bluuebunny/crossref_metadata_2025_split huggingface dataset:
TCR-T cells armored with immune checkpoint blockade in EBV-positive nasopharyngeal carcinoma: The first-in-human phase 1/2 trial.
Authors: Jia Qingzhu , Peng Ling , Chen Gang , Wu Haiyang , Zeng Dong , Liu Tao , Zhan Yunpeng , Li Si , Su Frank , Zhu Bo , Li Qi-Jing 
Published: June 2023

6047 Background: Nasopharyngeal carcinoma (NPC) refraction and metastasis is common, but therapeutics are limited. As adoptive immunotherapy has emerged as effective against other cancers, engineered T cells bearing a transgenic Epstein-Barr virus (EBV)-specific TCR (TCR-T) represent a viable approach to treat EBV-associated NPC. Given PD-1/PD-L1 induced T cell hypofunction, we herein report preliminary findings of a phase I trial of EBV-targeting TCR-T cells armored with secreted PD-1 blockade for patients who failed in two or more lines of standard therapies. Methods: Patients with advanced NPCs were consented and screened for EBV serotype and HLA haplotype. EBV+/HLA-A*02+ patients were enrolled in a rapid titration setting to escalate the single infusion dose from 5x106 to 1.0x107 and 5.0x107 /kg TCR-T cells. After safety evaluation, the 5.0X107 /kg cohort was expanded for further investigation of combining with IL-2 administration. Fludarabine/cyclophosphamide were administered prior to TCR-T cell transfer as pre-conditioning. Patient monitoring and peripheral blood analysis occurred weekly over the first month and then monthly until disease progression or patient withdrawal. The primary objective was to determine safety and a recommended phase 2 dose (RP2D), while the secondary objective was investigator assessed ORR (RECIST v1.1). Results: One patient per TCR-T dose was treated, and, as no dose-limiting toxicity (DLT) has been observed, dose level 3 (5.0x107 /kg) was expanded with IL-2 administration upon TCR-T cell infusion. As of January 2023, six patients have been treated. One patient (16.7%) exhibited grade 1 CRS (n=6). No grade 4 treatment-related adverse events (TRAEs) have been observed, with leukopenia and fever being the most common AEs. Two patients (33.3%) were assessed as partial response (PR), with one reaching a response duration of 9 months to date. Three patients (50%) were assessed as stable disease (SD). For all patients, pharmacokinetic analysis revealed that levels of TCR-T cells in peripheral blood peak between 3- and 14-days post-infusion, with a maximum duration of 180 days. Conclusions: EBV-targeting TCR-T cells armored with PD-1 blockade are well tolerated. Initial results from this ongoing study indicate that EBV proteins may be safe and effective TCR-T targets to achieve superior outcomes in advanced EBV-positive NPC patients. Clinical trial information: NCT04139057 . [Table: see text]
Induction therapy of toripalimab combined with docetaxel and cisplatin in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC): A single-arm, phase II clinical trial.
Authors: Bai Chunmei , Wang Chenyu , Jia Ning , Chen Xingming , Zhu Xiaoli , Sun Shuai , Shi Xiaohua , Chen Yu , Luo Yaping 
Published: June 2023

6070 Background: PD-1 (programmed cell death protein-1) inhibitors combination with chemotherapy has a significant efficacy and approved indications in the first-line treatment of head and neck squamous cell carcinoma (HNSCC), but the efficacy of these combination therapies in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC) remains unexplored. We conducted a single-arm, phase II trial to assess the efficacy and safety of toripalimab (a novel PD-1 inhibitor) combined with chemotherapy as induction treatment in locally advanced HPSCC. Methods: Patients with locally advanced HPSCC (cT1N+M0 or T2-4NanyM0, AJCC 8.0) were eligible. All patients received 2 cycles of intravenous docetaxel (75mg/m2), cisplatin (75mg/m2) and toripalimab (240mg) on day 1 every 21 days, followed by radical surgery or concurrent chemoradiotherapy (CCRT) with cisplatin (100mg/m2, q21d). The primary endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Secondary endpoints were major pathologic response (MPR), 2 year disease-free survival (DFS) rate in patients received surgery, 2 year progression-free survival (PFS) rate in patients received CCRT and 2 year overall survival (OS) rate in all patients. Results: From July 2020 to January 2023, 34 patients (median age: 59, range: 46-72, male: 100%, stag IV: 100%) were enrolled. Patients with stage IVA an IVB disease were 19 (19/34, 55.9%) and 15 (15/34, 44.1%), respectively. 33 patients completed 2 cycles induction treatment and efficacy evaluation (1 patient dropped out). The evaluated ORR was 54.5%, including 3 pts achieving complete response and 15 achieving partial response. PD-L1 status (combined positive score, CPS) were known in 8 patients, ORR were 80% (4/5) and 66.7% (4/6) in patients with CPS≥20 and CPS≥1, respectively, 2 patients with CPS＜1 had stable disease. Treatment-related grade 3-4 adverse events occurred in 45.5% (15/33) of patients, leukopenia (42.4%) and neutropenia (3.1%). Immune-related AEs were acceptable, 1 patient (1/33, 3.0%) experienced grade 2 interstitial pneumonia and 2 patients (2/33, 6.1%) experienced grade 1 rash. In the following treatment, 27 patients (27/33, 81.8%) performed CCRT. 4 patients (4/33, 12.1%) underwent surgery followed by CCRT and 2 patients (2/33, 6.1%) refused further treatment. Among these 17 patients finished CCRT and radiological assessment, 9 patients (9/17, 52.9%) had complete response, 7 patients (7/17, 41.2%) had partial response and 1 patient (1/17, 5.9%) had progressive disease. Survival data are not mature by cut-off date. Conclusions: Induction therapy of toripalimab combined with docetaxel and cisplatin was well tolerated and highly efficient for locally advanced HPSCC. Clinical trial information: NCT04296747 .
Impact of acute kidney injury on overall survival in postoperative patients with head and neck cancer who received chemoradiotherapy with cisplatin: A supplementary analysis of a phase II/III trial of JCOG1008.
Authors: Imamura Yoshinori , Kiyota Naomi , Tahara Makoto , Kodaira Takeshi , Hayashi Ryuichi , Nishino Hiroshi , Asada Yukinori , Mitani Hiroki , Iwae Shigemichi , Nishio Naoki , Onozawa Yusuke , Hanai Nobuhiro , Ohkoshi Akira , Hara Hiroki , Monden Nobuya , Nagaoka Masato , Minami Shujiro , Kitabayashi Ryo , Sasaki Keita , Homma Akihiro ,   The Head and Neck Cancer Study Group of the Japan Clinical Oncology Group (JCOG-HNCSG)
Published: June 2023

6079 Background: A randomized phase II/III trial of JCOG1008 demonstrated that chemoradiotherapy (CRT) with weekly cisplatin at 40 mg/m2 (Weekly arm) was noninferior to 3-weekly cisplatin at 100 mg/m2 (3-weekly arm) in terms of overall survival (OS) for postoperative high-risk head and neck cancer (hazard ratio [HR], 0.69 [99.1% CI, 0.37 to 1.27 < 1.32]; J Clin Oncol 2022; 40: 1980-90). Acute kidney injury (AKI) is a major dose-limiting toxicity of cisplatin. Here, we investigated the impact of AKI on OS in patients treated with CRT in JCOG1008. Methods: A total of 251 patients who were treated with CRT in JCOG1008 were analyzed. AKI was defined as an increase in serum creatinine of ≥0.3 mg/dL or a 1.5-fold or more increase from baseline (≥stage I) within 30 days after completion of CRT, based on the AKI Network classification/staging system. OS in the two arms was compared by the development of AKI using the log-rank test. Results: The total incidence of AKI in the weekly arm was lower than that in the 3-weekly arm (38 of 122 [31.1%] vs. 56 of 129 [43.4%]). The incidence of stage II/III AKI was also lower in the weekly arm (8 of 122 [6.6%] vs. 19 of 129 [14.7%]). Total cisplatin dose was similar in patients who did and did not develop AKI in the weekly arm, but was lower in patients who developed AKI in the 3-weekly arm (Table). Moreover, no difference in OS was observed between patients who did and did not develop AKI in the weekly arm (HR, 1.06 [95% CI, 0.53 to 2.10]), whereas patients who developed AKI in the 3-weekly arm had poorer OS than those who did not (HR, 1.83 [95% CI, 1.04 to 3.21]). Conclusions: In this supplementary analysis of JCOG1008, development of AKI impacted OS in the 3-weekly arm, but not in the weekly arm. Consistent exposure to cisplatin through weekly fractionated administration appears of greater clinical significance than cumulative dose, providing maintenance of treatment intensity and better kidney safety, and likely also improving outcomes. Clinical trial information: jRCTs031180135 . [Table: see text]
Use of machine learning derived features from CT and H&E whole-slide images to predict overall survival in head and neck squamous cell carcinoma.
Authors: Song Bolin , Leroy Amaury , Yang Kailin , Viswanathan Vidya Sankar , Li Xiao , Lee Jonathan , Stock Sarah , Fu Pingfu , Saba Nabil F. , Koyfman Shlomo A. , Lewis James S. , Deutsch Eric , Madabhushi Anant 
Published: June 2023

6086 Background: Computed tomography (CT) and H&E whole-slide images (WSI) have been found to carry rich prognostic information for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). However, most machine learning models aimed for outcome prediction only took advantage of single image modality. In this work, we developed and validated a prognostic machine learning method incorporating both CT and WSI to predict overall survival in HNSCC patients. Methods: Matched radiographic CT scans and digitized WSI were acquired from the Cleveland Clinic for 167 HNSCC patients, including 120 HPV-associated oropharyngeal cancer and 47 laryngeal cancer. Both primary tumor and the largest suspicious lymph node were annotated on CT scans and primary tumor was delineated on H&E WSI. We split the dataset into training and validation set using a 7:3 ratio, which resulted in 119 patients in the training set and 48 for hold-out validation. We applied a machine learning model (M_ML) using both CT and WSI as input to perform end-to-end predictions of overall survival. We used the harrell’s concordance index (C-index) to evaluate the prognostic performance. Finally, we performed the multivariable cox proportional hazard analysis adjusting for clinicopathological variables (i.e. age, gender, smoking pack-year [PY], AJCC 7th edition overall stage, and treatment modality) to validate the independent prognostic significance of the model. Results: The combined machine learning model M_ML (C-index = 0.81) outperformed the model using CT images alone (C-index = 0.63) and WSI alone (C-index = 0.64) on the validation set. In multivariable analysis, M_ML is still statistically significant accounting for clinicopathologic factors (p = 0.0007). Conclusions: This pilot study shows that a multi-omic machine learning model utilizing both radiographic CT and digitized WSI can predict HNSCC overall survival and outperforms models using only a single modality. [Table: see text]
Whole-genome sequencing based assessment of HER2 focal amplification for precision oncology of breast cancers.
Authors: Kim Ryul , Lim Joonoh , Park Hansol , Park Seongyeol , Oh Baek-Lok , Lee Sangmoon , Kim Ji-Yeon , Nam Seok Jin , Kim Seok Won , Lee Jeong Eon , Yu Jonghan , Ryu Ji In , Lee Jeong Seok , Kwon Minsuk , Lee Jeongmin , Park Yeon Hee , Ju Young Seok 
Published: June 2023

609 Background: Focal oncogene amplification confers a growth advantage to tumor cells and drives cancer evolution. Herein, we aimed to explore focally amplified HER2 in breast carcinomas. Methods: We performed whole genome sequencing (WGS) and whole-transcriptome sequencing (WTS) in 787 breast cancer samples. HER2 focal amplification was defined as having a segment length less than 3Mbp and ≥4 higher copy number than the surrounding region. Results: Most of the patients were premenopausal women (n = 574, 72.9%) with a median age of 37 (range 21-76) years. We identified 57 (58.8%) and 27 (5.0%) samples with HER2 focal amplification in HER2-positive (n = 97) and even HER2-negative (n = 536) by immunohistochemistry (IHC) and in-situ hybridization (ISH) according to ASCO guideline for breast cancer, respectively. Regardless of HER2-positivity, HER2 focal amplification was significantly associated with higher HER2 RNA expression. Among 28 patients who received six cycles of docetaxel/carboplatin/trastuzumab/pertuzumab neoadjuvant therapy followed by curative surgery, 21 patients had HER2 focal amplification and 14 (66.7%) achieved pathologic complete remission (pCR). Intriguingly, all patients without HER2 focal amplification (n = 7) failed to achieve pCR. HER2 focal amplification showed enrichment of TP53 mutations (OR 0.245, q < 0.001), but was mutually exclusive with GATA3 mutations (OR 2.82, q = 0.055). The mutational spectrums suggested that the activity in APOBEC family of cytidine deaminases were responsible for the somatic single-nucleotide variants of breast cancer with HER2 focal amplification. Compared to samples without HER2 focal amplification, samples with HER2 focal amplification were less likely to have defective homologous recombination DNA repair pathway. HER focal amplifications were closely associated with various types of structural variations. Translocation partners of HER2 were widespread across the entire genome with notable exceptions on chromosome 2, and most of them were close to super-enhancers implying enhancer hijacking as one of mechanisms of HER2 overexpression. Breast cancers with or without HER2 focal amplification showed distinct RNA expression patterns. Notably, activity of genes involved in doxorubicin-resistance and AKT1 signaling were significantly associated with HER2 focal amplification. Conclusions: Our analysis demonstrates that WGS enables better classification of the HER2 amplification status in breast cancer than IHC with ISH, suggesting WGS as a sensitive tool for screening breast cancers for anti-HER2-targeted therapies.
Darolutamide for patients with androgen receptor positive salivary gland cancers (DISCOVARY): The results of phase 2 study of darolutamide monotherapy.
Authors: Okano Susumu , Tahara Makoto , Imamura Yoshinori , Uryu Hideoki , Otsuka Tomoyuki , Ohkoshi Akira , Sano Daisuke , Tsukahara Kiyoaki , Ono Kazuchika , Hanazawa Toyoyuki , Kano Satoshi , Nishio Naoki , Nagaoka Masato , Kiyota Naomi 
Published: June 2023

6093 Background: There is no standard first-line treatment for recurrent/metastatic (R/M) or unresectable locally advanced (LA) salivary gland cancer (SGC). Androgen receptor (AR) overexpression is known to be particularly high (43-92%) in SDC, depending on histology, and has been identified as a potential molecular target for SGC treatment. However, the clinical utility of this approach has not been well investigated. Here, we evaluated the efficacy and safety of darolutamide for patients with AR-positive SGC. Methods: Eligibility included LA or R/M, SGC histologically confirmed positive for AR by the central laboratory; PS 0-1; adequate organ function; and no suitable local therapy. The study consists of two sequential components: a monotherapy part with darolutamide alone (monotherapy part) and a combination part with darolutamide and goserelin (combination part). Darolutamide was given orally at 1,200 mg daily until disease progression or unacceptable toxicity. Primary endpoint for the monotherapy part was overall response rate (ORR) as determined by the investigator. Secondary endpoints were ORR by independent central review (ICR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. (ClinicalTrials.gov NCT05694819). Results: From Mar 2020 to Jan 2021, 24 patients were enrolled in the monotherapy component. Median age was 64.6 years and 23 were male. ECOG PS was 0/1 in 18/6 cases. Pathological diagnosis was salivary duct carcinoma, adenocarcinoma NOS, and carcinoma ex pleomorphic adenoma in 16, 4 and 4 patients, respectively. ORR by investigator was 8.3% (90% CI 1.5–24.0) and ORR by ICR was 20.8% (95% CI 7.1–42.2). CBR and DCR were 41.7% (95% CI 22.1–63.4) and 58.3% (95% CI 36.6–77.9), respectably. Median PFS and OS were 5.7 months (95% CI, 1.9–15.2) and not reached (95% CI, 15.5–not estimable [NE]), respectively, with a median follow-up period of 19.1 months. Nine patients (37.5%) had grade 3 or 4 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: This is the first prospective trial of darolutamide for AR-positive SGC. The response rate by ICR and other secondary endpoints confirmed clinically meaningful activity and a well-tolerated safety profile. Patient enrollment to the combination component is now ongoing to evaluate additional benefits. Clinical trial information: NCT05694819 .
Monitoring epithelial, epithelial-mesenchymal, and mesenchymal circulating tumor cells on papillary thyroid cancer following thyroidectomy: A prospective cohort study.
Authors: Park Eunju , Yu Hyeong Won , Lee Seon Kyoung , Kong Ju Hyun , Sunoo Joseph , Hong Soon-Cheol , Choi June Young 
Published: June 2023

6097 Background: Monitoring the effectiveness of cancer-removal surgery is challenging in most cases. Therefore, robust and non-invasive techniques have been developed, and liquid biopsy is an apparent method for that purpose. In this prospective cohort study, we examined whether one type of liquid biopsy, an enumeration of circulating tumor cells (CTCs), can monitor the effectiveness of thyroidectomy in patients with papillary thyroid cancer (PTC). Methods: From January 2021 to January 2022, we recruited 62 PTC patients who had operated on isthmectomy, lobectomy, and total thyroidectomy for this study at Seoul National University Bundang Hospital. The blood samples from the recruited patients were collected before surgery and two weeks and three months after the surgery for CTC detection. We collected peripheral blood samples by venipuncture from each patient in EDTA tubes and stored them at 4°C until isolation and characterization of CTCs (within 6 hours). Results: We found the CTCs in 87% (54/62) of PTC patients, with an average number of 8.0. This number significantly decreased after thyroidectomy, with an average of 5.3 and 4.3 post-operation of two weeks and three months, respectively. In the peripheral blood of PTC patients, the CTCs with epithelial-mesenchymal and mesenchymal phenotypes were significantly more frequent than the epithelial phenotype of CTCs. Furthermore, PTC patients with lymphatic invasion, lymph node metastasis, or BRAF V600E mutation showed significantly decreased CTC count after surgery. Conclusions: PTC patients had a significantly higher number of CTCs undergoing epithelial-mesenchymal transition and showed a significant decrease in CTC count after surgery. This indicates that liquid biopsy using CTC enumeration can satisfy the purpose of monitoring the effectiveness of cancer-removal surgery. Clinical trial information: KCT0008179.
Social determinants of health and utilization of neoadjuvant chemotherapy in patients with triple negative breast cancer (TNBC) in the community oncology setting.
Authors: Danso Michael A. , Dye Joseph , Leong Traci , Reid Robert Lawrence , Kidd Angel , Espirito Janet L. , Robert Nicholas J. 
Published: June 2023

610 Background: TNBC has a higher incidence in African American women compared to European American, often presents at a younger age or more advanced stage, and is associated with worse outcomes. The use of multi-agent neoadjuvant chemotherapy (NC) improves event-free survival and overall survival in patients with early-stage TNBC and is considered standard of care. Race and other social determinants of health (SDOH) have been shown to affect outcomes in patients with TNBC. Differences in use of NC associated with SDOH may be a contributing factor to inferior outcomes. The aim of this study is to determine if SDOH measures affect utilization of NC in patients with early-stage TNBC. Methods: This retrospective observational cross-sectional study examined patient profiles, treatment patterns and SDOH indicators among patients newly diagnosed with early-stage breast cancer in The US Oncology Network. Using iKnowMed EHR data, patients diagnosed with TNBC between 03/31/2017 and 09/30/2021 with stages II-IIIB disease or tumor size ≥2cm (T2 or higher) were included. The initial TNBC diagnosis date was used as the index date for each patient and records were assessed from 6 months pre- to 6 months post-diagnosis for NC initiation, baseline characteristics, and social determinants, including Area Deprivation Index (ADI), a validated measure of socioeconomic status. Results: 3321 patients with TNBC were identified, with a mean age of 58 years; 59% were White, 15% Black, 3% Asian, and 23% other/unknown; and 2139 (64%) received NC. Patients who received NC relative to those who did not were younger (mean 55.9 vs 61.8; p=0.001), had higher BMIs (70% with BMI>25 vs ≤25, p=0.045), and had commercial or Medicaid insurance (67.5% with commercial insurance or Medicaid vs. 52.5% with Medicare; p=0.001). Regional differences were observed, with proportionally fewer patients receiving neoadjuvant chemotherapy in the south US census regions and more in the west. There was no difference in NC use in Black vs White patients (66% vs 64%). No significant differences in receipt of NC were found for race, ethnicity, or ADI. Conclusions: In the community oncology setting, we did not observe inequities in the use of NC based on social determinants analyzed in this study, such as race, ethnicity, and ADI. Poorer outcomes observed in Black patients with TNBC may not be a result of underutilization of NC.