bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ex ante budget impact analysis (BIA) of PD-1 inhibitor toripalimab plus gemcitabine-cisplatin (T+GC) versus a simulated pembrolizumab regimen in first line (1L) treatment of recurrent or metastatic nasopharyngeal cancer (rmNPC).
Authors: Abraham Ivo , Geller Robert B. , Walden Paul D. , MacDonald Karen 
Published: June 2022

e18024 Background: Interim results of the JUPITER-02 randomized double-blind phase 3 trial demonstrated a PFS benefit for T+GC (11.7 m) vs placebo+GC (8m) in 1L treatment of rmNPC. The KEYNOTE-028 nonrandomized (single group assignment) phase 1b trial showed the potential benefit of pembrolizumab in previously treated NPC. The trials were not comparable in population and design, precluding a direct comparison. We performed an ex ante BIA comparing T+GC to a simulated pembrolizumab+GC (sP+GC) regimen under an assumed equivalence in efficacy and safety. Methods: An ex ante budget impact model (budget holder perspective; accrual approach) compared a treatment mix “without” T+GC (only sP+GC) to one “with” T+GC in an annual incident US population of 1200 patients (year 1), a 5y time horizon, and a fixed 50/50 market share split. Population adjustments were for discontinuation, death, and progression with corresponding medication adjustments to estimate fully treated patient equivalents. Cost inputs included: drugs (average sales price), drug administration, and grade 3/4 adverse event (AE) management. Three scenarios were modeled: toripalimab priced at 70%, 80% and 90% of pembrolizumab. Results: In the “without” scenario, the 5y costs of sP+GC treatment totaled $2,062,509,042 and the 5y cost of managing AEs $210,382,926, for a total of $2,272,891,967. In the “with” scenario at 50% market share, the corresponding 5y costs for sP+GC declined to $1,031,254,521 for treatment and $105,191,463 in AE costs, for a total of $1,136,445,984. The corresponding costs for T+GC priced at 70%, 80%, 90% of pembrolizumab were $746,834,887, $841,641,432 and $936,447,976 (treatment) and $105,191,463 (AE management), for 5y gross budget impacts of $852,026,350, $946,832,895 and $1,041,639,439. Net savings “with” T+GC were $49,331,430, $32,887,620 and $16,443,810 in 2022 rising to $64,974,264, $43,316,176 and $21,658,088 by 2026. The total 5y net budget impact of adding T+GC to the treatment mix totaled $284,419,634, $189,613,089 and $94,806,545 in savings. Conclusions: Citing the findings from the JUPITER-02 trial of T+GC, regimens including a PD-1 inhibitor, gemcitabine and cisplatin are now a NCCN category 2A recommendation for 1L treatment of rmNPC. This ex ante BIA demonstrates the substantial savings potential of toripalimab (at a discounted cost compared to pembrolizumab) in rmNPC. With forthcoming final JUPITER-02 data showing a PFS benefit of 21.4m, the value of an available, lower-priced and efficacious anti-PD1 agent is highly significant to patients, providers and payers in terms of both clinical efficacy and cost efficiency. Emerging data suggest that toripalimab may be effective in more frequently occurring tumor types and the savings from such expanded access are likely to be multifold.
Camrelizumab plus apatinib in patients with recurrent and/or metastatic nasopharyngeal carcinoma: A single-arm, multicenter, phase 2 trail.
Authors: Mo Yunyan , Pan Yufei , Zhang Bin , Zhang Jian , Liu Zhengchun , Luo Meiqing , Su Yixin , Jiang Wei 
Published: June 2022

e18025 Background: Our previous study demonstrated that apatinib has preliminary clinical benefit in recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC). Preclinical studies showed the combination of immune checkpoint inhibitors and antiangiogenic drugs produces a synergistic effect in anti-tumor activity. This phase 2 trail evaluated the efficacy and safety of camrelizumab combined with apatinib in patients with RM-NPC. Methods: In this study, patients with RM-NPC received 250 mg apatinib orally once per day plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed according to RECIST version 1.1. The key secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The study is registered with. Results: From January 14, 2021 to September 15, 2021, 26 patients with RM-NPC were enrolled in this clinical study with median follow-up duration of 8 months (range:4-12 months). The ORR was 38.5% (10/26), and the DCR was 61.5% (16/26). Median PFS (mPFS) was 6 months. Median OS was not reached. Of the 26 patients, 6 patients (23.1%) had treatment-related grade 3 or 4 adverse events, including anemia(7.7%), stomatitis(3.8%), headache(3.8%), pneumonia(3.8%) and myocarditis(3.8%). No treatment-related deaths occurred in this trial. Conclusions: Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with RM-NPC, and the mPFS by this combination regimen was longer than our previously reported mPFS by apatinib monotherapy. Larger randomized trials to evaluate this new combination strategy are warranted. Clinical trial information: NCT04350190. [Table: see text]
The predictive and prognostic value of weight loss and body composition prior to and during treatment with immune checkpoint inhibitors in patients with recurrent or metastatic head and neck cancer.
Authors: Willemsen Anna C. H. , De Moor Nina , Van Dessel Jeroen , Bila Michel , Baijens Laura W.J. , Hauben Esther , Van Den Hout Mari , Hoeben Ann , Clement Paul M. , Schols Annemie M.W.J. 
Published: June 2022

e18027 Background: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are relatively low. This study evaluates the predictive and prognostic value of weight loss and changes in body composition prior to and during ICI therapy in R/M HNSCC. Methods: This retrospective multicenter cohort study enrolled ninety-eight patients. Patient, tumor and treatment characteristics were retrieved from health records, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Cachexia was defined according to the international consensus (Fearon et al. 2011). Skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were evaluated on baseline and follow-up computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analysis were performed for six months progression free survival (PFS6m) and overall survival (OS). Results: Thirty-four patients (35%) experienced significant early weight loss (> 2%) during the first six weeks of therapy. This subgroup presented a significantly higher NLR and PLR at baseline. NLR and PLR were significantly correlated with VAT and SAT index. Independent predictors of PFS6m were lower world health organization performance status (WHO PS) (HR 0.16 [95% CI 0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [95% CI 1.02-1.08] p = 0.003), and early weight loss < 2% (HR 0.85 [95% CI 0.74-0.98] p = 0.03). WHO PS and baseline cachexia in combination with > 2% early weight loss were independent predictors of OS (HR 2.09 [95% CI 1.11-3.92] p = 0.02, HR 2.18 [95% CI 1.13-4.21] p = 0.02). Conclusions: The combination of cachexia at baseline and weight loss during the first six weeks of ICI therapy is associated with worse OS in HNSCC patients treated with ICI therapy. Patients with early weight loss during ICI treatment show an increase in systemic inflammation. The mechanism of how adipose tissue interferes with ICI response needs further investigation.
Improved laryngeal function after neoadjuvant therapy for advanced thyroid cancer: A potential outcome of interest for future clinical trials.
Authors: Abdelhamid Ahmed Amr Hesham , Silver Karcioglu Amanda , Feng Zipei , Shonka David C. , Iwata Ayaka J. , Cabanillas Maria E. , Wirth Lori J. , Zafereo Mark E. , Randolph Gregory W. 
Published: June 2022

e18030 Background: Advanced thyroid cancers can invade the recurrent Laryngeal Nerve (RLN) resulting in vocal cord paralysis (VCP). This can significantly impact the surgical strategy given the need to sacrifice the invaded RLN, the potential for bilateral VCP and tracheotomy. Methods: We retrospectively identified patients diagnosed with advanced thyroid carcinomas (of any histology) at 3 high-volume tertiary centers who met the following criteria: treated between 01/2017 and 12/2022, tested for driver/targetable somatic mutations, received targeted neoadjuvant therapy, underwent laryngoscopic exam to assess vocal cords (VC) functional status before, during and after neoadjuvant therapy, and underwent surgery. Results: We identified 6 patients who met the eligibility criteria. Mean age at diagnosis is 69. Five patients were diagnosed with anaplastic thyroid carcinoma, while 1 with papillary thyroid carcinoma. Somatic mutations were detected in BRAFV600E in 6 patients (100%), TERT promoter in 3 (50%) and in PIK3CA & TP53 in 2 patients each (33%). Five patients received dabrafenib/trametinib & 1 patient received lenvatinib. One patient received radiotherapy before neoadjuvant therapy. Baseline laryngoscopic exam detected 5 left-sided VCP and 1 right-sided VCP. After neoadjuvant therapy, 4 patients (67%) regained VC function after 3 months of therapy. By 13.5 months, all patients (100%) regained normal VC function, with a mean time-to-return of VC function of 5 months. The affected RLN could be surgically spared in 5 patients (83%). Conclusions: Use of neoadjuvant targeted therapy resulted in return of VC function in all patients after initially abnormal laryngeal exams, with 67% of patients showing return of function after 3 months. Additionally, neoadjuvant therapy resulted in tumor response sufficient to spare 5 RLNs from surgical resection (83%). Serial laryngoscopic exams during neoadjuvant therapy could guide surgical strategy, impact surgical timing, and provide an additional meaningful treatment outcome. VC function could be used as an endpoint in future neoadjuvant trials. Potential limitations include tertiary center referral bias and selection bias (patients who met eligibility criteria may have favorable trajectory, while patients with aggressive disease who didn’t respond to therapy were excluded). Clinical trials are undergoing to further validate our results. [Table: see text]
Induction chemotherapy using carboplatin and paclitaxel followed by hypofractionated radiation therapy in locally advanced hypopharyngeal and laryngeal squamous cell cancer.
Authors: Abdullah Famya , Adil Allah Rakha , Akhtar Muhammad Saeed , Quraishi Arif Moin , Hashmi Quratul Ain , Sattar Amir , Sanwal Isharat Shehrood , Mateen Abdul 
Published: June 2022

e18039 Background: Head and neck cancer (HNC) is one of the most common cancers in Pakistan due to excessive use of chewable tobacco. Locoregional control is not optimum due to advanced stage at presentation and suboptimal cancer treatment facilities. Innovations in treatment schedules are of utmost importance to tackle the problem of overburden of patients and shortage of resources for radiation therapy in the country. The aim of the study is to assess the efficacy of induction chemotherapy with carboplatin and paclitaxel (CP) followed by hypofractionated radiotherapy (HRT) in patients with locally advanced laryngeal and hypopharyngeal cancers. Methods: A total of 68 patients with biopsy proven HNC were included. Patients having primary tumor in larynx (35) and hypopharynx (33) with TNM stage III to IVB were selected. The patients were planned for three cycles of CP every three weeks in a dose of AUC = 5 and 175 mg/m² on day 1 of each cycle respectively. After three cycles of chemotherapy, patients were planned for hypofractionated radiotherapy (HRT). A total of 55 Gray (Gy) was planned with 2.75 Gy per fraction and five fractions a week. Spinal cord dose was limited to 33 Gy. Response Evaluation Criteria in Solid Tumor (RECIST) was used to assess various response rates using computed tomography (CT) six weeks after completion of HRT. Patients were followed for a median of 27.4 months to assess disease free survival (DFS) and overall survival (OS). Results: 61 patients (90%) were available for assessment. Others were excluded due to inability to complete the planned treatment. Eight patients (12%) showed disease progression during treatment and were switched to other form of treatment. Seven patients (10%) showed grade 3 mucosal toxicity and needed treatment interruption. Thirteen patients (19%) showed hematological related grade 1-2 toxicity. The complete response (CR) was seen in 18 (35%), partial response (PR) in 27 (52%) and stable disease SD in 7 (13%) patients. Three year DFS and OS were 45% and 58% respectively. Mean and median DFS (year) were 3.67±0.13 (95% confidence interval [CI] 3.19-3.94) and 4.24±0.43 (CI 3.46-4.52) respectively. Mean and median OS (year) were 3.89±0.11 (CI 3.72-4.15) and 4.12±0.23 (CI 3.87-4.38) respectively. Conclusions: Induction CP followed by HRT is a reasonable in locally advanced laryngeal and hypopharyngeal cancer. A larger phase III randomized trial will be better to define its role before routinely recommending this schedule in these patients.
Cytokine-induced memory-like (CIML) NK cells and association with circulating immune microenvironment.
Authors: Xiao Shanshan , Fan Tongqiang , Wang Qian , Wang Tao ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e18042 Background: Cytokine-induced memory-like (CIML) NK cells are attractive for adoptive cell therapeutic approaches due to their key characteristics which include anti-tumor responses, prolonged proliferation and persistence in vivo. Several NK cell subsets have been reported in human and mice, but their heterogeneity and trajectories in human peripheral blood remains poorly characterized. We aimed to evaluate the developmental trajectories and prognosis outcomes of several CIML NK subsets between HPV+ and HPV- HNSC patients. Methods: A publicly available scRNA-seq dataset (only CD45+PBMC data sets were used) (Kürten et al., 2021) was obtained and stratified by two definitions of CIML NKs: (1) increased granzyme B mRNA expression and (2) preactivated with iterleukin-12 (IL-12), IL-15 and IL-18. Single-cell analysis was performed, followed by sub-clustering of NK populations. Results: 4,794 NK cells from 6 HPV+ and 11 HPV- HNSC patients were analyzed in our study. Expression profiles showed that these NK cells were CD56dimCD16+CD57-NKs. Further investigation showed that these cell populations exhibit a cytokine-induced memory-like phenotype, including increased granzyme B mRNA and preactivated with IL-12, IL-15 and IL-18. Transcriptomic profiles demonstrated that CIML NK cells can be classified into three subsets, including Bl1, Bl2, and Bl3, where Bl1 and Bl3 were found to be consistent with the previous studies, Bl2 was a newly identified NK cluster in this study. Pseudotime analyses suggested that CIML NK cells transitioned from Bl3 (is in cytolytic state) to Bl2, and then (maintains intermediate cell states) to Bl1 (supports cytotoxic activity), regardless of HPV status. There were 20, 60, and 26 Up-regulated genes in Bl, Bl2, and Bl3 in HPV+ patient compared to HPV- patients, respectively. Biocarta pathway analyses showed that NK cell pathway was highly enriched in all NK subsets from HPV+ patients, instead of HPV- patients, indicating a developmental independent characteristic. Survival analyses showed poor prognosis outcomes for high expressed CIML NK signatures in no matter HPV+ or HPV- patients. Conclusions: We investigated CIML NK cells in human peripheral blood and found that Bl1, Bl2, and Bl3 NK clusters showing the developmental patterns of increased cytotoxicity independent of HPV status. The Bl2 is a novel NK cell cluster which presents intermediate cell states. The cluster signatures were correlated with poor clinical outcomes, highlighting its’ potential clinical values for CIML NK-targeted immunotherapies.
Spatial transcriptomics unravels novel signaling patterns at the leading edge of oral squamous cell carcinoma.
Authors: Arora Rohit , Cao Christian , Kumar Mehul , Chanda Ayan , Samuel Divya , Matthews Wayne , Chandarana Shamir , Hart Robert , Dort Joseph C. , Hyrcza Martin , Bose Pinaki 
Published: June 2022

e18043 Background: Head and neck cancer is the 6th most common cancer worldwide. Oral squamous cell carcinoma (OSCC) is the most prevalent head and neck cancer that is characterized by aggressive local invasion and metastasis. Despite the leading edge (invasive front) of the tumor being a driver of OSCC pathophysiology, its biology and clinical relevance have not been fully characterized. We used spatial transcriptomics to explore signaling patterns within the leading edge and tumor core. Methods: Fresh-frozen, surgically resected OSCC samples from three HPV-negative OSCC patients were profiled using the 10x Genomics Visium Spatial Gene Expression platform. Leading edge and tumor core regions were defined by pathologist annotations and expression of previously identified edge and core gene signatures from the literature. Spatial differential gene expression (DGE) analysis and pathway analysis was performed using the Seurat package and Ingenuity Pathway Analysis (IPA), respectively. Cell-cell interaction networks were reconstructed using the CellChat package. Results: The leading edge and tumor core displayed unique transcriptional and signaling profiles that were conserved across all three OSCC patient samples. DEG analysis revealed 31 genes enriched in the leading edge and 62 genes enriched in the tumor core with a log2FC > 0.58 and adjusted p-value < 0.01. The top genes upregulated in the leading edge were FN1, COL1A1, COL1A2, IFITM3, and SPARC. Top tumor-core genes included CRCT1, LCE3D, DEFB4A, SPRR2A, and CNFN. IPA analysis of upregulated DEGs in the leading edge and tumor core predicted the activation of wound healing and GP6 signaling pathways, and activation of intrinsic prothrombin activation and MSP-RON signaling pathways, respectively. Cell communication analysis revealed that the leading edge had higher intercellular signaling than the tumor core. Upregulated leading edge cell signaling modules included collagen, CD99, CSPG4, and non-canonical WNT pathways, which have been linked to tumor invasion, metastasis, and adhesion. COL1A1 and COL1A2 ligands and CD44 and SDC1 receptors were upregulated in leading edge signaling. The tumor core was enriched for ANGPTL and PERIOSTIN cell signaling modules. Conclusions: This is the first study to characterize the tumor core and leading edge of OSCC tumors using spatial transcriptomics. Further investigation of the therapeutic potential of identified signaling pathways may improve OSCC outcomes.
Tumor mutation burden (TMB) and Notch1 gene alteration are associated with short disease-free survival in early laryngocarcinoma.
Authors: Chen Xi , Gong Xiao-yang , Chen Hai-bing , Chen Dong-sheng , Zhao Lele 
Published: June 2022

e18049 Background: Patients with early-stage laryngocarcinoma, even stage T1-2N0, are at substantial risk of relapse and death. Molecular alterations are thought to be associated with the immune microenvironment in the tumor and to have an important role in predicting the prognosis. In this study, we explored the distinct features of molecular alterations and immune-related gene expression and examined the relationship between molecular alterations and prognosis. Methods: A total of 42 stage T1-2N0 laryngocarcinoma patients were enrolled, no patients received chemotherapy or immunotherapy before surgery, tissue samples from radical operation were collected. Of these, 23 cases developed disease progression within 24 months after operation [shorter disease-free survival (shorter DFS)], while others 19 cases showed longer DFS over 24 months (longer DFS). Distinct features of molecular alterations and immune-related gene expression in Formalin-fixed paraffin-embedded (FFPE) samples through using DNA sequencing and an immune oncology panel RNA sequencing platform were performed. Results: A total of 293 mutations were detected within 42 patients, the median number of mutations in the short-DFS group was higher than that in the long-DFS group (9.0 vs. 5.2; P = 0.045). No correlation between mutation type and DFS was found. TMB-high (Top 25%) was associated with worse DFS (TMB-L: Not reached, TMB-H: 11.5 months, p = 0.036; HR, 2.4; 95% CI 1.05 to 5.48). Among 522 cancer-related genes, alterations in 51 genes were detected. TP53 (33/42, 79%) was the most common mutation gene in the entire cohort. Mutations of LRP1B (30.4% vs 5.3%, p = 0.039) and Notch1 (21.7% vs 0%, p = 0.030) were significantly occurred in the short-DFS group, patients with Notch1 mutation had a significantly shorter DFS period (P = 0.0012). Univariate and multivariate analysis showed that high TMB and Notch1 mutation were independent prognostic factors in DFS. Conclusions: In early-stage laryngocarcinoma, Notch1 mutation and high TMB were associated in patients with short-DFS, indicating the potential prognostic biomarkers and therapeutic molecular targets for early-stage laryngocarcinoma.