房的建设,主要内容包括病区管理、受试者管理、研究团队管理、质量控制、信息化建设等.结果 I期临床研究病房成立以来,病房在研项目160余项,I期病房方案违背率低于1％,采血及处理生物样本超窗发生率均低于0.8％,受试者护理不良事件发生率低于0.45％,第三方测评满意度均高于96％,肿瘤受试者和家属满意度增高.结论 我院基于肿瘤专科特色建设高效的I期临床研究病房管理体系,搭建了湖南省临床试验培训、科研、信息交流平台,其服务模式和管理体系可推广至其他医院,进一步推动临床研究在全国范围的发展.

目的 对抗肿瘤药物临床试验方案违背进行分析,了解方案违背的整体情况及存在的问题并提出解决措施,减少临床试验过程中方案违背的发生,保证临床试验的质量.方法 对2019年1月至2020年12月本院伦理委员会审查的方案违背报告进行回顾性分析,包括方案偏离的类别、例数以及导致方案违背发生的责任主体;并比较国内外申办方的项目方案违背发生情况的差异,分析方案违背的上报过程中存在的问题,提出相应的解决措施,加强方案违背的管理.结果 共245个项目发生2768例次方案违背.最常见的方案违背类型为检查/生命体征/体格检查漏查(534例次,占19.3％),少服/多服/漏服药物(378例次,占13.7％).38.8％的方案违背由受试者造成,其次为研究者(29.5％).国内申办方的项目发生的方案违背较国外申办方的项目发生率高,方案违背发生时间与发现时间间隔0～648 d,均值为63 d,中位数为31 d;发现时间与上报时间间隔0～668 d,均值为225 d,中位数为127 d.结论在抗肿瘤药物临床试验过程中,通过加强培训和沟通提高受试者依从性,通过管理部门监管及激励措施提高研究者的积极性和依从性,伦理委员会采取措施加强对方案违背上报的监管,使用信息化等手段提高抗肿瘤药物临床试验的方案依从性,不断完善对方案违背的规范管理以减少方案违背的发生,提高临床试验质量.

ObjectiveTo explore the potential of CT radiomics in detecting acquired T790M mutation and predicting prognosis in patients with advanced lung adenocarcinoma with progression after first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.Materials and MethodsContrast-enhanced thoracic CT was collected from 250 lung adenocarcinoma patients (with acquired T790M mutation, n = 146, without mutation, n = 104) after progression on first- or second-generation TKIs. Radiomic features were extracted from each volume of interest. The maximum relevance minimum redundancy and the least absolute shrinkage and selection operator (LASSO) regression method were used to select the optimized features in detecting acquired T790M mutation. Univariate Cox regression and LASSO Cox regression were used to establish the radiomics model to predict the progression-free survival of osimertinib treatment. Finally, nomograms (which) combined clinical factors with radscore to predict the acquired T790M mutation and prognosis were built separately. In addition, the two nomograms were validated by the concordance index (C-index), decision curve analysis (DCA), and calibration curve analysis where appropriate.ResultsClinical factors including the progression-free survival of first-line EGFR TKIs, EGFR mutation, and N stage and 12 radiomic features were useful in predicting the acquired T790M mutation. The area under the receiver operating characteristic curves (AUC) of clinical, radiomics, and nomogram models were 0.70, 0.74, and 0.78 in the training set and 0.71, 0.71, and 0.76 in the validation set, respectively. The DCA and calibration curve analysis demonstrated a good performance of the nomogram model. Clinical factors including age and first-generation EGFR TKIs and 12 radiomic features were useful in patients’ outcome prediction. The C-index of the combined nomogram was 0.686 in the training set and 0.630 in the validation set, respectively. Calibration curves demonstrated a relatively poor performance of the nomogram model.ConclusionNomogram combined clinical factors with radiomic features might be helpful to detect whether patients developed acquired T790M mutation or not after progression on first- or second-generation EGFR TKIs. Nomogram prognostic model combined clinical factors with radiomic features might have a limited value in predicting the survival of patients harboring acquired T790M mutation treated with osimertinib.

Background To determine whether antibiotic treatment is a risk factor for immune-related adverse events (irAEs) across different patients with cancer receiving anti-PD-1/PD-L1 therapies. Methods The retrospective analysis includes clinical information from 767 patients with cancer treated at Hunan Cancer Hospital from 2017 to 2020. The pharmacovigilance data analysis includes individual cases of 38,705 safety reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2014 to 2020, and 25,122 cases of safety reports from the World Health Organization database VigiBase from 2014 to 2019. All cases that received anti-PD-1/PD-L1 treatment were included. Multiomics data from patients across 25 cancer types were download from The Cancer Genome Atlas. Logistic regression and propensity score algorithm was employed to calculate OR of irAEs. Results Retrospective analysis of in-house patients showed that irAE potential risks are higher in all cancer (OR 2.12, 95% CI 1.38 to 3.22, false discovery rate (FDR) adjusted-p=1.93x10(-3)) and patients with lung cancer (OR 3.16, 95% CI 1.67 to 5.95, FDR adjusted-p=1.93x10(-3)) when using antibiotics. Potential risk of irAEs in patients with lung cancer with antibiotic treatment is significantly higher in FAERS (OR 1.39, 95% CI 1.21 to 1.59; FDR adjusted-p=1.62x10(-5)) and VigiBase (OR 1.32, 95% CI 1.09 to 1.59, FDR adjusted-p=0.05). Mechanistically, decreased microbial diversity caused by antibiotics use may increase the irAE risk through mediating the irAE-related factors. Conclusions Our study is the first to comprehensively demonstrate the associations of irAEs and antibiotic during anti-PD-1/PD-L1 therapy across a wide spectrum of cancers by analyzing multisource data. Administration of antibiotics should be carefully evaluated in patients with cancer treated by anti-PD-1/PD-L1 to avoid potentially increasing irAE risk.