Publications by authors named "Takashi Nakagawa"

257 Publications

PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma.

Mod Pathol 2021 Jul 3. Epub 2021 Jul 3.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.
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http://dx.doi.org/10.1038/s41379-021-00868-wDOI Listing
July 2021

Management of Residual Hearing with Cartilage Conduction Hearing Aid after Lateral Temporal Bone Resection: Our Institutional Experience.

Audiol Res 2021 Jun 9;11(2):263-274. Epub 2021 Jun 9.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Background: There is no guideline for hearing compensation after temporal bone resection. This study aimed to retrospectively analyze surgical cases with reconstruction for hearing preservation after temporal bone malignancy resection and propose a new alternative to compensate for hearing loss.

Methods: We retrospectively reviewed the medical records of 30 patients who underwent lateral temporal bone surgery for temporal bone malignancy at our institution and examined their hearing abilities after surgery.

Result: The hearing outcomes of patients with an external auditory meatus reconstruction varied widely. The mean postoperative air-bone gap at 0.5, 1, 2, and 4 kHz ranged from 22.5 dB to 71.25 dB. On the other hand, the average difference between the aided sound field thresholds with cartilage conduction hearing aid and bone conduction thresholds at 0.5, 1, 2, and 4 kHz ranged from -3.75 to 41.25. More closely located auricular cartilage and temporal bone resulted in smaller differences between the aided sound field and bone conduction thresholds.

Conclusions: There is still room for improvement of surgical techniques for reconstruction of the auditory meatus to preserve hearing after temporal bone resection. The cartilage conduction hearing aid may provide non-invasive postoperative hearing compensation after lateral temporal bone resection.
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http://dx.doi.org/10.3390/audiolres11020024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293261PMC
June 2021

Programmed Death-Ligand 1 Expression and Tumor-Infiltrating Lymphocytes in Temporal Bone Squamous Cell Carcinoma.

Laryngoscope 2021 Jun 18. Epub 2021 Jun 18.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objectives/hypothesis: The tumor immune microenvironment in temporal bone squamous cell carcinoma (TBSCC), including the programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs), has not been established.

Study Design: Retrospective cohort study.

Methods: We performed immunohistochemistry analyses to retrospectively analyze 123 TBSCC cases for PD-L1 expression and TILs and their prognostic significance. We also evaluated the prognostic correlations between these immunomarkers and the therapeutic responses to chemoradiotherapy (CRT).

Results: PD-L1 expression (≥1%) was detected in 62 (50.4%) TBSCC cases and was significantly associated with worse prognosis: progression-free survival (PFS), P < .0001; overall survival (OS), P = .0009. A high density of CD8 TILs was significantly associated with better prognosis (PFS, P = .0012; OS, P = .0120). In contrast, a high density of Foxp3 TILs tended to be associated with an unfavorable prognosis (PFS, P = .0148; OS, P = .0850). With regard to the tumor microenvironment subtypes defined by CD8 TILs and PD-L1 expression, the CD8 /PD-L1 group showed significantly worse prognosis. Among the 36 neoadjuvant CRT-treated cases, PD-L1 expression was significantly associated with worse OS (P = .0132). Among the 32 CRT-treated cases without surgery, a high density of CD8 TILs tended to be more highly associated with complete response to CRT compared to a low density of CD8 TILs (P = .0702).

Conclusions: These results indicate that the evaluation of the tumor immune microenvironment may contribute to the prediction of prognoses and the selection of an individualized therapeutic strategy for patients with TBSCC.

Level Of Evidence: 4 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29689DOI Listing
June 2021

Coil embolization for ruptured coronary pseudoaneurysm causing haemopericardium: a case report.

Eur Heart J Case Rep 2021 May 12;5(5):ytab129. Epub 2021 May 12.

Department of Cardiology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.

Background: Coronary artery pseudoaneurysm is a rare disease that can rupture and cause haemopericardium. It can occur principally as a complication after coronary artery instrumentation, but it can also result from trauma.

Case Summary: A 15-year-old male patient with a history of spontaneous pneumothoraces treated twice with video-assisted thoracoscopic thoracic surgery presented with pericarditis and increasing haemopericardium. During the hospitalization, he had developed cardiogenic shock and he underwent emergent pericardiocentesis. Coronary angiography revealed a small right coronary artery pseudoaneurysm. We successfully coil embolized the pseudoaneurysm.

Discussion: This is a rare case of a ruptured coronary artery pseudoaneurysm associated with prior tube thoracostomy. The treatments for a coronary pseudoaneurysm should be tailored based on the pathologic and anatomical characteristics.
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http://dx.doi.org/10.1093/ehjcr/ytab129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189297PMC
May 2021

Establishment and characterization of a primary cell culture derived from external auditory canal squamous cell carcinoma.

FEBS Open Bio 2021 Jun 11. Epub 2021 Jun 11.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

There are no human cancer cell lines of external auditory canal origin available for research use. This report describes the establishment of a culture condition for external auditory canal squamous cell carcinoma, derived from human tumor tissue. Successive squamous cell carcinoma colonies were dissociated by trypsin, subcultured, and maintained on a feeder layer (MMC-TIG-1-20), yielding a clonally proliferating cell culture. Two morphological types of colony were observed: (a) densely packed colonies and (b) colonies with indistinct boundaries characterized by cell-cell complexes with fibroblast feeder cells. The SCC-like characteristics of these cells were evidenced by positivity for p53, SCCA1/2, cytokeratin, and vimentin, and cancer stem cell properties were indicated by positivity for CD44, CD133, Oct3/4, and alkaline phosphatase (ALP). One of the unique properties of cell cultures is their tendency to form steric colonies in vitro on feeder layer cells. In addition, in the presence of fresh macrophages, the cells very slowly transform to break away from colonies as free cells, a process that resembles the epidermal-mesenchymal transition, whereby cell-cell interactions are weakened and migration activity is enhanced. These factors are purported to play a key role in cancer cell metastasis.
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http://dx.doi.org/10.1002/2211-5463.13225DOI Listing
June 2021

Subtotal temporal bone resection en bloc with the parotid gland and temporomandibular joint: a 2-dimensional operative video.

Am J Otolaryngol 2021 Jul-Aug;42(4):103081. Epub 2021 May 23.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Primary temporal bone squamous cell carcinoma is sporadic. According to previous studies, margin-negative resection provides the best prognosis (Nakagawa et al., 2006; Moody et al., 2000; Yin et al., 2006; Komune et al., 2021 [1-4]). When tumors extend behind the tympanic membrane, lateral temporal bone resection, which is a well-established procedure, is insufficient to achieve a tumor-free margin. For these cases, subtotal temporal bone resection (STBR) can achieve a complete en bloc resection with a tumor-free margin. Furthermore, STBR en bloc with surrounding structures, including the temporomandibular joint and parotid gland, complicates surgical techniques. We previously reported this surgical procedure in a stepwise manner using cadaveric dissection (Komune et al., 2014 [5]). The STBR en bloc with the parotid gland and temporomandibular joint is composed of three approaches according to our previous report: high cervical exposure (neck dissection), a subtemporal-infratemporal fossa approach, and a retromastoid-paracondylar approach. However, we currently lack demonstrative surgical videos. According to our previous report, this video first demonstrates STBR en bloc with the parotid gland and temporomandibular joint (Komune et al., 2014 [5]). The histopathological diagnosis of a 57-year-old woman suffering from a large tumor protruding from her auricle indicated squamous cell carcinoma; after the diagnosis she was referred to our hospital. Computed tomography revealed the full extent of the tumor, which was about 8 cm in diameter and had damaged the middle cranial base, mastoid bone, and middle ear cavity. Magnetic resonance imaging indicated invasion of the glenoid fossa and parotid gland, equivalent to a Pittsburg stage cT4 tumor. The patient underwent STBR en bloc with the parotid gland and temporomandibular joint. Lower cranial nerves (CN IX-XII) were preserved, and the patient achieved normal oral intake without additional procedures after surgery. At six months post-operation, no recurrence was noted. In this video, we first demonstrate the surgical procedure of the STBR en bloc with the parotid gland and temporomandibular joint for far-advanced temporal bone squamous cell carcinoma, and it can be one of the surgical options to achieve the complete resection without exposure of the tumor. Informed consent was obtained from the patient. The video was reproduced with the written informed consent of the patient. Primary temporal bone squamous cell carcinoma is sporadic. According to previous studies, margin-negative resection provides the best prognosis (Nakagawa et al., 2006; Moody et al., 2000; Yin et al., 2006; Komune et al., 2021 [1-4]). When tumors extend behind the tympanic membrane, lateral temporal bone resection, which is a well-established procedure, is insufficient to achieve a tumor-free margin. For these cases, subtotal temporal bone resection (STBR) can achieve a complete en bloc resection with a tumor-free margin. Furthermore, STBR en bloc with surrounding structures, including the temporomandibular joint and parotid gland, complicates surgical techniques. We previously reported this surgical procedure in a stepwise manner using cadaveric dissection (Komune et al., 2014 [5]). The STBR en bloc with the parotid gland and temporomandibular joint is composed of three approaches according to our previous report: high cervical exposure (neck dissection), a subtemporal-infratemporal fossa approach, and a retromastoid-paracondylar approach. However, we currently lack demonstrative surgical videos. According to our previous report, this video first demonstrates STBR en bloc with the parotid gland and temporomandibular joint (Komune et al., 2014 [5]). The histopathological diagnosis of a 57-year-old woman suffering from a large tumor protruding from her auricle indicated squamous cell carcinoma; after the diagnosis she was referred to our hospital. Computed tomography revealed the full extent of the tumor, which was about 8 cm in diameter and had damaged the middle cranial base, mastoid bone, and middle ear cavity. Magnetic resonance imaging indicated invasion of the glenoid fossa and parotid gland, equivalent to a Pittsburg stage cT4 tumor. The patient underwent STBR en bloc with the parotid gland and temporomandibular joint. Lower cranial nerves (CN IX-XII) were preserved, and the patient achieved normal oral intake without additional procedures after surgery. At six months post-operation, no recurrence was noted. In this video, we first demonstrate the surgical procedure of the STBR en bloc with the parotid gland and temporomandibular joint for far-advanced temporal bone squamous cell carcinoma, and it can be one of the surgical options to achieve the complete resection without exposure of the tumor. Informed consent was obtained from the patient. The video was reproduced with the written informed consent of the patient.
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http://dx.doi.org/10.1016/j.amjoto.2021.103081DOI Listing
May 2021

Auricular complications following temporal bone resection for temporal bone malignancies: A clinical consideration.

Clin Otolaryngol 2021 May 7. Epub 2021 May 7.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1111/coa.13796DOI Listing
May 2021

Clinical Management of Early-Stage Hypopharyngeal Squamous Cell Carcinoma: A Single-Institution Clinical Analysis.

Ear Nose Throat J 2021 Apr 28:1455613211013084. Epub 2021 Apr 28.

Department of Otorhinolaryngology, Graduate School of Medical sciences, 12923Kyushu University, Fukuoka, Japan.

Objective: Early detection of hypopharyngeal squamous cell carcinoma (SCC) is important for both an improved prognosis and less-invasive treatment. We retrospectively analyzed the detection rates of early hypopharyngeal SCCs according to the evaluation methods and the clinical management of early hypopharyngeal SCCs.

Methods: Sixty-eight patients with early hypopharyngeal SCC who were diagnosed were reviewed.

Results: The number of early hypopharyngeal cancer patients with asymptomatic or synchronous or metachronous esophageal cancer examined by upper gastrointestinal endoscopy with narrow-band imaging (NBI) was significantly higher than those examined by laryngopharyngeal endoscopy with NBI. The 3-year disease-specific survival rates according to T classification were as follows: Tis, 100%; T1, 100%; T2, 79.8%; and overall, 91.2%, respectively.

Conclusions: Early-stage hypopharyngeal SCC can be cured by minimally invasive transoral surgery or radiotherapy. Observation of the pharynx using NBI in patients with a history of head and neck cancer, esophageal cancer, gastric cancer, or pharyngeal discomfort is very important, and routinely examining the pharynx with NBI, even in patients undergoing endoscopy for screening purposes, is recommended.
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http://dx.doi.org/10.1177/01455613211013084DOI Listing
April 2021

A Multi-Institutional Study of Older Hearing Aids Beginners-A Prospective Single-Arm Observation on Executive Function and Social Interaction.

J Am Med Dir Assoc 2021 06 1;22(6):1168-1174. Epub 2021 Apr 1.

Department of Otolaryngology-Head and Neck Surgery, Nagoya City University, Graduate School of Medical Sciences and Medical School; East Medical Center, Nagoya, Aichi, Japan.

Objectives: To obtain new insights into research questions on how executive function and social interaction would be observed to change after the introduction of hearing aids (HAs) in older people with hearing impairment.

Design: Multi-institutional prospective single-arm observational study.

Setting And Participants: Outpatients with complaints of hearing difficulty who visited HA clinics between October 18, 2017, and June 30, 2019, in 7 different university hospitals in Japan.

Methods: The inclusion criteria of the study named Hearing-Aid Introduction for Hearing-Impaired Seniors to Realize a Productive Aging Society-A Study Focusing on Executive Function and Social Activities Study (HA-ProA study) were age ≥60 years and no history of HA use. A series of multi-institution common evaluations including audiometric measurements, the digit symbol substitution test to assess executive functions, convoy model as an index of social relations, and hearing handicap inventory for the elderly (HHIE) were performed before (pre-HA) and after 6 months of the HA introduction (post-HA).

Results: Out of 127 enrollments, 94 participants completed a 6-month follow-up, with a mean age of 76.9 years. The digit symbol substitution test score improved significantly from 44.7 at baseline to 46.1 at 6 months (P = .0106). In the convoy model, the social network size indicated by the number of persons in each and whole circles were not significantly different between pre- and post-HA; however, the total count for kin was significantly increased (P = .0344). In the analyses of HHIE, the items regarding the family and relatives showed significant improvement.

Conclusions And Implications: HA use could benefit older individuals beginning to use HAs in executive function and social interaction, though the results should be interpreted cautiously given methodological limitations such as a single-arm short 6 months observation. Reduction in daily hearing impairment would have a favorable effect on relationships with the family.
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http://dx.doi.org/10.1016/j.jamda.2021.02.035DOI Listing
June 2021

A Pedicled Posterior Septal-Nasal Floor Flap and a Novel Rescue Flap for Skull Base Reconstruction.

World Neurosurg 2021 06 6;150:197-204.e1. Epub 2021 Mar 6.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: We devised a new surgical alternative to the conventional nasoseptal flap, a pedicled posterior septal-nasal floor flap that we named the Kegon flap. We evaluated the effectiveness of this flap for skull base reconstruction in patients with high-flow cerebrospinal fluid (CSF) leakage after sellar/parasellar tumor resection.

Methods: The Kegon flap with a novel rescue flap was designed to preserve blood flow and mucosa anterior to the nasal septum and to avoid flap damage during surgery. We retrospectively evaluated postoperative flap perfusion with T1-weighted contrast-enhanced magnetic resonance imaging and characterized complications and wound healing in 5 patients who experienced high-flow CSF leakage after sellar/parasellar tumor resection requiring reconstruction.

Results: Postoperative T1-weighted contrast-enhanced magnetic resonance imaging demonstrated good flap perfusion in all patients. The area reconstructed with the Kegon flap healed within the first month following surgery. No postoperative CSF leakage or nasal hemorrhage was observed. There was no perforation of the anterior nasal septum after surgery. The mucosal defect had completely epithelialized in all patients by 3 months after surgery. There were no instances of prolonged nasal crusting or any subjective decrease in olfactory function 3 months after surgery.

Conclusions: The use of a Kegon flap with a novel rescue flap was effective and helped preserve nasal structure and function in patients undergoing skull base reconstruction after sellar/parasellar tumor resection associated with high-flow CSF leakage.
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http://dx.doi.org/10.1016/j.wneu.2021.02.138DOI Listing
June 2021

Prognostic Significance of Systemic Inflammatory Response in Cases of Temporal Bone Squamous Cell Carcinoma.

Laryngoscope 2021 08 4;131(8):1782-1789. Epub 2021 Feb 4.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective/hypothesis: Squamous cell carcinoma (SCC) of the temporal bone is an extremely rare condition. This rarity has led to a delay in the establishment of a standard treatment protocol and adequate staging system. Identification of prognostic markers of this disease from a variety of fields is desirable in the establishment of treatment guidelines for temporal bone SCC. The aim of this study is to assess the prognostic role of inflammation-based prognostic scores in cases of temporal bone SCC.

Study Design: Case reries with chart review.

Methods: A total of 71 cases of primary malignancy eligible for curative treatment at a single tertiary medical institute were retrospectively analyzed. Univariate and multivariate regression analyzes were used to investigate the association between the inflammation-based scores and 5-year overall survival.

Results: Univariate Cox regression analyzes showed that a high neutrophil-to-lymphocyte ratio, high platelet-to-lymphocyte ratio, low lymphocyte-to-monocyte ratio, a Glasgow prognostic score of 2, and the systemic inflammation score of 2 were significantly associated with a poor prognosis, as well as a classification of T4 stage, presence of cervical lymph node metastasis, high white blood cell counts, and high C-reactive protein levels. The multivariate analysis showed that a clinical stage of T4 and a systemic inflammation score of 2 were independent prognostic markers.

Conclusions: Inflammation-based prognostic markers are associated with the survival of patients with temporal bone SCC, as well as other head and neck SCCs.

Level Of Evidence: 4 Laryngoscope, 131:1782-1789, 2021.
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http://dx.doi.org/10.1002/lary.29421DOI Listing
August 2021

Differences Among Mixed, Chest, and Falsetto Registers: A Multiparametric Study.

J Voice 2021 Jan 28. Epub 2021 Jan 28.

Department of Otorhinolaryngology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Introduction: Typical singing registers are the chest and falsetto; however, trained singers have an additional register, namely, the mixed register. The mixed register, which is also called "mixed voice" or "mix," is an important technique for singers, as it can help bridge from the chest voice to falsetto without noticeable voice breaks.

Objective: The present study aims to reveal the nature of the voice-production mechanism of the different registers (chest, mix, and falsetto) using high-speed digital imaging (HSDI), electroglottography (EGG), and acoustic and aerodynamic measurements.

Study Design: Cross-sectional study.

Methods: Aerodynamic measurements were acquired for twelve healthy singers (six men and women) during the phonation of a variety of pitches using three registers. HSDI and EGG devices were simultaneously used on three healthy singers (two men and one woman) from which an open quotient (OQ) and speed quotient (SQ) were detected. Audio signals were recorded for five sustained vowels, and a spectral analysis was conducted to determine the amplitude of each harmonic component. Furthermore, the absolute (not relative) value of the glottal volume flow was estimated by integrating data obtained from the HSDI and aerodynamic studies.

Results: For all singers, the subglottal pressure (P) was the highest for the chest in the three registers, and the mean flow rate (MFR) was the highest for the falsetto. Conversely, the P of the mix was as low as the falsetto, and the MFR of the mix was as low as the chest. The HSDI analysis showed that the OQ differed significantly among the registers, even when the fundamental frequency was the same; the OQ of the mix was higher than that of the chest but lower than that of the falsetto. The acoustic analysis showed that, for the mix, the harmonic structure was intermediate between the chest and falsetto. The results of the glottal volume-flow analysis revealed that the maximum volume velocity was the least for the mix register at every fundamental frequency. The first and second harmonic (H1-H2) difference of the voice source spectrum was the greatest for the falsetto, then the mix, and finally, the chest.

Conclusions: We found differences in the registers in terms of the aeromechanical mechanisms and vibration patterns of the vocal folds. The mixed register proved to have a distinct voice-production mechanism, which can be differentiated from those of the chest or falsetto registers.
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http://dx.doi.org/10.1016/j.jvoice.2020.12.028DOI Listing
January 2021

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effect while maintaining bone mineral density in mice.

Eur J Pharmacol 2021 Mar 18;895:173880. Epub 2021 Jan 18.

Faculty of Agriculture, Department of Agrobiology, Niigata University, Niigata, Japan.

Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids.
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http://dx.doi.org/10.1016/j.ejphar.2021.173880DOI Listing
March 2021

Simultaneous Measurement of Amino Acid Enantiomers in Aged Mouse Brain Samples by LC/MS/MS Combined with Derivatization Using -(5-Fluoro-2,4-dinitrophenyl)-l-leucinamide (l-FDLA).

Metabolites 2021 Jan 15;11(1). Epub 2021 Jan 15.

Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.

D-amino acids have distinct roles from their l-enantiomer. In particular, some D-amino acids function as agonists or antagonists of neuronal receptors and are involved in higher brain functions. Thus, it is important to precisely measure the levels of these amino acid enantiomers in cells and tissues. Various quantification methods have been developed for measurements of chiral amino acids. However, each method has advantages and disadvantages. Additionally, measuring the amino acid enantiomers in crude biological samples requires a higher selectivity. In this study, we developed a quantification method for amino acid enantiomers using derivatization with -(5-Fluoro-2,4-dinitrophenyl)-l-leucinamide (l-FDLA) followed by liquid chromatography-tandem mass spectrometry (LC/MS/MS) with a conventional reversed-phase column. We simultaneously identified 10 chiral amino acids. Furthermore, we applied this method to investigate murine tissue samples and examined the effect of aging on the amino acid levels in aged brain regions. We found that aging decreased the levels of both D-serine and D-aspartate in the hippocampus. In addition, D-Phenylalanine in the thalamus significantly increased with age. In conclusion, our method is suitable for the quantification of the D-amino acids in crude biological samples and may contribute to elucidating the biological roles of chiral amino acids.
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http://dx.doi.org/10.3390/metabo11010057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829926PMC
January 2021

p16 overexpression and Rb loss correlate with high-risk HPV infection in oropharyngeal squamous cell carcinoma.

Histopathology 2021 Jan 15. Epub 2021 Jan 15.

Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.

Aims: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC), but it is not sufficient in all clinical settings.

Methods And Results: We examined the p16 and Rb expression status in 177 OPSCC cases by immunohistochemistry and the presence of transcriptionally active HR-HPV infection by mRNA in-situ hybridisation. The 177 cases were divided into p16 /HPV (n = 105, 59.3%), p16 /HPV (n = 8, 4.5%) and p16 /HPV (n = 64, 36.2%) groups. The p16 /HPV and p16 /HPV groups had a trend towards worse overall survival (OS) or significantly worse OS than the p16 /HPV group (n = 105) (P = 0.0610, P = 0.0004, respectively). We divided the Rb status into preserved expression (> 90%, n = 68), partial loss (PL) (10-90%, n = 97) and complete loss (CL) (< 10%, n = 12). Among the HPV-positive cases (n = 105), the Rb pattern was typically PL (n = 97, 92.4%) and rarely CL (n = 8, 7.6%), but never preserved expression (0%). In contrast, among the HPV-negative cases (n = 72), the Rb pattern was typically preserved expression (n = 68, 94.4%) and rarely CL (n = 4, 5.6%), but never PL (0%). Compared to p16 alone, the combination of p16 overexpression and Rb-PL/CL showed equally excellent sensitivity (each 100%) and improved specificity (97.2 versus 88.9%) and positive predictive values (98.1 versus 92.9%).

Conclusions: These results suggest that the combined use of p16 and Rb immunohistochemistry could be a reliable, cost-effective method to predict HR-HPV infection in OPSCCs; however, HPV specific testing is necessary on inconclusive cases. We propose a diagnostic algorithm for practical use of these markers.
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http://dx.doi.org/10.1111/his.14337DOI Listing
January 2021

Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events.

Sci Rep 2021 01 14;11(1):1324. Epub 2021 Jan 14.

Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10-1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06-0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.
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http://dx.doi.org/10.1038/s41598-020-79397-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809015PMC
January 2021

Long-term effectiveness, safety, and quality of life outcomes following endoscopic posterior nasal neurectomy with submucosal turbinectomy for the treatment of intractable severe chronic rhinitis.

Auris Nasus Larynx 2021 Aug 11;48(4):636-645. Epub 2021 Jan 11.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: In recent decades, posterior nasal neurectomy (PNN) with submucosal inferior turbinectomy (ST) has been increasingly used for the treatment of intractable severe rhinitis; however, to the best of our knowledge, there have been few studies regarding its long-term therapeutic effects or its influence on patient quality of life (QOL). Therefore, this study examined the long-term therapeutic effects in patients who underwent PNN with ST, as well as their QOL and medication use after surgery.

Methods: This retrospective cohort study initially included 16 consecutive patients who underwent PNN with ST from January 2010 to December 2011. Ten of the 16 patients participated in a paper-based survey questionnaire between June 2018 and November 2018; the responses of these 10 patients were used for analysis in this study. To clarify the effects of surgical treatment on symptoms, QOL, and medication status, data recorded before and 3 months after surgery were compared with data recorded at 8 years after surgery using the Japan Rhinoconjunctivitis Quality of Life Questionnaire No. 1 and Classification of the Severity of Allergic Rhinitis Symptoms I and II.

Results: Nasal symptoms including runny nose and nasal congestion, medication score, respective total symptoms medication scores (i.e., combined average total symptoms score and medication score), and the scores of troubles with daily life and total QOL were significantly improved at 3 months and 8 years after surgery, compared with before surgery; scores were not significantly worsened at 8 years after surgery, compared with 3 months after surgery. In addition, there were no adverse events requiring treatment after surgery.

Conclusion: Our findings suggest that PNN with ST is effective and safe for long-term treatment of severe chronic rhinitis symptoms, as well as reduction of medication use and improvement of QOL.
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http://dx.doi.org/10.1016/j.anl.2020.12.009DOI Listing
August 2021

Genomic Sequencing of Cancer-related Genes in Sinonasal Squamous Cell Carcinoma and Coexisting Inverted Papilloma.

Anticancer Res 2021 Jan;41(1):71-79

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The genetic basis of sinonasal inverted papilloma (SNIP)-derived squamous cell carcinoma (SCC) has not yet been well characterized.

Aim: To characterize the genetic abnormalities of SNIP and SNIP-derived SCC and to uncover their differences.

Materials And Methods: Mutations of 409 genes were analyzed using amplicon targeted sequencing in a total of six papilloma/carcinoma samples from four patients with SNIP-derived SCC.

Results: The genes that were mutated in multiple cases were epidermal growth factor receptor (EGFR) (3/6), cyclin-dependent kinase inhibitor 2A (CDKN2A) (3/6), lysine methyltransferase 2D (KMT2D) (3/6), tumor protein p53 (TP53) (3/6), neurofibromin 1 (NF1) (3/6), phosphodiesterase 4D interacting protein (PDE4DIP) (3/6), cytochrome P450 family 2 subfamily D member 6 (CYP2D6) (2/6), fms-related receptor tyrosine kinase 4 (FLT4) (2/6) and myosin heavy chain 9 (MYH9) (2/6). Of the two cases analyzed in the papilloma-oncology carcinoma pair, one did not have any common mutations; the other showed a staged functional deletion of TP53 during the process of malignant transformation from SNIP to SCC.

Conclusion: CDKN2A, KMT2D, NF1, PDE4DIP, CYP2D6, FLT4, and MYH9 were identified as candidate novel SNIP-derived SCC-related genes.
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http://dx.doi.org/10.21873/anticanres.14752DOI Listing
January 2021

Drug-induced interstitial lung disease in recurrent and/or metastatic head and neck cancer patients treated with cetuximab and/or nivolumab.

Oral Oncol 2021 02 22;113:105129. Epub 2020 Dec 22.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Background: Drug-induced interstitial lung disease (DI-IP) is one of the most serious adverse reactions associated with the use of anticancer drugs. DI-IP prevalence among molecular-targeting drugs and immune checkpoint inhibitors (ICIs) is relatively high in Japanese patients. To assess the risk of cetuximab and/or nivolumab-related IP is important.

Patients And Methods: The medical records of 138 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with cetuximab-containing chemotherapy and/or nivolumab monotherapy were retrospectively reviewed.

Results: The incidence of DI-IP with R/M HNSCC was 7.2%. DI-IP occurred more frequently in patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy than in patients with other regimens. However, tumor suppression was detected in all patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy, and two achieved a complete response.

Conclusions: Although patients treated with cetuximab-containing chemotherapy following nivolumab showed dramatic efficacy, careful monitoring should be recommended.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105129DOI Listing
February 2021

NAD+ Metabolism Regulates Preadipocyte Differentiation by Enhancing α-Ketoglutarate-Mediated Histone H3K9 Demethylation at the PPARγ Promoter.

Front Cell Dev Biol 2020 24;8:586179. Epub 2020 Nov 24.

Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan.

Obesity has become a serious problem in public health worldwide, causing numerous metabolic diseases. Once the differentiation to mature adipocytes is disrupted, adipocyte hypertrophy and ectopic lipid accumulation leads to the inflammation in adipose tissue and systemic metabolic disorders. Intracellular metabolic state is known to change during cell differentiation and it affects the cell fate or the differentiation through epigenetic mechanism. Although the mechanism of preadipocyte differentiation has been well established, it is unknown how metabolic state changes and how it affects the differentiation in predipocyte differentiation. Nicotinamide adenine dinucleotide (NAD+) plays crucial roles in energy metabolism as a coenzyme in multiple redox reactions in major catabolic pathways and as a substrate of sirtuins or poly(ADP-ribose)polymerases. NAD+ is mainly synthesized from salvage pathway mediated by two enzymes, Nampt and Nmnat. The manipulation to NAD+ metabolism causes metabolic change in each tissue and changes in systemic metabolism. However, the role of NAD+ and Nampt in adipocyte differentiation remains unknown. In this study, we employed liquid chromatography-mass spectrometry (LC-MS)- and gas chromatography-mass spectrometry (GC-MS)-based targeted metabolomics to elucidate the metabolic reprogramming events that occur during 3T3-L1 preadipocyte differentiation. We found that the tricarboxylic acid (TCA) cycle was enhanced, which correlated with upregulated NAD+ synthesis. Additionally, increased alpha-ketoglutarate (αKG) contributed to histone H3K9 demethylation in the promoter region of PPARγ, leading to its transcriptional activation. Thus, we concluded that NAD+-centered metabolic reprogramming is necessary for the differentiation of 3T3-L1 preadipocytes.
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http://dx.doi.org/10.3389/fcell.2020.586179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732485PMC
November 2020

Deletion of the GAPDH gene contributes to genome stability in Saccharomyces cerevisiae.

Sci Rep 2020 12 3;10(1):21146. Epub 2020 Dec 3.

Biomedical Research Support Center (BRSC), Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan.

Cellular metabolism is directly or indirectly associated with various cellular processes by producing a variety of metabolites. Metabolic alterations may cause adverse effects on cell viability. However, some alterations potentiate the rescue of the malfunction of the cell system. Here, we found that the alteration of glucose metabolism suppressed genome instability caused by the impairment of chromatin structure. Deletion of the TDH2 gene, which encodes glyceraldehyde 3-phospho dehydrogenase and is essential for glycolysis/gluconeogenesis, partially suppressed DNA damage sensitivity due to chromatin structure, which was persistently acetylated histone H3 on lysine 56 in cells with deletions of both HST3 and HST4, encoding NAD-dependent deacetylases. tdh2 deletion also restored the short replicative lifespan of cells with deletion of sir2, another NAD-dependent deacetylase, by suppressing intrachromosomal recombination in rDNA repeats increased by the unacetylated histone H4 on lysine 16. tdh2 deletion also suppressed recombination between direct repeats in hst3∆ hst4∆ cells by suppressing the replication fork instability that leads to both DNA deletions among repeats. We focused on quinolinic acid (QUIN), a metabolic intermediate in the de novo nicotinamide adenine dinucleotide (NAD) synthesis pathway, which accumulated in the tdh2 deletion cells and was a candidate metabolite to suppress DNA replication fork instability. Deletion of QPT1, quinolinate phosphoribosyl transferase, elevated intracellular QUIN levels and partially suppressed the DNA damage sensitivity of hst3∆ hst4∆ cells as well as tdh2∆ cells. qpt1 deletion restored the short replicative lifespan of sir2∆ cells by suppressing intrachromosomal recombination among rDNA repeats. In addition, qpt1 deletion could suppress replication fork slippage between direct repeats. These findings suggest a connection between glucose metabolism and genomic stability.
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http://dx.doi.org/10.1038/s41598-020-78302-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713361PMC
December 2020

Use of negative pressure wound therapy to treat a cochlear implant infection around the auricle: a case report.

J Wound Care 2020 Oct;29(10):568-571

Department of Plastic and Reconstructive Surgery, Kyushu University Hospital, Japan.

Although negative pressure wound therapy (NPWT) is widely used, its application to the head and neck region remains challenging due to anatomical complexities. This report presents the case of a female patient presenting with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, uncontrolled diabetes and severe bilateral sensorineural hearing loss. The patient had undergone cochlear implant surgery and five months later the wound was infected with methicillin-resistant (MRSA). NPWT was started shortly after removing the internal receiver and was stopped 11 days later. NPWT helped in controlling infection and led to a successful wound closure. In this case, NPWT was effective in treating infectious wounds around the auricle after cochlear implant surgery. Declaration of interest: The authors have no financial support for this article and no conflict of interest directly relevant to the content of this article.
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http://dx.doi.org/10.12968/jowc.2020.29.10.568DOI Listing
October 2020

Clinicopathologic Significance of EGFR Mutation and HPV Infection in Sinonasal Squamous Cell Carcinoma.

Am J Surg Pathol 2021 01;45(1):108-118

Departments of Anatomic Pathology.

Sinonasal squamous cell carcinoma (SNSCC) is sometimes associated with high-risk human papillomavirus (HR-HPV) infection and inverted sinonasal papilloma or oncocytic sinonasal papilloma. Frequent mutations of EGFR and KRAS are reported in inverted sinonasal papilloma-related sinonasal squamous cell carcinoma (ISP-SCC) and oncocytic sinonasal papilloma-related SNSCC, respectively. Here, we attempted to determine the prevalence and the prognostic significances of these alterations in SNSCC. We retrospectively collected 146 SNSCCs, including 14 ISP-SCCs, and comprehensively analyzed the HR-HPV infection by human papillomavirus (HPV)-RNA in situ hybridization, EGFR gene copy number gain (CNG) by chromogenic in situ hybridization, and gene mutations in EGFR and KRAS by Sanger sequencing. HR-HPV was detected in 11 cases (7.5%), whereas all 14 ISP-SCCs were negative. EGFR mutations were present in 21 (14.7%) of 143 SNSCCs, including 13/14 (92.9%) ISP-SCCs and 8/129 (6.2%) non-ISP-SCCs (P<0.0001). The majority of EGFR mutations were exon 20 insertions, with the remainder composed of deletions and single-nucleotide substitutions in exons 19 and 20. All of 142 SNSCCs harbored no KRAS mutation. EGFR CNG was detected in 41 (28.1%) of 146 SNSCCs; all of them were HPV negative and 3 had EGFR mutations. Collectively, EGFR mutation, EGFR CNG, and HR-HPV were essentially mutually exclusive, and each subgroup had distinct clinicopathologic features. The HPV-negative/EGFR-mutant group, the HPV-negative/EGFR CNG-positive group, and the triple-negative group had significantly worse prognoses than the HPV-positive group (P=0.0265, 0.0264, and 0.0394, respectively). In conclusion, EGFR mutation may play a pathogenetically important role in some populations of SNSCCs, especially ISP-SCCs. The molecular subclassification of SNSCCs may contribute to prognostic prediction and molecular-targeted precision medicine.
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http://dx.doi.org/10.1097/PAS.0000000000001566DOI Listing
January 2021

Prognostic Impact of Tumor Extension in Patients With Advanced Temporal Bone Squamous Cell Carcinoma.

Front Oncol 2020 7;10:1229. Epub 2020 Aug 7.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The extreme rarity of temporal bone squamous cell carcinoma (TB-SCC) has delayed the accumulation of high-quality clinical evidence. Our objective here was to explore anatomical factors associated with the prognosis of T4 TB-SCC cases. Case series with chart review. Two academic tertiary care medical centers. The medical records of all TB-SCC cases were retrospectively reviewed in two institutions. The resulting data set contained 30 cases of primary T4 cancer eligible for initial definitive (curative) treatment. Disease-specific survival was calculated according to the Kaplan-Meier method. Cox proportional hazards model was used to identify anatomical prognosis factors. The disease-specific 5-years survival rate of 30 cases of T4 TB-SCC was 53.9%. The tumor invasion to the pterygoid muscle, posterior fossa dura, and sigmoid sinus and destruction of the ossicles were associated with poor prognosis in univariate analysis. The multivariate analysis reveals that the invasion of the ossicles, posterior fossa dura, and sigmoid sinus is an independent prognostic factor [hazard ratio (HR): 4.528 (95% CI: 1.161-17.658), p = 0.030; HR: 5.135 (95% CI: 1.616-16.315), p = 0.006; HR: 4.292 (95% CI: 1.385-13.303), p = 0.012]. The invasion of the carotid canal, petrous apex, middle fossa dura, otic capsule, pterygoid muscle, and middle ear had a high HR (HR > 2). The more invaded anatomical factors present in patients resulted in a poorer patient disease-specific prognosis, with a statistically significant difference. Assessing which anatomical structures are susceptible to invasion by tumors may be important for predicting TB-SCC patient prognosis and selecting appropriate treatment planning, especially surgical intervention. In addition to previously reported factors, the destruction of the ossicles in the middle ear cavity can be an anatomical prognosis factor.
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http://dx.doi.org/10.3389/fonc.2020.01229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427636PMC
August 2020

Prognostic Biomarkers of Salvage Chemotherapy Following Nivolumab Treatment for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2020 Aug 15;12(8). Epub 2020 Aug 15.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Recent studies have suggested the benefit of salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). We retrospectively examined the outcome of SCT and the usefulness of the serum C-reactive protein level (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic biomarkers. Thirty-nine patients with R/M HNSCC were enrolled in this study. Twenty-five patients (64.1%) received combination chemotherapy of weekly paclitaxel and cetuximab (PC) as SCT, and 14 patients (35.9%) received tegafur-gimestat-otastat potassium (S1), an oral fluoropyrimidine. In all patients, the response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 45.2%, 85.7%, 6.5 months, and 13.5 months, respectively. No chemotherapy-related deaths were observed. These PC groups had low CRP (<1.2 mg/dL) or low NLR (<7.0) values at the time of SCT induction, which was significantly associated with an improved OS ( = 0.0440, = 0.0354). A multivariate analysis also showed that a lower CRP value was significantly associated with a better OS ( = 0.0078). We clarified the usefulness of the PC and S1 regimens as SCT. In addition, SCT with the PC regimen showed a better prognosis with a lower CRP or NLR at induction than a higher CRP or NLR. This is the first report on biomarkers of SCT in R/M HNSCC.
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http://dx.doi.org/10.3390/cancers12082299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463840PMC
August 2020

Clinical outcome in recurrent and/or metastatic head and neck cancer patients after discontinuation of nivolumab monotherapy due to immune-related adverse events.

Acta Otolaryngol 2020 Dec 18;140(12):1043-1048. Epub 2020 Aug 18.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Significant immune-related adverse events (irAEs) requiring therapy discontinuation sometimes occur. The influence of discontinuation on disease control after an irAE is unclear.

Objectives: The aim of this study was to investigate whether or not patients continued to show a response or durable disease control even after stopping therapy following an irAE.

Material And Methods: The response after nivolumab monotherapy discontinuation was examined for 14 patients in whom therapy was stopped without progression.

Results: The best response was CR in 5 (36%) patients, PR in 8 (57%) patients and SD in 1 (7%) patient. The estimated 1-year overall and progression-free survival rates were 92.9% and 78.6%, respectively. The best response during nivolumab therapy in patients who developed PD was CR in 0 of 5 patients (0%), PR in 3 of 8 patients (38%) and SD in 1 patient (100%). Patients obtaining CR tended to have a lower risk of PD than those with PR or SD.

Conclusions And Significance: Patients with CR status may continue to show a response or durable disease control even after stopping therapy due to an irAE.
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http://dx.doi.org/10.1080/00016489.2020.1807601DOI Listing
December 2020

Awareness of stuttering in Japanese children aged 3-7 years.

Pediatr Int 2021 Feb 18;63(2):150-153. Epub 2021 Feb 18.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Boey et al. (2009) devised a questionnaire for measuring children's awareness of stuttering and showed that even very young children were often aware of their stuttering. There has been no replication of studies using Boey et al.'s parent-reported questionnaire. The aim of this study was to test whether using Boey et al.'s seven questions, developed for a Dutch speaking population could be effective for measuring the awareness of stuttering in Japanese children.

Methods: Participants were 54 children who stutter (CWS) aged 3-7 years. Parents answered seven questions about their child's awareness of stuttering according to the questions developed Boey et al. RESULTS: Parental-reported observations of the child responses citing at least one awareness incident were 76%. The percentage of stuttering children with awareness of their own speech difficulties, according to chronological age, were as follows: 70% at age 3 years; 67% at age 4 years; 75% at age 5 years; 81% at age 6 years; and 90% at age 7 years.

Conclusions: We found that even at age 3 years, many CWS were already aware of their stuttering. The similarity of the data with the seminal study by Boey et al. suggests that the question-based assessment is reproducible even in a country with a different spoken language. The seven questions in Boey et al. are useful for evaluating whether children's awareness of stuttering could contribute to a clinical decision as well as stuttering severity.
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http://dx.doi.org/10.1111/ped.14405DOI Listing
February 2021

Genetic landscape of external auditory canal squamous cell carcinoma.

Cancer Sci 2020 Aug 11;111(8):3010-3019. Epub 2020 Jul 11.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

External auditory canal squamous cell carcinoma (EACSCC) is an extremely rare and aggressive malignancy. Due to its rarity, the molecular and genetic characteristics of EACSCC have not yet been elucidated. To reveal the genetic alterations of EACSCC, we performed whole exome sequencing (WES) on 11 primary tumors, 1 relapsed tumor and 10 noncancerous tissues from 10 patients with EACSCC, including 1 with a rare case of synchronous bilateral EACSCC of both ears. WES of the primary tumor samples showed that the most frequently mutated gene is TP53 (63.6%). In addition, recurrent mutations in CDKN2A, NOTCH1, NOTCH2, FAT1 and FAT3 were detected in multiple samples. The mutational signature analysis of primary tumors indicated that the mutational processes associated with the activation of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases are the most common in EACSCC, suggesting its similarity to SCC from other primary sites. Analysis of arm-level copy number alterations detected notable amplification of chromosomes 3q, 5p and 8q as well as deletion of 3p across multiple samples. Focal chromosomal aberrations included amplifications of 5p15.33 (ZDHHC11B) and 7p14.1 (TARP) as well as deletion of 9p21.3 (CDKN2A/B). The protein expression levels of ZDHHC11B and TARP in EACSCC tissues were validated by immunohistochemistry. Moreover, WES of the primary and relapsed tumors from a case of synchronous bilateral EACSCC showed the intrapatient genetic heterogeneity of EACSCC. In summary, this study provides the first evidence for genetic alterations of EACSCC. Our findings suggest that EACSCC mostly resembles other SCC.
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http://dx.doi.org/10.1111/cas.14515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419060PMC
August 2020

Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma.

Cancer Sci 2020 Aug 22;111(8):3045-3056. Epub 2020 Jun 22.

Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.

Squamous cell carcinoma of the external auditory canal (SCC-EAC) is rare and has a poor prognosis. The SCC-EAC cases with high-grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low-grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP-2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP-2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC-EAC patients. High tumoral emmprin expression was associated with high-grade TB, whereas high stromal CD73 expression was associated with high-grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP-2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP-2 in tumor invasiveness.
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http://dx.doi.org/10.1111/cas.14508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419056PMC
August 2020

Therapeutic effect of Nivolumab for advanced / recurrent temporal bone squamous cell carcinoma.

Auris Nasus Larynx 2020 Oct 20;47(5):864-869. Epub 2020 May 20.

Department Otolaryngology Head and Neck Surgery, Kyushu University, 3-1-1 Maidashi, Fukuoka, Japan.

Objective: The immune checkpoint inhibitor Nivolumab was approved for the treatment of platinum-refractory head and neck squamous cell carcinoma (SCC), expanding the treatment options for recurrent or advanced head and neck SCC. However, since temporal bone squamous cell carcinoma (TB-SCC) is very rare cancer, the effectiveness of Nivolumab remains unclear. We investigated the effects of Nivolumab for TB-SCC.

Method: Chart information was collected for all patients who underwent the first administration of Nivolumab for recurrent or residual TB-SCC in our hospital between September 2017 and December 2019. Tumor staging followed the modified Pittsburgh classification. Changes in the tumor burden and survival outcome were examined.

Results: We examined 9 patients with recurrent or residual TB-SCC who started administration of Nivolumab. In these cases, recurrent or residual SCC was observed after chemotherapy and/or chemoradiotherapy including platinum. The duration of Nivolumab was 2-54 weeks (median 20.0 weeks). The evaluation of the therapeutic effect according to the RECIST method showed partial response in 1 case, stable disease in 2 cases, progressive disease in 4 cases, and size unevaluated in 2 case. Although the number of cases was small, comparing with 5 cases without Nivolumab, these cases showed longer overall survival (1-year OS 33.3% vs 20.0%).

Conclusion: We used Nivolumab as palliative chemotherapy in 9 patients with recurrent/residual TB-SCC, and we were able to obtain a certain therapeutic effect on TB-SCC as well as other head and neck SCC.
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http://dx.doi.org/10.1016/j.anl.2020.03.011DOI Listing
October 2020
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