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Antibiotic Use and Survival in Patients With Late-Stage NSCLC Treated With Chemoimmunotherapy 化疗免疫疗法晚期 NSCLC 患者的抗生素使用与生存率
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-31 DOI: 10.1016/j.jtocrr.2024.100710
Emanuela Taioli MD, PhD , Raja M. Flores MD , Arwa Abdelhamid MPH , Matthew Untalan MPH , Tara Ivic-Pavlicic MPH , Stephanie Tuminello PhD, MPH

Introduction

Immunotherapy has improved survival in patients with advanced NSCLC. Efficacy may decrease when patients are treated with antibiotics, possibly due to gut microbiome disruption, but few studies have investigated this using real-world, patient-level populations in the United States.

Methods

We have analyzed antibiotic use in patients with stage IV first, primary NSCLC diagnosed in 2015 and treated with chemotherapy or chemoimmunotherapy, drawn from the Surveillance, Epidemiology, and End Results-Medicare data set. Patients had to have continuous part A, part B, and part D Medicare coverage. Survival was determined through Kaplan-Meier and Cox proportional hazards models. All data analyses were performed using SAS.

Results

The study included 788 patients, 440 (56%) of whom received antibiotics within 2 months before or after starting systemic treatment. The median follow-up time was 11.64 months. There was a statistically significant difference in survival for patients who received antibiotics (p = 0.007) and who had more than 1 round of antibiotics versus zero or 1 round (p < 0.0001). After adjustment, receipt of antibiotics (hazard ratio [HR]adj: 1.17, 95% confidence interval [CI]: 0.99–1.37) and receipt of multiple rounds of antibiotics (HRadj: 1.35, 95% CI: 1.14–1.60) were statistically significantly associated with worse survival. Among just those receiving chemoimmunotherapy (n = 203; 26%), there was still an increased risk of death for those receiving multiple antibiotic rounds (HRadj: 1.52, 95% CI: 1.09–2.13).

Conclusions

Antibiotic use concurrent with chemoimmunotherapy seems to be associated with worse survival. This is more pronounced when more cycles of antibiotics are given.

IRB approval number

STUDY-19-00500.
导言免疫疗法提高了晚期 NSCLC 患者的生存率。可能由于肠道微生物组的破坏,患者接受抗生素治疗时疗效可能会下降,但很少有研究利用美国真实世界的患者群体对此进行调查。方法我们分析了2015年确诊的IV期初治NSCLC患者中使用抗生素的情况,这些患者接受了化疗或化学免疫疗法,数据来自监测、流行病学和最终结果-医疗保险数据集。患者必须连续参加 A 部分、B 部分和 D 部分医疗保险。生存率通过卡普兰-梅耶(Kaplan-Meier)和考克斯比例危险模型确定。所有数据分析均使用 SAS 进行。研究共纳入 788 名患者,其中 440 人(56%)在开始系统治疗前后 2 个月内接受了抗生素治疗。中位随访时间为 11.64 个月。接受过抗生素治疗的患者(p = 0.007)与接受过一轮以上抗生素治疗的患者(p <0.0001)在生存率上有显著统计学差异。经调整后,接受抗生素治疗(危险比[HR]adj:1.17,95% 置信区间[CI]:0.99-1.37)和接受多轮抗生素治疗(HRadj:1.35,95% 置信区间[CI]:1.14-1.60)在统计学上与较差的生存率显著相关。仅在接受化学免疫疗法的患者(n = 203;26%)中,接受多轮抗生素治疗的患者死亡风险仍然增加(HRadj:1.52,95% CI:1.09-2.13)。结论化疗免疫疗法同时使用抗生素似乎与生存率降低有关,当使用抗生素的周期越多,生存率越低。
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引用次数: 0
Tarlatamab for Large Cell Neuroendocrine Carcinoma in a Young Adult: A Case Report 塔拉他单抗治疗一名年轻成人的大细胞神经内分泌癌:病例报告
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-31 DOI: 10.1016/j.jtocrr.2024.100712
Shetal A. Patel MD, PhD , Young Whang MD, PhD , Chaely Medley NP , Kevin Chen PharmD , Jasmine Jordan BS , Dante Bortone PhD , Benjamin Vincent MD, PhD , Jared Weiss MD

A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3–targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.

一名患有转移性肺大细胞神经内分泌癌的 20 岁男子接受了 delta-like ligand 3 靶向双特异性 T 细胞捕获剂 tarlatamab 的治疗。治疗过程中出现了一过性细胞因子释放综合征,但最终取得了部分疗效。双特异性T细胞捕获剂可能会为肺大细胞神经内分泌癌提供一种新的治疗方法。
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引用次数: 0
Immune Cell Dynamics in EGFR-Mutated NSCLC Treated With Afatinib and Pembrolizumab: Results From a Phase IB Study 用阿法替尼和 Pembrolizumab 治疗表皮生长因子受体 (EGFR) 突变的非小细胞肺癌 (NSCLC) 的免疫细胞动态:IB期研究结果
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-14 DOI: 10.1016/j.jtocrr.2024.100706
Jonathan W. Riess MD , Matthew S. Lara BS , Miguel Lopez de Rodas MD , Guillaume Luxardi PhD , Samantha Herbert MSPH , Michiko Shimoda PhD , Karen Kelly MD , Alexander Meerlev PhD , Elizabeth Moore MD , Laurel Beckett PhD , Arta Monjazeb MD, PhD , Kurt Schalper MD, PhD , Emanual Maverakis MD , David R. Gandara MD

Introduction

EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC.

Methods

Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood.

Results

A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment.

Conclusions

Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

导言表皮生长因子受体(EGFR)突变的非小细胞肺癌对程序性细胞死亡蛋白1或程序性死亡配体1的阻断反应微弱。我们评估了EGFR酪氨酸激酶抑制剂(TKI)阿法替尼联合程序性细胞死亡蛋白1抗体pembrolizumab治疗EGFR突变NSCLC患者的安全性、耐受性和免疫调节作用。方法符合以下条件的晚期表皮生长因子受体突变型NSCLC患者:既往接受过表皮生长因子受体抑制剂(TKI)治疗,病情进展(PD);年龄大于或等于18岁;东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现状态小于或等于1;器官功能可接受;无明显自身免疫性疾病;病情可测量;脑转移得到控制。主要终点是确定最大耐受剂量和第二阶段推荐剂量。通过组织中的定量免疫荧光和血液中的 Luminex 及流式细胞术,收集序列标本以评估细胞因子和免疫细胞亚群的变化。未观察到剂量限制性毒性。确定的最大耐受剂量为每日口服阿法替尼40毫克,每21天静脉注射pembrolizumab 200毫克。4名患者(36%)出现了免疫相关不良事件(irAEs)。10名患者可评估反应:2名部分反应,7名病情稳定,1名病情恶化。治疗期间,外周自然杀伤细胞和自然杀伤 T 细胞增加(p = 0.027,p = 0.01),CD8+ T 细胞减少(p = 0.0035)。外周 CD4/CD8 T 细胞(曲线下面积 = 0.96,p = 0.042)和中枢记忆 T 细胞(CD4/CD8)(曲线下面积 = 1.0,p = 0.结论阿法替尼和pembrolizumab在既往EGFR TKI治疗PD后具有与irAEs相关的适度活性。检测到组织和血液中免疫细胞亚群的促炎性变化与抗肿瘤活性和irAEs有关。
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引用次数: 0
Identifying Novel Germline Mutations and Copy Number Variations in Patients With SCLC 鉴定 SCLC 患者的新型基因突变和拷贝数变异
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1016/j.jtocrr.2024.100702
Sami Ul Haq MSc , Gregory Downs PhD , Luna Jia Zhan MPH , Sabine Schmid MD , Devalben Patel BSc , Danielle Sacdalan MD , Janice J.N. Li BSc , Dangxiao Cheng PhD , Nicolas Meti MD , Vivek Philip MSc, PhD , Raymond H. Kim MD, PhD , Geoffrey Liu MSc, MD , Scott V. Bratman MD, PhD , Peter J.B. Sabatini PhD , Benjamin H. Lok MD

Introduction

SCLC has traditionally been considered to arise from toxic exposure factors, such as smoking. Recent evidence has revealed that germline mutations may also affect the development of SCLC; however, these alterations remain understudied. We sought to identify novel germline mutations in SCLC including germline copy number variations (CNVs) in our cohort of patients.

Methods

We designed a custom hybrid-capture gene panel to evaluate germline alterations in 192 cancer-predisposition and frequently mutated genes in SCLC. We applied this panel to germline analysis of a treatment-naive cohort of 67 patients with SCLC at our institution. Subsequently, we annotated the variants using the American College of Medical Genetics criteria and further classified variants of uncertain significance using a set of in silico tools, including DeepMind AlphaMissense, MutationTaster, SIFT, and Polyphen2.

Results

We identified American College of Medical Genetics pathogenic or likely pathogenic alterations in seven of 67 patients. Five (71%) were novel alterations (BCORL1, FANCC, ATR, and BBC3) and a novel CNV (SLFN11) with two (29%) previously described mutations (CHEK1 and BRIP1). We also identified 191 variants of uncertain significance in 60 of 67 patients, of which, depending on the in silico tool, 5% to 14% were predicted to be pathogenic. Patients with SCLC with the seven pathogenic alterations were observed to have a numerically longer overall survival (hazard ratio = 0.50) and progression-free survival (hazard ratio = 0.45) though not statistically significant compared with the remaining cohort.

Conclusions

Our study identifies novel germline alterations, including a CNV, and provides additional evidence that germline factors could be important contributing factors to the development of SCLC.
导言:SCLC 传统上被认为是由吸烟等毒性暴露因素引起的。最近的证据显示,种系突变也可能影响SCLC的发展;然而,这些改变仍未得到充分研究。我们试图在我们的患者队列中发现SCLC中的新型种系突变,包括种系拷贝数变异(CNV)。方法我们设计了一个定制的杂交捕获基因面板,以评估SCLC中192个癌症易感基因和频繁突变基因的种系改变。我们对本机构的 67 例未经治疗的 SCLC 患者进行了种系分析。随后,我们使用美国医学遗传学会的标准对变异进行了注释,并使用一套硅学工具(包括 DeepMind AlphaMissense、MutationTaster、SIFT 和 Polyphen2)对意义不确定的变异进行了进一步分类。其中五例(71%)为新型变异(BCORL1、FANCC、ATR和BBC3)和一种新型CNV(SLFN11),两例(29%)为先前描述过的突变(CHEK1和BRIP1)。我们还在67名患者中的60名患者中发现了191个意义不确定的变异,其中5%到14%被预测为致病性变异,具体取决于硅学工具。我们观察到,与其他队列相比,具有 7 个致病性变异的 SCLC 患者的总生存期(危险比 = 0.50)和无进展生存期(危险比 = 0.45)在数字上更长,但无统计学意义。
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引用次数: 0
Combination of Cytologic Findings and Circulating Tumor DNA From Cerebrospinal Fluid Revealed SCLC Transformation in Patients With Leptomeningeal Metastases of Lung Adenocarcinoma 结合细胞学和脑脊液中的ctDNA,揭示肺腺癌多脑膜转移患者的小细胞肺癌转化过程
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-06 DOI: 10.1016/j.jtocrr.2024.100704
Jia-Xin Lin PhD , Kai Yin PhD , Li-Xu Yan PhD , Mei-Mei Zheng PhD , Yang-Si Li PhD , Shi-Ling Zhang MS , Kang-Hui Zeng MS , Hong-Hong Yan MS , Hai-Yan Tu PhD , Zhi-Hong Chen MS , Xu-Chao Zhang PhD , Qing Zhou PhD , Jin-Ji Yang PhD , Ben-Yuan Jiang PhD , Qing-Ling Zhang PhD , Yi-Long Wu MD

Introduction

Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce.

Methods

We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing.

Results

Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo).

Conclusions

SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

导言向SCLC转化是表皮生长因子受体(EGFR)突变的肺腺癌(LUAD)对酪氨酸激酶抑制剂的一种耐药机制。方法 我们回顾性地收集了237例因出现脑脊液转移(LM)而接受腰椎穿刺的NSCLC患者。所有脑脊液(CSF)中的 SCLC 转移均由两位经验丰富的病理学家通过细胞学评估确认。结果111例患者(237例中有111例,占46.8%)的CSF样本中发现了肿瘤细胞,8例(111例中有8例,占7.2%)被确定为CSF中有SCLC细胞。七名患者携带表皮生长因子受体突变,其中四名患者的表皮生长因子受体外显子19缺失,三名患者的表皮生长因子受体外显子21 L858R突变。另一名患者携带 ERBB2 插入基因。其中七名患者对靶向治疗耐药。CSF ctDNA分析显示,TP53和RB1突变很常见。从诊断为晚期NSCLC到CSF中发现SCLC转化的中位时间为9.7个月(95%置信区间[CI]:4.0-17.5个月)。转移性 NSCLC 初次诊断后的中位总生存期为 15.3 个月(95% 置信区间:1.2-29.4 个月)。在CSF中检测到SCLC转化后的中位总生存期为5.0个月(95% CI:4.0-5.9个月)。CSF中的SCLC转化可为酪氨酸激酶抑制剂治疗进展期LM的LUAD患者的耐药机制提供信息,而LM的耐药机制与患者的生存率较低有关。
{"title":"Combination of Cytologic Findings and Circulating Tumor DNA From Cerebrospinal Fluid Revealed SCLC Transformation in Patients With Leptomeningeal Metastases of Lung Adenocarcinoma","authors":"Jia-Xin Lin PhD ,&nbsp;Kai Yin PhD ,&nbsp;Li-Xu Yan PhD ,&nbsp;Mei-Mei Zheng PhD ,&nbsp;Yang-Si Li PhD ,&nbsp;Shi-Ling Zhang MS ,&nbsp;Kang-Hui Zeng MS ,&nbsp;Hong-Hong Yan MS ,&nbsp;Hai-Yan Tu PhD ,&nbsp;Zhi-Hong Chen MS ,&nbsp;Xu-Chao Zhang PhD ,&nbsp;Qing Zhou PhD ,&nbsp;Jin-Ji Yang PhD ,&nbsp;Ben-Yuan Jiang PhD ,&nbsp;Qing-Ling Zhang PhD ,&nbsp;Yi-Long Wu MD","doi":"10.1016/j.jtocrr.2024.100704","DOIUrl":"10.1016/j.jtocrr.2024.100704","url":null,"abstract":"<div><h3>Introduction</h3><p>Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in <em>EGFR</em>-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce.</p></div><div><h3>Methods</h3><p>We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing.</p></div><div><h3>Results</h3><p>Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the <em>EGFR</em> mutation, including four patients with <em>EGFR exon 19 deletion</em> and three patients with <em>EGFR</em> <em>exon</em> <em>21 L858R</em> mutation. Another patient harbored <em>ERBB2</em> insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that <em>TP53</em> and <em>RB1</em> mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo).</p></div><div><h3>Conclusions</h3><p>SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":"5 9","pages":"Article 100704"},"PeriodicalIF":3.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000742/pdfft?md5=870ec4f4f2918aac97890cf20e833f5f&pid=1-s2.0-S2666364324000742-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141710322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reproducibility of Assessment of Lepidic (Noninvasive) Patterns in Lung Adenocarcinoma With Cytokeratin Immunostain Compared With Hematoxylin and Eosin and the Proposed New International Association for the Study of Lung Cancer (IASLC) Algorithm 用细胞角蛋白免疫印迹评估肺腺癌鳞状(非侵袭性)模式的再现性与苏木精和伊红以及拟议的 IASLC 新算法进行比较
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.jtocrr.2024.100682
Ellen Yang MD, FRCPC , Najd Alshamlan MD , Katrina Hueniken MSc , Jessica Weiss MSc , Michael Cabanero MD , Ming-Sound Tsao MD, FRCPC

Introduction

Lepidic growth is considered noninvasive in lung nonmucinous adenocarcinoma, whereas other patterns are invasive. Considerable interobserver variability in assessing “invasion” has been reported. We assessed the utility of cytokeratin 7 (CK7) stain and recently proposed International Association for the Study of Lung Cancer criteria to improve assessment of noninvasion in lung adenocarcinoma.

Methods

Four pathologists (two staff, two trainees) assessed 158 hematoxylin and eosin (HE)- and CK7-stained slides of 108 pT1N0-2 nonmucinous lung adenocarcinoma cases. Scoring took place in four rounds. First, sections were independently scored for percentage of noninvasive or probable noninvasive and invasive or probable invasive patterns. Second, after a consensus scoring algorithm for CK7 was formulated, the slides were rescored. Subsequent third-round scoring was conducted only on HE slides using the 2023 International Association for the Study of Lung Cancer proposed criteria, and fourth-round scoring on both HE and CK7 slides simultaneously. Intraclass correlation coefficient (ICC) was calculated for each round. Recurrence-free survival was assessed using Cox proportional hazards regression methods.

Results

In the first two rounds, interobserver concordance was consistently higher with CK7 (ICC range = 0.44–0.6) than HE (range = 0.24–0.49) scores. The IASLC proposed algorithm improved ICC of HE scores to 0.60 (95% confidence interval: 0.52–0.67), and round 4 HE and CK7 combined improved ICC to 0.75 (95% confidence interval: 0.70–0.80). Continuous measures of averaged noninvasive and probable noninvasive scores on HE were associated with improved recurrence-free survival (hazard ratio: 0.83–0.86).

Conclusions

CK7 staining consistently increased interobserver concordance in assessment of invasive versus noninvasive patterns than HE. Combining CK7 with the 2023 IASLC criteria for morphologic features of invasion may further improve the interobservers’ concordance for the recognition of lepidic growth in nonmucinous lung adenocarcinoma.

导言在肺非粘液腺癌中,浸润性生长被认为是非侵袭性的,而其他形态则是侵袭性的。据报道,在评估 "侵袭 "时,观察者之间存在相当大的差异。我们评估了细胞角蛋白 7(CK7)染色和最近提出的国际肺癌研究协会标准对改善肺腺癌非侵袭性评估的实用性。方法四名病理学家(两名工作人员,两名实习生)评估了 108 例 pT1N0-2 非粘液性肺腺癌的 158 张苏木精和伊红(HE)及 CK7 染色切片。评分分四轮进行。首先,根据非浸润性或可能非浸润性和浸润性或可能浸润性模式的百分比对切片进行独立评分。其次,在对 CK7 的评分算法达成共识后,对切片进行重新评分。随后的第三轮评分仅对 HE 切片进行,采用 2023 年国际肺癌研究协会提出的标准,第四轮评分同时对 HE 和 CK7 切片进行。每轮评分均计算类内相关系数(ICC)。结果 在前两轮评分中,CK7评分的观察者间一致性(ICC范围=0.44-0.6)始终高于HE评分(ICC范围=0.24-0.49)。IASLC 提出的算法将 HE 评分的 ICC 提高到了 0.60(95% 置信区间:0.52-0.67),第 4 轮 HE 和 CK7 的组合将 ICC 提高到了 0.75(95% 置信区间:0.70-0.80)。HE上平均非侵袭性和可能非侵袭性评分的连续测量与无复发生存率的改善相关(危险比:0.83-0.86)。结论CK7染色比HE能持续提高侵袭性与非侵袭性模式评估的观察者间一致性。将 CK7 与 2023 年 IASLC 侵袭形态学特征标准相结合,可进一步提高观察者之间在识别非黏液性肺腺癌鳞状生长方面的一致性。
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引用次数: 0
Successful Lorlatinib Rechallenge After Severe Drug-Induced Psychosis in ALK-Positive Metastatic NSCLC: A Case Report ALK 阳性转移性非小细胞肺癌(NSCLC)患者在严重的药物诱发精神病后成功重试洛拉替尼:病例报告
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.jtocrr.2024.100689

Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system–active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.

据报道,在服用中枢神经系统活性 ALK 强效抑制剂洛拉替尼(lorlatinib)的患者中,神经认知不良事件(NAEs)的发生率高达 60%。表现可能包括精神、情绪、言语和认知症状。目前的指南建议,在出现IV级非神经系统毒性反应时,应永久停用lorlatinib。在此,我们报告了一例ALK阳性NSCLC患者在恢复IV级精神病后成功重新挑战剂量降低后的lorlatinib的病例。
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引用次数: 0
Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report 胸腺癌中滋养层细胞表面抗原 2 的表达:简要报告
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.jtocrr.2024.100693
Kana Kurokawa MD, PhD , Tetsuhiko Asao MD, PhD , Takuo Hayashi MD, PhD , Satsuki Kishikawa MD, PhD , Koichiro Kanamori MD, PhD , Takehito Shukuya MD, PhD , Yosuke Miyashita MD , Ikuko Nakamura MD, PhD , Taichi Miyawaki MD, PhD , Ryota Kanemaru MD, PhD , Tomoyasu Mimori MD, PhD , Yoichiro Mitsuishi MD, PhD , Ken Tajima MD, PhD , Naoko Shimada MD, PhD , Fumiyuki Takahashi MD, PhD , Kazuya Takamochi MD, PhD , Kenji Suzuki MD, PhD , Kazuhisa Takahashi MD, PhD

Introduction

Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma.

Methods

TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University.

Results

RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%–100%) and 25.0 (range: 0–200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival.

Conclusions

TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

导言滋养体细胞表面抗原 2(TROP2)是一种跨膜糖蛋白,在多种癌症类型中过度表达。尽管TROP2靶向治疗目前正备受关注,但人们对TROP2在胸腺癌中的表达却知之甚少。结果癌症基因组图谱的 RNA-seq 数据分析显示,胸腺癌中 TACSTD2(编码 TROP2 的基因)的表达明显高于胸腺瘤(调整后 p = 6.64e-05)。胸腺瘤 B1 型、B2 型、B3 型和胸腺癌的表达也呈上升趋势。在胸腺癌的 IHC 中,TROP2 的表达定位于癌细胞膜。强度为 0、1 和 2 的病例分别有 6 例(23.1%)、11 例(42.3%)和 9 例(34.6%),TROP2 阳性的病例有 20 例(76.9%)。TROP2阳性肿瘤细胞的中位比例和H评分的中位数分别为25.0%(范围:0%-100%)和25.0(范围:0-200)。在对TROP2表达和患者背景的分析中未发现相关因素。结论RNA-seq和IHC均证实了TROP2在胸腺癌中的表达,其中IHC观察到的高表达为强度(76.9%)和比例。TROP2可能是胸腺癌的潜在靶点。
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引用次数: 0
Avelumab in Combination With Lorlatinib or Crizotinib in Patients With Previously Treated Advanced NSCLC: Phase 1b/2 Results From the JAVELIN Lung 101 Trial 阿维单抗联合洛拉替尼或克唑替尼治疗既往接受过治疗的晚期非小细胞肺癌患者:JAVELIN Lung 101试验的1b/2期结果
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.jtocrr.2024.100685
Benjamin J. Solomon M.B.B.S., PhD , Ibiayi Dagogo-Jack MD , Se-Hoon Lee MD , Michael J. Boyer M.B.B.S., PhD , Suresh S. Ramalingam MD , Enric Carcereny MD , Enriqueta Felip MD, PhD , Ji-Youn Han MD, PhD , Toyoaki Hida PhD , Brett G.M. Hughes M.B.B.S. , Sang-We Kim MD, PhD , Makoto Nishio MD, PhD , Takashi Seto MD , Tatsuro Okamoto MD, PhD , Xiaoxi Zhang PhD , Jean-Francois Martini PhD , Erjian Wang MD, PhD , Steven De Beukelaer MD , Todd M. Bauer MD

Introduction

The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively.

Methods

Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1.

Results

In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses).

Conclusions

Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group.

ClinicalTrials.gov identifier

NCT02584634

简介:JAVELIN Lung 101 1b/2 期试验评估了阿韦利单抗(免疫检查点抑制剂)与洛拉替尼或克唑替尼(酪氨酸激酶抑制剂)分别用于 ALK 阳性或 ALK 阴性晚期 NSCLC 的治疗效果。方法起始剂量为洛拉替尼 100 毫克,每天一次或克唑替尼 250 毫克,每天两次,每 2 周给予阿韦利单抗 10 毫克/千克。主要目标是评估第一阶段的最大耐受剂量(MTD)和第二阶段的推荐剂量,以及第二阶段的客观反应率。结果在阿维单抗加洛拉替尼组(ALK阳性;n = 31;1b期28例;2期3例),28例可评估患者中有2例(7%)出现DLT,MTD和2期推荐剂量为阿维单抗10 mg/kg,每2周1次,加洛拉替尼100 mg,每日1次。在阿韦鲁单抗加克唑替尼组(ALK阴性;n = 12;均为1b期)中,12名可评估患者中有5名(42%)出现了DLT,阿韦鲁单抗10毫克/千克,每2周一次,加克唑替尼250毫克,每天两次,超过了MTD;未评估其他克唑替尼剂量。阿维单抗加氯拉替尼的客观反应率为52%(95%置信区间,33%-70%)(完全反应,3%;部分反应,48%),阿维单抗加克唑替尼的客观反应率为25%(95%置信区间,6%-57%)(均为部分反应)。结论阿维单抗加氯拉替尼治疗ALK阳性NSCLC是可行的,但阿维单抗加克唑替尼治疗ALK阴性NSCLC在测试剂量下无法实施。两组均未观察到抗肿瘤活性增强的证据。
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引用次数: 0
Brief Report: Real-World Eligibility for Clinical Trials in Patients With Extensive-Stage SCLC at a Tertiary Care Center 简要报告:一家三级医疗中心的极重度SCLC患者参加临床试验的实际情况
IF 3 Q2 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.jtocrr.2024.100696
Navdeep Dehar M.B.B.S., MD, MBT, FRCPC , Mahbuba Meem MD , Ishita Aggarwal MD, MPH , Wilma Hopman MA , Pierre-Olivier Gaudreau MD, PhD, MPs, FRCPC , Andrew Robinson MD, MSc, FRCPC , Andrea S. Fung MD, PhD

Introduction

The CASPIAN and IMpower133 trials revealed a significant survival benefit of chemotherapy plus immunotherapy in patients with extensive-stage SCLC. The current study characterizes the proportion of real-world patients who would have met eligibility for these trials and highlights factors influencing eligibility in the real-world setting.

Methods

A retrospective analysis of patient data was conducted for stage IV patients with SCLC treated at the Cancer Centre of Southeastern Ontario, Canada. Trial eligibility was based on criteria used in the IMpower133 and CASPIAN trials. Data were summarized using descriptive statistics. Overall survival was assessed using the Kaplan–Meier method.

Results

Of the 116 patients included, only 12.1% met the overall eligibility criteria for the IMpower133 trial, and 14.7% for the CASPIAN trial. The most common reasons for ineligibility included: Eastern Cooperative Oncology Group (ECOG) 2 or greater (77.5%), inadequate organ function (48%), and the presence of brain metastases at diagnosis (37.3%). Sixty-one patients (59.8%) met two or more major ineligibility criteria. If trial eligibility was expanded to include ECOG 2 patients, an additional 10.3% would have met eligibility. The median overall survival for all-comers was 6.5 months.

Conclusions

Only a small minority of real-world patients with extensive-stage SCLC would have met eligibility for the IMpower133 and CASPIAN trials, with ECOG greater than or equal to 2, inadequate organ function, and brain metastases comprising the most common reasons for trial ineligibility. Future clinical trials should expand the inclusion criteria to better represent real-world patient populations.

导言CASPIAN和IMpower133试验显示,化疗加免疫疗法对广泛期SCLC患者有显著的生存获益。本研究描述了现实世界中符合这些试验资格的患者比例,并强调了在现实世界环境中影响试验资格的因素。方法对加拿大安大略东南部癌症中心治疗的IV期SCLC患者数据进行了回顾性分析。试验资格基于IMpower133和CASPIAN试验中使用的标准。数据采用描述性统计进行总结。结果 在纳入的116名患者中,只有12.1%符合IMpower133试验的总体资格标准,14.7%符合CASPIAN试验的资格标准。不符合条件的最常见原因包括东部合作肿瘤学组(ECOG)2级或以上(77.5%)、器官功能不全(48%)和确诊时存在脑转移(37.3%)。61名患者(59.8%)符合两个或两个以上的主要不合格标准。如果将试验资格扩大到包括 ECOG 2 患者,将有另外 10.3% 的患者符合试验资格。结论现实世界中只有少数广泛期SCLC患者符合IMpower133和CASPIAN试验的资格,ECOG大于或等于2、器官功能不全和脑转移是不符合试验资格的最常见原因。未来的临床试验应扩大纳入标准,以更好地代表现实世界中的患者群体。
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引用次数: 0
期刊
JTO Clinical and Research Reports
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