Evaluation of bovine embryo quality based on gene expression profiling using whole-transcriptome amplification.

This study aimed to develop a method to evaluate the quality of bovine in vitro fertilized (IVF) embryos based on gene expression profiling via whole-transcriptome amplification. The expression of 11 developmentally important genes in individual bovine in vivo-derived (IVD) and IVF embryos were examined. Gene expression profiling was conducted by classifying the expression level of each gene in individual embryos as low, medium, or high. The IVF group had a higher (P < 0.01) proportion of embryos with low expression of SOX2, NANOG, and FGF4. In addition, a correlation analysis between the expression levels of each gene in individual embryos demonstrated that the relationship between gene expression differed with respect to IVD and IVF embryos. Our results suggest that the expression profiling of developmentally important genes using IVD embryos as normal controls could be a useful indicator for evaluating the quality of bovine IVF embryos.

Validation and comparison of prognostic scoring systems in patients with head and neck squamous cell carcinoma treated with nivolumab.

OBJECTIVE: Several scoring systems have been developed to predict prognosis in patients with refractory cancer. We aimed to validate eight scoring systems and determine the best method for predicting the prognosis of head and neck squamous cell carcinoma treated with nivolumab. METHODS: This multicentre retrospective study involved 154 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with nivolumab between 2017 and 2020. Oncological outcomes were assessed according to the scoring systems, including MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scores. Objective response, overall survival and progression-free survival were evaluated using logistic regression and Cox proportional hazards analyses. Receiver operating curve analysis was used to calculate the area under the curve and estimate the efficacy of each score. RESULTS: No significant associations were found between the responses and any score. Seven of the eight scoring systems were associated with disease control (odds ratio, 0.26-0.70). Amongst the eight scoring systems, MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio showed the highest area under the curve for predicting response and disease control. Seven scoring systems were prognostic factors for progression-free survival (hazard ratio, 1.22-1.95). All eight scoring systems were prognostic factors for overall survival (hazard ratio, 1.62-3.83). According to the time-dependent receiver operating characteristics analysis for overall survival, the Hammersmith scoring system had the best predictive ability at 3 months, and the MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio scoring system had the highest area under the curve between 6 and 24 months. CONCLUSIONS: MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scoring systems were better predictors of prognosis in patients with head and neck squamous cell carcinoma treated with nivolumab.

Polarization change of femtosecond laser pulses in air measured by electric-field-induced second-harmonic generation.

We experimentally demonstrated the polarization change of femtosecond laser pulses in air by using electric-field-induced second-harmonic generation (E-FISHG) for the first time to our knowledge. The polarization change from linear to elliptical was observed at the laser intensity over the filamentation threshold. These results suggest that the polarization change can occur by the birefringence caused by filamentation. This phenomenon can be used for new applications such as an ultra-fast and precise three-dimensional electric field measurement by E-FISHG. In addition, E-FISHG can be an excellent tool to investigate the characteristics of femtosecond laser propagation such as filamentation.

Woven Endo Bridge shape modification contributes to decrease in adequate occlusion rate after Woven Endo Bridge implantation for wide-neck bifurcation intracranial aneurysms.

PURPOSE: Recently, a novel device, the Woven Endo Bridge (WEB), was developed for wide-neck bifurcation intracranial aneurysms (WNBAs). The aim of this study is to investigate factors that contribute to adequate occlusion (AO) after the operation using detailed radiological images. METHODS: The subjects were 29 patients with 29 aneurysms who received WEB implantation for WNBAs between December 2020 and April 2022. We assessed the contributing factors to AO by retrospectively comparing the AO group and non-AO group. RESULTS: The mean age was 64.6 ± 13.1 years, and 18 were female (62.1%). The mean aneurysm dome width, aneurysm height, and aneurysm neck diameter were 4.8 ± 0.6 mm, 5.1 ± 0.6 mm, and 3.7 ± 0.6 mm, respectively. After about 6 months, 22 of 29 patients (75.9%) had AO. Complications were observed in 2 patients (6.9%), renal artery injury in one, and minor cerebral infarction in another, but the modified Rankin scale scores of both patients remained unchanged. Multivariate analysis extracted only WEB shape modification (WSM) as a contributing factor to AO (odds ratio: 0.912, p = 0.0287). CONCLUSION: WEB implantation for WNBAs was a treatment modality with acceptable efficacy and safety. WSM was the only significant factor contributing to non-AO after the treatment. We should clarify the mechanisms or causes of WSM to achieve AO after WEB implantation in future.

Prognostic significance of C-reactive protein in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

AIM: C-reactive protein (CRP) is both an inflammatory and prognostic marker in various cancers. This study aimed to elucidate the characteristics of CRP and the prognostic factors in patients who were administered with atezolizumab plus bevacizumab (ATZ + BEV) for unresectable hepatocellular carcinoma (HCC). METHODS: A total of 213 patients who received ATZ + BEV for HCC from November 2020 to March 2023 at 15 hospitals were enrolled in this retrospective study. The prognosis was analyzed by subdividing the patients based on baseline characteristics, radiologic response, and treatment lines. Accuracy of survival prediction was assessed using CRP, alpha fetoprotein (AFP), C-reactive protein and alpha fetoprotein in immunotherapy (CRAFITY), and Glasgow Prognostic Score. RESULTS: Compared with patients with baseline CRP <1 mg/dL, those with baseline CRP ≥1 mg/dL (n = 45) had a significantly higher baseline albumin-bilirubin score and AFP levels, significantly lower disease control rate (62.2%), and significantly shorter median overall survival (hazards ratios 2.292; 95% confidence interval 1.313-5.107; log-rank test, p < 0.001). Multivariate analysis identified CRP ≥1 mg/dL, AFP ≥100 ng/mL, and modified albumin-bilirubin grade as the significant prognostic factors. The baseline CRP, AFP, CRAFITY, and Glasgow Prognostic Score demonstrated higher discrimination for 1-year survival prediction after first-line ATZ + BEV administration, compared with beyond second line, with area under the receiver operating characteristic curves of 0.759, 0.761, 0.805, and 0.717, respectively. CONCLUSIONS: CRP was a significant biomarker in patients treated with ATZ + BEV for HCC. Elevated CRP levels may indicate aggressive cancer progression and potential resistance to ATZ + BEV therapy.

COVID-19 severity is associated with the risk of gastrointestinal bleeding.

OBJECTIVE: The association between the severity of COVID-19 and gastrointestinal (GI) bleeding is unknown. This study aimed to determine whether the severity of COVID-19 is a risk factor for GI bleeding. DESIGN: A multicentre, retrospective cohort study was conducted on hospitalised patients with COVID-19 between January 2020 and December 2021. The severity of COVID-19 was classified according to the National Institute of Health severity classification. The primary outcome was the occurrence of GI bleeding during hospitalisation. The main analysis compared the relationship between the severity of COVID-19 and the occurrence of GI bleeding. Multivariable logistic regression analysis was performed to evaluate the association between the severity of COVID-19 and the occurrence of GI bleeding. RESULTS: 12 044 patients were included. 4165 (34.6%) and 1257 (10.4%) patients had severe and critical COVID-19, respectively, and 55 (0.5%) experienced GI bleeding. Multivariable analysis showed that patients with severe COVID-19 had a significantly higher risk of GI bleeding than patients with non-severe COVID-19 (OR: 3.013, 95% CI: 1.222 to 7.427). Patients with critical COVID-19 also had a significantly higher risk of GI bleeding (OR: 15.632, 95% CI: 6.581 to 37.130). Patients with severe COVID-19 had a significantly increased risk of lower GI bleeding (OR: 10.349, 95% CI: 1.253 to 85.463), but the risk of upper GI bleeding was unchanged (OR: 1.875, 95% CI: 0.658 to 5.342). CONCLUSION: The severity of COVID-19 is associated with GI bleeding, and especially lower GI bleeding was associated with the severity of COVID-19. Patients with severe or critical COVID-19 should be treated with caution as they are at higher risk for GI bleeding.

Ten-Year Clinical Observation of Immunoglobulin G4-Related Coronary Periarteritis with Aneurysms.

Coronary periarteritis with aneurysms has been reported as a cardiovascular manifestation of immunoglobulin G4 (IgG4) -related disease. We report a 10-year clinical observation of a patient with IgG4-related coronary periarteritis (IgG4-rCP) characterized by multiple thickening of periarterial tissue and coronary artery aneurysms (CAAs).A 60-year-old man with a history of IgG4-related autoimmune pancreatitis had an incidental detection of a total of 5 tumor-like lesions surrounding the right and left coronary arteries on coronary computed tomography angiography (CCTA) in 2012. Among them, 3 lesions were located at the middle to the distal portions of the right coronary artery (RCA) and the most proximal lesion was accompanied by a CAA. Although corticosteroid therapy was continued, 4-year follow-up of CCTA in 2016 showed the most proximal lesion gradually increased from 33 to 45 mm and the CAA enlarged from 9 to 22 mm. In order to avoid aneurysmal rupture, the patient underwent resection of the most proximal lesion with an enlarged aneurysm concomitant with coronary artery bypass grafting (CABG). Histopathological findings were coincident with IgG4-rCP. CCTA in 2018, however, showed the remaining distal tumor-like lesion of RCA had slightly enlarged and a new CAA developed despite the corticosteroid therapy. Follow-up CCTA in 2022 revealed the CAA increased to 13 mm, which showed rapid enlargement by 4 mm/year. A second operation through a re-median sternotomy was planned. The residual lesions with the CAA were resected followed by CABG. The other lesions at the left coronary artery remained stable without aneurysmal change, but careful follow-up has been continued.

Safety and efficacy of pipeline embolization device treatments for intradural internal carotid artery aneurysms in a single center in a Japanese population.

Background: The pipeline embolization device (PED) is the most common flow diverter device in the world. To date, there have been no reports of treatment outcomes specific to intradural internal carotid artery (ICA) aneurysms. The safety and efficacy of the PED treatments for intradural ICA aneurysms are reported. Methods: 131 patients with 133 aneurysms underwent PED treatments for intradural ICA aneurysms. The mean aneurysm dome size and neck length were 12.7 ± 4.3 mm and 6.1 ± 2.2 mm, respectively. We used adjunctive endosaccular coil embolization for 88 aneurysms (66.2%). A total of 113 aneurysms (85%) were angiographically followed up 6 months following the procedure, and 93 aneurysms (69.9%) were followed up for 1 year. Results: The angiographic outcome at 6 months showed that 94 (83.2%) aneurysms had O'Kelly-Marotta (OKM) grade D, 6 (5.3%) had C, 10 (8.8%) had B, and 3 (2.7%) had A. At 1 year, 82 (88.2%) aneurysms had OKM grade D, 6 (6.5%) had C, 3 (3.2%) had B, and 2 (2.2%) had A. Multivariate analysis showed that aneurysm neck size and adjunctive coiling were statistically significant in aneurysm occlusion status. Major morbidity modified Rankin Scale >2 and mortality rates related to procedures were 3.0% and 0%, respectively. Delayed aneurysm ruptures were not observed. Conclusion: These results reveal that PED treatment of intradural ICA aneurysms is safe and efficacious. The combined use of adjunctive coil embolization not only prevents delayed aneurysm ruptures but also contributes to an increase in the rate of complete occlusion.

Feasibility of Simple Evaluation of Coronary Artery Calcium Using a Number of Chest Computed Tomography Slices: A Multicenter Study.

Objective: We aimed to evaluate the visual measurements of coronary artery calcium (CAC) on nonelectrocardiogram (ECG)-gated chest computed tomography (CT) using a simple scoring method that involves counting the number of CT slices containing CAC. Materials and Methods: We analyzed 163 participants who underwent both coronary and chest CT examinations at six centers within 3 months. Agatston scores were calculated on standard ECG-gated scans and classified as none (0), mild (1-99), moderate (100-400), or severe (>400). Next, chest CT images were reconstructed to standard 5.0 mm axial slices. Then, CAC on chest CT scans was measured using two methods: the Weston score (sum of the assigned score of each vessel, range: 0-12) and number of slices showing CAC (Ca-slice#). Results: When the Weston score and Ca-slice# were divided into four levels according to the optimal divisional levels corresponding to the Agatston score classes, good agreements with the 4-grade Agatston score were observed (kappa value=0.610 and 0.794, respectively). The sensitivity and specificity of Ca-slice# ≥9 to identify severe Agatston scores of >400 were 86% and 96%, respectively. Conclusion: The Ca-slice#, a simple scoring method using chest CT scans, was in good agreement with the ECG-gated Agatston score.

Does oral intake of thin fluids increase aspiration pneumonia for dysphagia after head and neck cancer surgery? A retrospective study for a total of 654 cases.

OBJECTIVE: Head and neck cancer (HNC) treatment causes dysphagia, which may lead to aspiration pneumonia (AP). Thickened fluids are widely used to prevent aspiration in patients with dysphagia; however, there is little evidence that they can prevent AP. This study aimed to clarify the differences between restriction of oral intake of fluids (R), only thickened fluids (TF), and no restriction of fluids (NR) for AP in patients with dysphagia after HNC treatment. METHODS: We retrospectively studied 654 patients with dysphagia after HNC surgery between 2012 and 2021. Of these, 255 had some restriction of fluids. The development of possible AP and administration of antibacterial drugs were used as outcomes. Multivariate linear regression and propensity score matching analyses were performed. RESULTS: The mean patient age was 64 ± 13, 67 ± 11, and 68 ± 10 years, while the Dynamic Imaging Grade of Swallowing Toxicity score 3-4 was 2.8%, 27.5, and 53.3%% water in NR, TF, and R groups, respectively. AP was diagnosed or suspected after starting oral intake in 37 (9.3%), 11 patients (15.9%), and 45 (17.6%) and antibacterial drugs were administered in 11 (2.8%), 7 patients (10.1%), and 25 (9.8%) in NR, TF, and R groups, respectively. R and TF had significant negative impacts on AP. CONCLUSIONS: Fluid restrictions may not reduce the risk of AP or affect the administration of antibacterial drugs. Medical staff should bear in mind that fluid restrictions do not necessarily prevent AP in patients with HNC.

Post-operative progress of arm abduction function and rate of lymph node metastasis around the region of the accessory nerve: a multicentre prospective observational study.

OBJECTIVE: Although neck dissection is an essential technique in the surgical treatment of head and neck carcinoma, arm abduction disorders occurring after neck dissection reduce the patient's quality of life. METHODS: We prospectively evaluated the rate of lymph node metastasis in Levels IIB and V in head and neck cancer patients who underwent neck dissection at eight centres in Japan. In addition, post-operative arm abduction disability was classified according to functional assessment values at 1 month post-operatively, and the rate of maintained function at 6 and 12 months was evaluated. RESULTS: Lymph node metastasis occurred in Level IIB in 12 of 242 cases (4.9%) and in Level V in 5 cases (2.1%) during the 12-month post-operative course. In patients with preservation of the ipsilateral accessory nerve, arm abduction function was maintained in 142 of 209 patients (67.9%) at 12 months after surgery. Post-operative radiotherapy and Level V dissection had no statistically significant effect on the recovery of arm abduction function. Level V dissection caused a temporary loss of abduction function post-operatively. A higher arm abduction test score at 1 month post-operatively was associated with a higher rate of subsequent ability to maintain arm abduction function. CONCLUSIONS: In patients classified as cN0, metastatic rate at Levels IIB and V was low. In this cohort, omitting Level V dissection may be an option in strategies aimed at maintaining arm abduction function.

Head and Neck Reconstruction With 2-Stage External Pectoralis Major Myocutaneous Flap Transfer.

BACKGROUND: In head and neck surgery cases where skin is severely scarred or adhered to surrounding tissue, reconstruction can be difficult to perform using microsurgical tissue or conventional pedicled pectoralis major myocutaneous flap (PMMF) transfer given the risks, which include damage to major vessels when manipulating scarred skin. For such cases, we perform a 2-stage external PMMF transfer, whereby the PMMF is directly sutured to the defect over the neck skin (without manipulation the hardened skin), and the flap division is then performed secondarily. METHODS: A total of 30 patients who had histories of radiotherapy (60-70 Gy) and prior neck dissection received the 2-stage external PMMF transfer procedure. Indications for the flaps included pharyngeal fistula closure in 12 patients, reconstruction for mandibular necrosis after radiotherapy in 8 patients, salvage surgery for partial or total necrosis of the free flap in 4 patients, and simultaneous reconstruction after tumor excision in 6 patients. Two patients underwent a second external PMMF transfer from the contralateral side because of postoperative complications, yielding a total of 32 flap transfers. RESULTS: Twenty-nine flaps showed complete flap survival, whereas 3 had partial necrosis. Other complications, despite complete flap survival, included large fistulas requiring additional surgery for fistula closure (1 patient) and small fistulas that were closed without requiring reoperation (7 patients). CONCLUSIONS: External PMMF transfer offers a safe, simple, and effective option in cases where free flap surgery is considered difficult or the risks associated with neck manipulation are high.

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease.

Enarodustat (JTZ-951) is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has been approved and marketed in Japan for patients with anemia with chronic kidney disease (CKD). The pharmacometric approach was applied to assess the relationship between plasma concentrations of enarodustat and hemoglobin (Hb) levels, and to provide information regarding the optimal use of enarodustat in clinical practice by simulations based on the pharmacokinetic and pharmacodynamic (PK/PD) model that was developed. The PK/PD data of enarodusat obtained from phase 2 and phase 3 studies in Japanese patients with CKD were well described by the models: a 1-compartment model with first-order absorption and elimination for PK, and a semimechanistic model based on transit compartment model for PD. Although several factors were identified as statistically significant covariates on the PK/PD of enarodustat, model-based simulations showed that none of them had clinically relevant impacts on the treatment effect (ie, Hb levels) of enarodustat. Hence, enarodustat treatment provides the stable Hb control with the initial dose (hemodialysis-dependent CKD: 4 mg/day, non-dialysis-dependent CKD: 2 mg/day) and maintenance dose (1-8 mg/day) to the patients with varied demographic characteristics.

Pipeline Flex with Shield Technology Placement for Small- and Medium-sized Aneurysms Achieves Early Complete Occlusion.

The flow diverter has been shown to be a safe and effective device for large cerebral aneurysms in the proximal internal carotid artery (ICA). Recently, its indication has been expanded to small- and medium-sized cerebral aneurysms in the distal segment of the ICA. In this study, we report a single-center, retrospective investigation of the safety and efficacy of the Pipeline Flex device to treat these aneurysms. Of the patients who underwent Pipeline implantation for small- and medium-sized ICA aneurysms (≤12 mm) at our hospital between July 2013 and October 2021, 102 patients with 104 aneurysms were included in this study. The mean age of the patients was 57.7 ± 12.1 years, and 94 (90.4%) were female. The mean aneurysmal dome diameter was 9.2 ± 2.3 mm, the mean neck diameter was 5.3 ± 1.6 mm, and the mean dome-to-neck ratio was 1.8 ± 0.5. Twenty-five patients (24.0%) had incorporated vessels from the aneurysm. Complete occlusion of the aneurysms was obtained in 96 patients (92.3%). There were no cases of parent artery stenosis or major stroke after the procedure. Absence of incorporated vessel from the aneurysm dome and adjunctive coil embolization are statistically significant factors indicating complete occlusion in multivariate analysis. The time to complete occlusion was determined earlier with the use of the Pipeline Shield (p = 0.0386) and with adjunctive coils (p = 0.0025). We showed that Pipeline implantation for small- and medium-sized aneurysms was safe and highly effective.

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

Thoracic spinal metastasis as recurrence of borderline Brenner tumor without local recurrence: A case report.

Background: Brenner tumor is a rare epithelial ovarian neoplasm that accounts for 2-3% of all ovarian neoplasms. Herein, we report the first case of thoracic spinal metastasis of recurrent Brenner tumor without local recurrence.Case Description.A 70-year-old female presented with a feeling of abdominal distension. Computed tomography revealed cystic lesions in her bilateral ovaries. Blood examination revealed high CA-125 [74.9 U/ml]. We excised bilateral ovaries, uterus, and omentum. Borderline Brenner tumor was diagnosed [Ki-67 labeling index: 10 %]. Follow-up abdominal echo and CA-125 examination revealed no local recurrence. 26 months later she developed paraplegia. Magnetic resonance imaging revealed tumor in the 5th-9th thoracic vertebra and compression of spinal cord at the 6th thoracic vertebra level. Her paraplegia was progressive. We performed semi-urgent partial resection of tumor and release of spinal cord compression. Spinal metastasis from Brenner tumor was diagnosed [Ki-67 labeling index: 50-60 %]. She received adjuvant radiation of 30 Gy in 10 fractions to the 4th-10th thoracic vertebra. After radiation and rehabilitation, she was discharged home on foot. She received adjuvant radiation and chemotherapy but died 11 months after spinal surgery. An autopsy has not been performed on her, and the cause of death is unknown. Conclusion: We report the first case of thoracic metastasis of recurrent Brenner tumor without local recurrence.

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048.

BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.