bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of sensitivity to platinum-based chemotherapy in PD-1 blockade-refractory head and neck cancer.
Authors: Burkitt Kyunghee 
Published: June 2023

e18003 Background: Our clinical observation from recurrent/metastatic head and neck patients who treated with platinum based combination after progression on pembrolizumab showed a striking response rate of 80% (8 out of 10 patients), this impressive ORR is dramatically higher than the historical ORR of 27% in the first-line setting. Our mouse model of ‘immune-cold’ head and neck cancer is developed to investigate the mechanism of sensitivity to platinum- based chemotherapy in PD-1 blockade-refractory head and neck cancer. Methods: For ‘immune-cold’ syngeneic model of HNSCC, C57BL/6 mice were injected with 5 × 104 MOC2 tumor cells in the right flank. After 11 days, mice with palpable tumors were randomized and treated concurrently with 4 groups (n = 5 per group): control, anti–PD1 antibody (200 mcg three times/week × 3 cycles), cisplatin (3mg/kg) +paclitaxel (5mg/kg) once a week x 3 cycles, or anti-PD1 antibody (200 mcg three times/week × 1 cycle) followed by cisplatin (3mg/kg) + paclitaxel (5mg/kg) once a week x 2 cycle. Cisplatin + paclitaxel arm received total of 4 cycles of treatment, while PD-1 followed by cisplatin and paclitaxel arm received total of 3 cycles of cisplatin and paclitaxel, this schedule was set up to maintain every 3 week regimen with same duration of treatment time to mimic patient’s treatment schedule in clinic setting. Tumor volume was measured 3 times per week. Results: Our initial pilot mouse model study showed similar tumor response seen in patient population. Starting on D24, average tumor size of PD1 inhibitor followed by cisplatin+paclitaxel group is significantly decreased compared to PD1 inhibitor or cisplatin+paclitaxel group and the difference is statistically significant. Most of mice in control and PD1 inhibitor group died at day 24 due to tumor progression. Our IHC data showed that the expression levels of immune markers such as CD8+, CD4+ and PDL1 in tumors treated with PD1 inhibitor followed by cisplatin and paclitaxel were increased, compared to almost no or scant expression (CD8+, CD4+) and lower expression (PDL1) in tumors treated with cisplatin and paclitaxel alone. With our expansion cohort, we will be further exploring key changes in immune signatures using both peripheral blood samples and tumor blocks for flow cytometry (myeloid/lymphoid subtypes, alterations in cytokine expression and circulating tumor DNA levels) and RNA sequencing analysis. Conclusions: We successfully established an ‘immune-cold’ mouse model of head and neck and reproduced similar tumor response seen in clinic. Preliminary data showing increased expression of immune makers such as CD8+, CD4+ and PDL warrants further investigation on tumor immune microenvironment remodeling as a potential mechanism of sensitivity to platinum-based chemotherapy in PD-1 blockade-refractory head and neck cancer.
The changes of HER3 expression in head and neck cancer patients treated with induction chemotherapy.
Authors: Kim Joori , Kim Jeong-Oh , Lee Youn Soo , Shin Jung-Young , Kim Min Young , Lee Mi-Ran , Kim Seoree , Fujita-Sato Saori , Kobayashi Maki , Kakegawa Tomoya , Kang Jin Hyoung 
Published: June 2023

e18004 Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is broadly expressed in various types of cancer and is associated with poor prognosis. Recent evidence supports HER3 plays a role in acquired resistance to chemotherapy. The change of HER3 expression by chemotherapy in head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods: We evaluated 95 patients with locally advanced HNSCC who had received induction chemotherapy (ICT) between 2009 and 2019. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. H-score of membrane staining was evaluated. Results: Median age of patients was 64 years, and 85% were male. Primary locations included oropharynx (54.8%), hypopharynx (21.5%), oral cavity (17.2%), and salivary gland (6.5%). Mean H-score of HER3 in tumor tissues was 77.6 ± 7.9. H-score of HER3 in HPV-positive tumors was higher than HPV-negative tumors (p = 0.019), which was more pronounced in oropharynx and hypopharynx tumors. While, H-score of HER3 in adjacent normal tissues of these tumors did not significantly differ. Compared with the non-smokers, tumor tissues of current or ex-smokers demonstrated higher H-score of HER3 (p = 0.033), independent of tumor location. In contrast, in adjacent normal tissues, no significant differences of H-score of HER3 were observed depending on the smoking status. The H-score higher than 100 was defined as HER3-high group. Among oropharynx and hypopharynx tumors with positive correlation between H-score of HER3 and HPV status (n = 56), HER3-high group was significantly correlated with HPV positivity (p = 0.009) and good response to ICT (p = 0.035). Good clinical response was also strongly related to HPV-positivity (p = 0.001). In addition, there was a tendency for longer overall survival in HER3-high group than low HER3 expression group (93 vs. 70 months, p = 0.053). The paired tumor samples collected at pre- and post-ICT (n = 21) were analyzed. HER3 expressions in adjacent normal tissue were higher at post-ICT compared to pre-ICT (p = 0.003), and these results were more pronounced in the non-smoking group, but no differences were found according to HPV-status. Conclusions: Taken together, our results showed that H-score of HER3 was significantly higher in both HPV-positive and smoking group. Interestingly, high HER3 expression in oropharynx and hypopharynx tumors was associated with HPV positivity and good clinical response to ICT. Additional analysis of tumor immune microenvironment in tumor tissues are underway.
A phase II study cohort of penpulimab plus anlotinib in patients with recurrent or metastatic non-squamous cell carcinomas of head and neck.
Authors: Zhang Changgong , Sun Yan , Wang Jun , Liu Zhigang , Su Haichuan , Chen Jianhua , Tian Youxin , Wu Huijuan , Gao Liying , Shi Yuankai 
Published: June 2023

e18013 Background: Recurrent or metastatic non-squamous cell carcinoma of head and neck (R/M non-SCCHN) lack effective systemic treatment. The feasibility of the combination of immune checkpoint inhibitor and anti-angiogenic agents in the treatment of R/M non-SCCHN was unknown. Penpulimab is a novel anti-programmed cell death-1 (PD-1) antibody with complete elimination of FcγR binding activity. Anlotinib is a multi-kinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. ALTN-AK105-II-01 is a single-arm, multi-cohort, multi-center phase II study to investigate the efficacy and safety of penpulimab plus anlotinib in the treatment of various advanced cancers. Here we report the results of the cohort 2 for patients (pts) with R/M non-SCCHN. Methods: Eligible pts were aged 18 years or older and diagnosed with histologically confirmed R/M non-SCCHN. Other inclusion criteria included ECOG PS 0-1 and having at least one measurable lesion according to RECIST 1.1, and anti-angiogenic agents or immune checkpoint inhibitor treatment-naïve. Pts were given penpulimab 200mg intravenously on day 1 and oral anlotinib 12mg once daily from day 1 to day 14 every 3 weeks until disease progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: From May 21, 2020 to October 14, 2020, 21 pts were enrolled in 7 centers in China. The most common site of primary tumor was salivary gland (15/21, 71.4%) and the most common pathological types included adenoid cystic carcinoma (7/21, 33.3%) and duct carcinoma (4/21, 19.0%). 15 pts (71.4%) had distant metastatic lesions and 12 pts (57.1%) had prior chemotherapy history. As of October 20, 2022 (data cut-off), 4 pts achieved confirmed partial response and the ORR was 19.0%. Stable disease (SD) was observed in 17 pts and the DCR was 100%. The median follow-up for PFS was 14.2 months (95%CI: 7.8, 20.6), 9 pts suffered disease progression and the median PFS was 10.6 months (95%CI: 0.0, 22.4). 14 pts (66.7%) experienced at least one ≥grade 3 treatment-related adverse events (TRAEs) and the most common ≥grade 3 TRAEs was hypertension (15.0%). No treatment-related death was reported. Conclusions: The combination of penpulimab and anlotinib showed encouraging efficacy and favorable safety profile in R/M non-SCCHN and is worthy of further investigation. Clinical trial information: NCT04203719 .
Patterns and outcomes of palliative radiation therapy with immunotherapy in locally recurrent head and neck squamous cell carcinoma.
Authors: Roof Logan , Buchberger David , Yalamanchali Anirudh , Campbell Shauna , Miller Jacob , Koyfman Shlomo A. , Woody Neil McIver , Geiger Jessica Lyn , Yilmaz Emrullah 
Published: June 2023

e18015 Background: Immune checkpoint inhibitors (ICI) have been shown to improve outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Radiation therapy (RT) is commonly incorporated into R/M HNSCC treatment for symptom management and disease control. RT is a potential immunostimulatory treatment modality that may enhance the antitumor activity of ICI; however, ideal sequencing of RT and ICI in the palliative treatment setting is not defined. The objective of this study was to describe the patterns and outcomes of RT and ICI in locally recurrent HNSCC. Methods: All adults (≥ 18 years) with HNSCC who received palliative ICI for R/M disease from 2015-2021 were identified from the institutional electronic medical record via ICD codes under an IRB approved protocol. Patients who received ICI for non-HNSCC, had synchronous primary tumors, or had history of hematologic malignancy or immunodeficiency were excluded. Patients without documentation of clinical outcomes after palliative RT were excluded. Retrospective data were collected and underwent descriptive analysis. Results: We identified 26 patients who received palliative ICI and RT for locally recurrent HNSCC. Twelve underwent palliative RT while on ICI. In this group, there were 0 patients with complete response (CR), five with partial response (PR), two with stable disease (SD), and four with progression of disease (PD) in the target lesion. There were 10 grade 3 events. Fourteen patients had RT separately from ICI: 6 before and 8 after receiving ICI. In this group, there was one patient with CR, six with PR, one with SD, and six with PD in the target lesion. There were 3 grade 3 events. Most common grade 3 events in both groups were: dysphagia, mucositis, and voice change. The most common modalities of RT were SBRT, IMRT, and 3D conformal; 7 patients underwent SBRT, 19 underwent IMRT/3D conformal, with similar responses in target lesions. Conclusions: These data suggest that concurrent ICI and palliative RT for locally recurrent HNSCC is effective in the target lesions, but has an increase in toxicities. Although there was a small number of patients who underwent concurrent ICI and RT, the disease control rate (DCR) in this group was 58%, which is promising. Similarly, the DCR for patients receiving ICI and RT separately was 57%. Further study on the optimal type and sequence of palliative RT in this patient population is warranted.
Hypofractionated radiotherapy compared with conventionally fractionated radiotherapy to treat initial distant metastases in nasopharyngeal carcinoma: A multicenter, prospective, randomized, phase II trial.
Authors: Jiang Wei , Liu Jian , Zhang Bin , Su Yixin , Qin Guanjie , Kong XiangYun , Mo Yunyan , Zhang Rongjun 
Published: June 2023

e18019 Background: To investigate the safety and efficacy of hypofractionated plus chemotherapy in patients with initially distant metastatic nasopharyngeal carcinoma (mNPC). Methods: Between May 2014 and June 2020, 35 patients initially diagnosed with mNPC were enrolled on prospective trial. The enrolled patients were assigned randomly to receive either hypofractionated plus chemotherapy (HFRT) or conventionally fractionated radiotherapy plus chemotherapy (CFRT). 60 Gy over 25 fractions was administered to the HFRT group (n = 17) and 69.96 Gy over 33 fractions was administered to the CFRT group (n = 18), both groups five times each week. Progression free survival (PFS) comprised the primary endpoint. Overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and acute and late toxicity comprised the secondary endpoints. Results: Twenty-eight patients (seven were excluded) were enrolled. The 2-year PFS was 33.3% (HFRT group) versus 30.0% (CFRT group) (stratified hazard ratio (HR):1.09; 95% confidence interval (CI): 0.45–2.65, P = .843). The 2-year OS was 66.7% (HFRT group) versus 62.5% (CFRT group) (stratified HR, 0.88; 95% CI; 0.31–2.51, P= .806). All patients experienced acute grade 1 or 2, skin toxicity, oral mucositis, dysphagia, dry mouth, but no acute grade 3 or 4 toxicities. All patients had grade 1 late xerostomia. Two patients experienced hearing loss (one grade 1 and one grade 3). One patient developed mucosal necrosis. Conclusions: The two groups had similar outcomes. Improving the balance between severe late toxicities and local control by appropriately reducing the total dose but increasing the fractionated dose has marked clinical significance for patients with initially diagnosed mNPC. The trial has been registered with clinicaltrials.gov (NCT03598218). Clinical trial information: NCT03598218 . [Table: see text]
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced head and neck squamous cell carcinoma.
Authors: Liu Juying 
Published: June 2023

e18028 Background: Intratumoral heterogeneity (ITH) is associated with the poor prognosis in a variety of solid tumors, because of the therapeutic failure and drug resistance. However, we still lack understanding of the relationship between ITH and immunotherapy for advanced head and neck squamous cell carcinoma (HNSCC). Methods: We used the Bioconductor R package Maftools to analyze somatic variants of HNSCC from MSK-IMPACT-1611 study cohort (PMID: 30643254) with data from 68 patients. Then, a mutant-allele tumor heterogeneity (MATH) algorithm was used to measure ITH score. Finally, we analyzed the difference in the genomes, and the association with tumor mutational burden (TMB) between the ITH score high (ITH-H) and ITH score low (ITH-L) groups, and the effect of ITH on the prognosis of immunotherapy. Results: There was no significant difference in the high frequency mutated genes between the high ITH and low ITH groups. The genes with the highest mutation frequency in ITH-H group were TP53 (90.48%), TERT (47.62%), CDKN2A (38.1%), FAT1 (33.33%), NOTCH1 (28.57%), KMT2D (19.05%), APC (14.29%), and ASXL1 (14.29%), while the genes with the highest mutation frequency in ITH-L group were TP53 (44.68%), PIK3CA (38.3%), TRET (36.17%), FAT1 (21.28%), NOTCH1 (19.15%), KMT2C (17.02%), KMT2D (17.02%), and CDKN2A (14.89%). The median overall survival (mOS) of ITH-L group was significantly higher than that of ITH-H group (not reach versus 10 months, hazard ratio (HR) = 2.15, 95%CI 1.05−4.4, P = 0.032). There was no significant difference in median TMB levels between ITH-L and ITH-H groups (P = 0.55). The TMB high (TMB-H) patients had no significantly better mOS than the TMB low (TMB-L) group (HR = 0.54, 95%CI 0.25−1.16, P = 0.11). A pooled analysis of ITH and TMB show that the ITH-L+TMB-H group had significantly better improvement mOS than that in the ITH-L+TMB-L, ITH-H+TMB-H, and ITH-H+TMB-L group (HR = 0.71, 95%CI 0.13−1.35, P = 0.048). Conclusions: ITH may serve as a positive predictor of immunotherapy in patients with advanced HNSCC and is independent of TMB.
Atypical new metastatic sites after immunotherapy in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M H&NSCC).
Authors: Deeken John F. , Ahmadi Mahsa , Johnston Laura , Heyer David M. , Lee Patty , Niknia Katherine , Bajaj Gopal Krishna 
Published: June 2023

e18032 Background: Immunotherapy with PD-1 inhibitors (PD-1Is) nivolumab (N) or pembrolizumab (P) has led to significant improvements in overall survival in pts with R/M H&NSCC. Common metastatic (met) sites for R/M H&NSCC are locoregional in the H&N area (LR), lung (L) and liver (LV). We investigated where patients developed met sites after successful treatment with PD-1Is. Methods: Eligible pts were treated with N or P for at least 3 months in the 1st or 2nd line setting and with at least stable disease as best response. Records were reviewed for initial sites of disease and whether metastatic sites developed after PD-1 therapies, including during subsequent lines of therapy. Patients could have more than one initial or progressive metastatic/recurrent sites of disease. Results: 26 eligible pts treated between 2016-2022 were identified with demographics as follows: 20 males/6 females; average age 65.3 yrs; primary diseases were 13 oropharynx (12 HPV+), 10 oral cavity, 1 larynx, and 2 nasopharynx; 8 received N and 18 got P (4 with chemotherapy); 22 were treated in 1st line and 4 in 2nd line. The median time on PD-1I therapy was 51.7 weeks (range 19 – 100). Best response was stable disease in 9 (35%), partial response in 15 (58%), and complete response in 2 (8%). Initial sites of disease were: LR 16 (62%), L 16 (62%), LV 2 (8%) and bone 2 (8%). In the 16 pts who developed new sites of disease, these included L in 5 (31%), LV in 4 (25%), bone in 7 (44%), abdomen/mesentery in 7 (44%), lower extremities in 4 (25%), and brain in 3 (19%). All 3 who developed CNS mets had HPV+ oropharynx cancer. Conclusions: Pts successfully treated with PD-1Is had uncommon sites of new metastatic disease, including in the lower extremities, abdomen, and brain. This has important ramifications for restaging scan requirements in these patients while on treatment. These results also raise the possibility of disease site sanctuaries resistant to immunotherapy, including in the abdomen, bone, and brain. Larger patient series should be investigated.
Patients characteristics, treatment patterns and clinical outcomes in patients with head and neck squamous cell carcinoma (aHNSCC) receiving immunotherapy in advanced setting: Retrospective cohort analysis of real-world data in Spain.
Authors: Ortega Granados Ana Laura , Vinueza German Paolo , Lopez Lopez Jose Antonio , García Verdejo Francisco José , Montosa Fernando Gálvez , Luque Caro Natalia , Ruiz Sanjuan María , Beltran Leticia Diaz , de la Torre Cabrera Capilla , Fernández Navarro Mónica , Cárdenas Quesada Nuria , Moreno Jimenez Miguel Angel , Marin Pozo Juan Francisco , Sanchez Rovira Pedro 
Published: June 2023

e18033 Background: This retrospective cohort analysis looked at real-world data from Spain to better understand the characteristics, treatment patterns and clinical outcomes of patients with aHNSCC who received immunotherapy in an advanced setting. In aHNSCC, the standard of care was platinum-based chemotherapy. However, this treatment modality is associated with significant toxicity and only a minority of patients achieve long-term disease control. As a result, there was an unmet need for effective and well-tolerated treatment till immunotherapy has shown efficacy in some clinical trials. However, data on the use of immunotherapy in routine clinical practice are limited. The aim of this study was to characterize the real-world safety and effectiveness of immunotherapy in patients with aHNSCC in real practice. Methods: This was a retrospective cohort study that included data from our database, a tertiary hospital in Spain. Patients with a diagnosis of aHNSCC who received immunotherapy between 2017 and 2022 were included, excluding those in clinical trials. Clinical outcomes assessed were overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicity profile. 97 patients were included in the analysis. The most common histological subtype was oral cavity cancer (43%), followed by laryngeal cancer (29%). Results: The majority of patients had stage IVA-B disease at diagnosis (62%). A 53% of patients received first line nivolumab as monotherapy, or pembrolizumab as monotherapy or combined with platinum chemotherapy, and a 58% of patients received second or third line nivolumab as monotherapy.With a median age of 64 years (range: 45-86), most patients received it as second-line or later treatment (70%). The overall response rate was 29%, with durable responses seen in some patients (28% longer than 1 y). The median overall survival was 13.9 months in first-line setting (3-24 mo), and the 1-year survival rate was 36%. In second-line setting, the median OS was 11.1 mo (3-89 mo), and 1-year survival rate was 33%. More frequent toxicities were skin (26%) and endocrine (21%). We had 8 cases of hyperprogressive disease (8.2%) and treatment was interrupted due toxicity in 6 patients. Conclusions: These results are very close to results found in clinical trials (KEYNOTE-048, CheckMate 141) and confirm that immunotherapy is safe and impacts on survival of aHNSCC patients. We need to identify predictive biomarkers for response and toxicity.
Effect of GNA13 on the alteration of tumor microenvironmental components through exosomes to promote the development of head and neck tumors.
Authors: Zhu Weili , Zhao Miaoqing , Li Xiaoming , Ma Yuting , Yao Zhi-Gang , Ru Kun 
Published: June 2023

e18035 Background: Guanine nucleotide-binding protein alpha subunit 13 (GNA13) is closely related to tumor development, but the effect of GNA13 on the biological behavior of head and neck tumors is unknown. The aim of this study was to investigate whether GNA13 can influence the alteration of tumor microenvironment components through exosomes, which in turn promotes the development of head and neck squamous carcinoma (HNSCC). Methods: Using the Gene Expression Omnibus database, the differentially expressed gene GNA13 was screened. Immunohistochemistry and western blotting were used to detect the expression of GNA13 in HNSCC tissues and control tissues. GNA13 expression was down-regulated in tumor cell lines using transfection techniques. The effect of GNA13 downregulation on tumor cell growth was examined by in vitro experiments. RT-PCR and dual luciferase reporter gene assays were used to validate GNA13-regulated miRNAs and their target genes. Clonogenesis assays were used to examine the effect of target gene expression on fibroblasts, and the HNSCC xenograft mouse model was used to verify the role of GNA13 in tumor growth in vivo. The peripheral blood from patients with different stages of HNSCC was collected to determine the expression level of GNA13 in serum exosomes and to analyze its relationship with metastasis and postoperative recurrence. Results: GNA13 expression was elevated in HNSCC tissues and cells. The growth capacity of HNSCC cells was significantly reduced after downregulation of GNA13, which induced fibroblast conversion to MAF via exosomes and promoted their proliferation and migration. Meanwhile, GNA13 was able to regulate miR-26a-5p/STRADB expression in fibroblasts via exosomes. The overexpression of STRADB promoted the proliferation and migration of fibroblasts and induced their conversion to MAF. More importantly, in the conditioned medium of STRADB overexpressing fibroblasts, the proliferation and migration of HNSCC cells were promoted. Furthermore, knockdown of GNA13 expression inhibited the tumor growth in nude mice. It appeared that high expression of GNA13 in serum exosomes of patients with HNSCC was associated with poor prognosis. Conclusions: GNA13 regulates the miR-26a-5p/STRADB axis in fibroblasts via exosomes to create a metastasis-friendly microenvironment for tumor cells, ultimately promoting the progression of HNSCC. Meanwhile, the expression of GNA13 was positively correlated with the pathological grade and clinical stage of HNSCC, which seems to be a reliable indicator of tumor recurrence. Targeting this signaling pathway would be a promising therapeutic strategy for HNSCC.