bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of nimotuzumab added to concurrent chemoradiotherapy after induction chemotherapy for patients with locally advanced nasopharyngeal carcinoma.
Authors: Wu Sangang , Wang Runjie , Yu Yifeng , Zhou Ping , Lian Chenlu , Wang Jun , Lin Qin 
Published: June 2024

6024 Background: To investigate the efficacy and toxicities associated with adding nimotuzumab to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LANPC) patients who received induction chemotherapy (IC). Methods: Patients with stage III-IVA nasopharyngeal carcinoma who received IC (TPF/TP/GP) and platinum-based CCRT between January 2017 and October 2021 were retrospectively included. We performed propensity score matching (PSM) to balance and control confounding factors, and the matching variables included gender, age, T stage, N stage, and Epstein-Barr virus (EBV) status. Patients were divided into two treatment groups: CCRT+nimotuzumab (200mg iv, weekly for 7 courses) and CCRT alone. Primary endpoints were overall survival (OS) and disease-free survival (DFS), the secondary endpoints were locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Results: We screened 242 patients in the analysis. After PSM, 121 (50.0%) and 121 (50.0%) had CCRT+nimotuzumab and CCRT alone, respectively. The 3-year OS was 95.4% and 88.0% in those with and without nimotuzumab treatment (P=0.041), and the 3-year DFS of the CCRT+nimotuzumab group was significantly better than that in the CCRT alone group (90.3% vs. 77.5%, P=0.003). Similar LRFS was found between those with and without nimotuzumab treatment (96.5% vs. 93.7%, P=0.297). The 3-year DMFS for CCRT+nimotuzumab versus CCRT alone was 92.9% versus 82.5% (P=0.008). No significant differences in major toxicities were found between the two treatment arms including hematologic toxicities, hepatoxicity, nephrotoxicity, gastrointestinal reactions, and mucositis (P>0.05). Conclusions: The addition of nimotuzumab to CCRT after IC in LANPC has shown promising results in treatment outcomes and acceptable toxicities.
The combination of patient-specific tumor and HPV sequencing to enable high-sensitivity detection of ctDNA in patients with HPV-associated oropharyngeal carcinoma.
Authors: Diplas Bill , Brown David N , Pei Xin , Chen Linda , Graybill Chiharu , Korn W. Michael , Westheimer Emily , Novaj Ardijana , Humm John , Shukla-Dave Amita , Schöder Heiko , Katabi Nora , Sherman Eric Jeffrey , Reis-Filho Jorge , Weigelt Britta , LEE NANCY Y. , Riaz Nadeem 
Published: June 2024

6058 Background: Detection of Human papillomavirus (HPV) in plasma has been used to monitor treatment response in HPV-associated oropharyngeal carcinoma (OPC) but was found to have limited sensitivity in patients with low disease burden. We hypothesized that the combined detection of personalized tumor-specific alterations and HPV could provide a more sensitive approach for detecting circulating tumor DNA (ctDNA) and for disease monitoring in early-stage HPV-associated OPC patients. Methods: Patients with HPV-associated OPC (T0-2/N1-N2c) enrolled in a phase II chemoradiation (CRT) de-escalation trial (NCT03323563) were chosen for this study. The patients underwent resection of the primary tumor prior to CRT and a baseline plasma was drawn at this time. Additional plasma samples were collected weekly throughout CRT. Whole-exome and targeted HPV sequencing was performed on the primary resection to build a dictionary of somatic variants and for HPV typing, respectively. A dual PCM-HPV assay was developed based on the Invitae Personalized Cancer MonitoringTM (PCM) platform and used to evaluate the plasma samples. Tumor volume was measured by T2 MRI using a region of interest outlining the largest lymph node in the undissected neck. Results: 158 patients with T0-2/N1-N2c HPV-OPC were enrolled on the trial and the dual PCM-HPV assay was successfully designed for 111 patients targeting a median of 50 patient-specific mutations (range: 26-50). Preliminary analyses were performed on 71/111 patients (64.0%) with HPV16-associated tumors and available baseline plasma. 64/71 (90.1%) and 61/71 (85.9%) were ctDNA positive by PCM testing and HPV testing alone, respectively. Combining HPV plasma testing with PCM (PCM-HPV) improved the sensitivity to 68/71 (95.7%). This increased sensitivity was maintained when analyzing plasma samples collected weekly following CRT. The 3 patients with double negative HPV and PCM results at baseline had a lower tumor volume (p=0.05) and lower levels of genome instability (p=0.02) than those with ctDNA or PCM positive baseline plasma. HPV cfDNA levels are weakly correlated with tumor HPV genome copy number (r=0.16; p=0.001). Conclusions: The combined detection of personalized tumor-specific alterations and HPV provides a highly sensitive approach for detecting low disease burden in early stage HPV-associated OPC patients before and during treatment. [Table: see text]
Genomic and immune profiling of rare non-squamous sinonasal tumors.
Authors: Steuer Conor Ernst , Lubin Daniel , Adeyelu Tolulope Tosin , Bates James Edward , Shin Dong Moon , Patel Mihir R. , Schmitt Nicole C. , Stokes William A. , Bracken-Clarke Dara Mark , Abdulla Farah R. , Floudas Charalampos S. , Oberley Matthew James , Johnson Jennifer Maria , Wise-Draper Trisha Michel , Posner Marshall R. , Saba Nabil F. 
Published: June 2024

e18008 Background: Sinonasal tumors (SNT) are rare tumors and make up less than 3% of all head and neck malignancies. The majority of SNTs have squamous cell histology and less common histologies remain understudied. We present a comprehensive analysis of genomic and immune profiles of rare SNTs that can help identify avenues for prognostic biomarkers and future targeted treatments. Methods: Non-squamous SNT samples (n =124) were profiled through Next Generation Sequencing (NGS) of DNA (592-genes; NextSeq or WES; NovaSeq) and RNA (WTS; NovaSeq) at Caris Life Sciences (Phoenix, AZ). Centralized pathology review was carried out to confirm histological subtypes. PD-L1 expression was tested by IHC (22c3, positive (+) >=1%; SP142, positive (2+)/ >=5%). Deficient mismatch repair/microsatellite instability (dMMR/MSI-H) was accessed by IHC/NGS. Immune cell fraction of the tumor microenvironment (TME) was estimated by quanTIseq, and gene expression profiles (transcript per million, TPM) were analyzed for transcriptional signatures predictive of response to immunotherapy. Mann-Whitney U and ChiSquare/Fisher-Exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Results: Non-squamous SNT samples included 35.5% (n = 44) adenoid cystic (ACC), 19.4% (n = 24) adenocarcinoma (AD), 10.5% (n = 13) undifferentiated carcinomas (SNUC), and 34.6% (n = 43) Esthesio/Olfactory Neuroblastomas (ENB). Notably, molecular features associated with each histological subtype are reported in the table. Furthermore, analysis of the inferred immune infiltrates showed that ENB had significantly higher fractions of NK cells (ACC: 5.6% vs AD: 4.6% vs SNUC: 4.4% vs ENB:10.5%, p <0.00001), CD8 T cells (0.1% vs 0.88% vs 0.22% vs 1%, p < 0.0001), CD4 T cells (0.4% vs 1.9% vs 0.03% vs 3.6%, p < 0.00001) and dendritic cells (4.5% vs 3.4% vs 2.6% vs 7.3%, p<0.00001) compared to the other sinonasal tumors. M1 macrophage (ACC: 2.6% vs AD: 1.9% vs SNUC: 1.1% vs ENB: 1.1%, p = 0.047) and Treg fractions (ACC: 2.0% vs AD: 1.6% vs SNUC: 1.2% vs ENB: 0.6%, p<0.00001) were significantly higher in ACC. There was also significantly increased expression of immune checkpoint genes in ENB compared to AD ( PD-1: 0.8 vs 0.5 TPM, p = 0.022) and in ENB compared to ACC ( HAVCR2: 3.4 vs 2.9 TPM, p = 0.047). Conclusions: To our knowledge, this is the largest study characterizing the genomic and immune alterations in non-squamous SNTs. Our findings offer potential for future targeted and immune therapeutic applications in these rare diseases. [Table: see text]
Economic evaluation of the novel PD-1 inhibitor toripalimab in recurrent or metastatic nasopharyngeal carcinoma: Cost-efficiency and expanded access modeling versus pembrolizumab.
Authors: Abraham Ivo , Pondel Marc , MacDonald Karen 
Published: June 2024

e18015 Background: Toripalimab, a novel anti-PD-1 antibody recently approved in the US as a breakthrough therapy in combination with gemcitabine and cisplatin (GemCis) for first-line treatment of adults with metastatic or recurrent locally advanced nasopharyngeal carcinoma (R/M NPC), is a category 1, NCCN-recommended preferred regimen. Although not FDA-approved for this indication, other PD-1 inhibitors, including pembrolizumab, are NCCN-recommended in combination with GemCis (category 2A but without direct evidence). The wholesale acquisition cost (WAC) of toripalimab at market entry is 80% that of pembrolizumab. This simulation modeling evaluates the cost-efficiency of toripalimab+GemCis versus pembrolizumab+GemCis in R/M NPC and the budget-neutral expanded access to the toripalimab regimen enabled by savings. Methods: Utilizing WAC drug costs and treatment administration costs, we modeled the cost-efficiency over a treatment duration equivalent to the toripalimab JUPITER-02 trial median PFS of 21.4 months (m). Without trial evidence for pembrolizumab+GemCis in R/M NPC, we assumed that such a regimen would be comparable to toripalimab+GemCis in median PFS. We also assumed that 31 cycles of PD-1 inhibitor (with GemCis in cycles 1-6) are administered over a median PFS of 21.4m. Using the cost-efficiency savings, we simulated the potential for budget-neutral expanded access to toripalimab treatment. A second model utilizing an ex ante toripalimab average sales price (ASP) of 80% of pembrolizumab ASP was estimated. Results: The WAC model estimated the toripalimab regimen to cost $292,316 (all agents over 21.4m or 31 cycles) while the pembrolizumab regimen costs $361,229, for savings of $68,913 per patient. These savings enable 7.7 additional toripalimab maintenance cycles to be purchased on a budget-neutral basis for every patient treated. For every 4.24 patients treated with toripalimab+GemCis instead of pembrolizumab+GemCis, one additional patient can be treated with the full toripalimab regimen (all agents) for 21.4m. Extrapolated to the 2024 US incident R/M NPC population of 1207 patients, if 50% of patients are treated with toripalimab+GemCis instead of pembrolizumab+GemCis savings of $41,589,183 provide access to 4,513 additional toripalimab maintenance cycles or 142 full toripalimab regimens (all agents for 21.4m) budget-neutrally. Similar results were demonstrated in the ASP model. Conclusions: With a market entry WAC that is 20% lower than pembrolizumab, toripalimab can generate approximate savings of $69,000 per patient over the median PFS treatment duration of 21.4m. If 50% of R/M NPC incident patients are treated with toripalimab, savings provide access to the full toripalimab+GemCis regimen to an additional 142 patients—effectively raising the treatment rate to 62% at no additional cost.
METTL3 as a potential predictive biomarker for immunotherapy response in metastatic head and neck cancer.
Authors: Arumugam Paramasivam , Jayaseelan Vijayashree Priyadharsini , Ramasubramanian Abilasha 
Published: June 2024

e18019 Background: Head and neck squamous cell carcinoma (HNSCC) that has metastasized presents a significant challenge for cancer treatment, requiring innovative approaches to predict immunotherapy response. Methyltransferase-like 3 (METTL3), a key component of the m6A RNA methylation machinery, has been shown to have various roles in cancer, including its potential impact on immunotherapy responses. In this study, we aim to explore the expression and related function of METTL3 in metastatic HNSCC. Methods: We investigated the expression level and its clinicopathological significance of METTL3 using The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) datasets. Further validation of the METTL3 mRNA and protein expression were carried out with real-time PCR and Western blot on tissues from 112 cases of HNSCC patients. In addition, the functional role of METTL3 was investigated in vitro studies. The treatment response prediction values of METTL3 in metastatic HNSCC were calculated using ROC-plotter. Results: Our investigation revealed a significant overexpression of METTL3 in HNSCC tissue samples than in normal tissues ( p < 0.001). The high expression of METTL3 was significantly correlated with nodal metastasis, advanced cancer stages, and higher tumor grades in HNSCC samples, indicating that METTL3 plays an important role in driving HNSCC progression and aggressiveness. The functional study revealed intricate connections between METTL3 and immune regulatory genes expression, highlighting its potential to influence the tumor immune microenvironment. Silencing or pharmacological inhibition of METTL3 by METTL3 inhibitor STM2457 reduced tumorigenic activity through decreasing PD-L1 expression. ROC-plotter calculations showed that the high METTL3 expression predicted powerful immunotherapy (AUC=0.588, p=6.3e-06) in metastatic HNSCC patients. Conclusions: In conclusion, METTL3 appears to be a promising predictive biomarker for the response to immunotherapy in patients with metastatic HNSCC. This research provides valuable insights into the multifaceted role of METTL3 and promising therapeutic response predictor in metastatic HNSCC.
A phase II umbrella clinical trial of advanced salivary gland cancer based on molecular typing.
Authors: Ji Dongmei , Guo Yanjing , Liu Xin , Yang Yanan , Sang Youzhou , Chen Guangliang , Dong Shu , Wang Yulong , He Xiayun , Ying Hongmei , Lu Xueguan , Wang Yu , Hu Chaosu , Ji Qinghai , Zhang Lu 
Published: June 2024

e18062 Background: Salivary gland cancers (SGCs) exhibit high heterogeneity in molecular and genomic characteristics, which provides a basis for targeted therapies of SGCs. Until recently, the gene targets of precision therapy drugs mainly included HER2, NTRK, TROP2, androgen-receptor (AR), etc. Herein, we report the preliminary result of a single-center, open-label, phase II umbrella clinical trial evaluating the efficacy and safety of molecular subtype-guided precision therapy for advanced salivary gland cancer (NCT05924256). Methods: Patients (pts) diagnosed as advanced SGC were recruited into 3 arms according to genetic subtypes. Pts with HER2 mutation/amplification or HER2 overexpression (IHC 3+ or IHC 2+/ISH+) will be assigned to arm 1 and receive SHR-A1811(anti-HER2) 4.8 mg/kg i.v. on day 1 of each 21-day cycle. IHC AR+ pts will be assigned to arm 2 and will receive rezvilutamide 240mg p.o. qd plus leuprolide 3.75mg s.c. on day 1 of each 28-day cycle. Pts with HER2 negative and AR negative will be assigned to arm 3 to receive SHR-A1921(anti-TROP2) 3.0 mg/kg or 4.0 mg/kg i.v. on day 1 of each 21-day cycle. A Simon’s two-stage optimal design was applied to each arm. The primary endpoint was the objective response rate (ORR) per RECIST1.1. Secondary endpoints included adverse events (AEs), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), etc. Results: Between Aug 2, 2023, and Jan 21, 2024, 21 pts were enrolled (arm 1/2/3: 9/5/7 pts, respectively). All pts were included in the safety set. In arm 1, of 6 evaluable pts, the unconfirmed ORR and DCR accounted for 100.0% and 100.0%, respectively. The most common treatment-related adverse events (TRAEs) in arm 1 were decreased lymphocyte count, neutrophil count, and decreased appetite (44.4% each). In arm 2, of 5 evaluable pts, the unconfirmed ORR and DCR were 20.0% and 100.0%, respectively. Rash, alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased (20% each) were the most common TRAEs. In arm 3, of 6 evaluable pts, the unconfirmed ORR and DCR were 33.3% and 66.7%, respectively. In this arm, the most common TRAEs were stomatitis and vomiting (42.9% each). Conclusions: This molecular subtype-guided precision therapy for advanced salivary gland cancer showed promising results with acceptable toxicity. Clinical trial information: NCT05924256 .
A first-in-human phase 1, multicenter, open-label study of CB-012, a next-generation CRISPR-edited allogeneic anti-CLL-1 CAR-T cell therapy for adults with relapsed/refractory acute myeloid leukemia (AMpLify).
Authors: Daver Naval Guastad , Maiti Abhishek , Sallman David Andrew , Roboz Gail J. , Solh Melhem M. , Milano Filippo , Strickland Stephen Anthony , Eghtedar Alireza , Kanner Steven Brian , Ledergor Guy , Marcy Donna , Garner Elizabeth , Francica Brian J. , Shaw McKay , Bird Kalin , Rattan Jennifer , Zudaire Enrique , Portella Socorro , Vachhani Pankit , Park Jae H. 
Published: June 2024

TPS6586 Background: CAR-T cell therapies have shown significant clinical benefit in treating adults with many hematologic malignancies. In acute myeloid leukemia (AML), a challenge in the development of CAR-T cell therapies has been the limitation of suitable target antigens since many are also expressed on hematopoietic stem cells (HSCs). The target antigen C-type lectin-like molecule-1 (CLL-1) has emerged as an attractive therapeutic target due to its expression on AML mature blasts and leukemic stem cells and its absence on HSCs. CB-012 is an allogeneic CAR-T cell therapy that targets CLL-1. CB-012 is derived from healthy donor T cells by using Cas12a CRISPR hybrid RNA-DNA (chRDNA) technology to introduce 5 genome edits: (1) TRAC gene knockout (KO), which eliminates T cell receptor expression to reduce the risk of graft-versus-host disease, (2) site-directed insertion of a fully human anti-CLL-1 CAR into the TRAC locus, (3) KO of PD-1 to enhance antitumor activity by reducing T cell exhaustion, (4) β2-microgobulin ( B 2M) gene KO, which eliminates HLA class I presentation to mitigate host T cell-mediated rejection, and (5) site-directed insertion of a B2M–HLA-E-peptide fusion into the B 2M locus to reduce NK cell-mediated rejection. In murine xenograft models of AML, CB-012 significantly reduced the tumor burden and increased the survival of mice bearing CLL-1+PD-L1+ tumors. Methods: CB-012 is being evaluated in a multicenter, Phase 1 clinical trial in patients with relapsed/refractory (r/r) AML. A 3+3 dose escalation design is being utilized with the primary objectives to determine the safety and tolerability of CB-012 and the recommended Phase 2 dose (RP2D). An expansion phase will follow dose escalation at the recommended dose(s) for expansion. Additional objectives include preliminary antitumor activity and pharmacokinetics. Key inclusion criteria include nonproliferative disease defined as ≤25% blasts in the bone marrow and peripheral blood, ECOG performance status ≤1, and adequate organ function. After receiving lymphodepletion therapy with cyclophosphamide (750 mg/m2/d) and fludarabine (30 mg/m2/d) administered concurrently for 3 days followed by a 2-day break, patients receive a single-dose infusion of CB-012 and are followed for safety and efficacy. The dose escalation portion of the study is actively enrolling patients. The AMpLify trial is registered at clinicaltrials.gov (NCT06128044). Clinical trial information: NCT06128044 .
Time Toxicity Experienced by Early-Phase Cancer Clinical Trial Participants
Authors: Durbin Sienna M. , Lundquist Debra M. , Pelletier Andrea , Jimenez Rachel , Petrillo Laura , Kim Janice , Lynch Kaitlyn , Healy Megan , Johnson Andrew , Ollila Nicholas , Yalala Vaishnavi , Malowitz Benjamin , Kehlmann Allison , Chevalier Nicholas , Turbini Victoria , Bame Viola , Heldreth Hope , Silva Jenipher , McIntyre Casandra , Juric Dejan , Nipp Ryan D. 
Published: June 2024

PURPOSE Early-phase clinical trials (EP-CTs) are designed to determine optimal dosing, tolerability, and preliminary activity of novel cancer therapeutics. Little is known about the time that patients spend interacting with the health care system (eg, time toxicity) while participating in these studies. METHODS We retrospectively reviewed the electronic health records of consecutive patients enrolled in EP-CTs from 2017 to 2019 to obtain baseline characteristics and number of health care–associated days, defined as all inpatient and outpatient visits while on trial. We used univariable and multivariable analyses to identify predictors of increased time toxicity, defined as the proportion of health care–associated days among total days on trial. For ease of interpretation, we created a dichotomous variable, with high time toxicity defined as ≥20% health care–associated days during time on trial and used regression models to evaluate relationships between time toxicity and clinical outcomes. RESULTS Among 408 EP-CT participants (mean age, 60.5 years [standard deviation, SD, 12.6]; 56.5% female; 88.2% White; 96.0% non-Hispanic), patients had an average of 22.5% health care–associated days while on trial (SD, 13.8%). Those with GI ( B = 0.07; P = .002), head/neck ( B = 0.09; P = .004), and breast ( B = 0.06; P = .015) cancers and those with worse performance status ( B = 0.04; P = .017) and those receiving targeted therapies ( B = 0.04; P = .014) experienced higher time toxicity. High time toxicity was associated with decreased disease response rates (odds ratio, 0.07; P < .001), progression-free survival (hazard ratio [HR], 2.10; P < .001), and overall survival (HR, 2.16; P < .001). CONCLUSION In this cohort of EP-CT participants, patients spent more than one-fifth of days on trial with health care contact. We identified characteristics associated with higher time toxicity and found that high toxicity correlated with worse clinical outcomes. These data could help inform patient-clinician discussions about EP-CTs, guide future trial design, and identify at-risk patients.
Respect for the Patient-Oncologist Relationship May Limit Serious Illness Communication by Acute and Postacute Care Clinicians After Discharge to a Skilled Nursing Facility
Authors: Singh Sarguni , Dafoe Ashley , Cagle John , Messersmith Wells A. , Kessler Elizabeth R. , Lum Hillary D. , Holliman Brooke Dorsey , Fischer Stacy 
Published: June 2024

PURPOSE
There is a need to increase palliative care access for hospitalized older adults with cancer discharged to a skilled nursing facility (SNF) at risk of poor outcomes. Assessing and Listening to Individual Goals and Needs (ALIGN) is a palliative care intervention developed to address this gap. This study gathered perspectives from clinicians across care settings to describe perceptions on serious illness communication and care coordination for patients with cancer after discharge to a SNF to guide ALIGN refinements.

METHODS
We conducted 37 semistructured interviews with clinicians and leaders in hospital medicine (n = 12), oncology (n = 9), palliative care (n = 12), home health care (n = 6), and hospice (n = 4). Some participants had experience working in more than one specialty. The Practical Robust Implementation and Sustainability Model framework was used to develop the interview guide that explored barriers to care, prognosis discussions, and hospice recommendations. Interviews were coded and analyzed using thematic content analysis.

RESULTS
Analysis identified four themes: (1) discharge to a SNF is recognized as a time of worsening prognosis; (2) care silos create communication and information barriers during a period of increasing palliative care need; (3) family caregiver distress escalates following care transitions; and (4) lack of clarity of roles and respect for the patient-oncologist relationship limits prognostic communication and changes in focus of treatment.

CONCLUSION
These findings suggest that acute and postacute care clinicians defer serious illness conversations to the oncologist when patients are on a steep trajectory of decline, experiencing multiple care transitions, and may have limited contact with their oncologist. There is a need to clarify roles among nononcology and oncology clinicians in discussing prognosis and recommending hospice for older adults discharged to SNF.