Faculty Profiles - NISHIO Naoki

Papers - NISHIO Naoki

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外耳道扁平上皮がんに対する手術治療について頭蓋底浸潤例を中心に

西尾直樹, 後藤聖也, 岩味健一郎, 吉田忠雄, 向山宣昭, 横井紗矢香, 丸尾貴志, 藤井正純, 亀井譲, 藤本保志, 曾根三千彦

日本癌治療学会学術集会抄録集 Vol. 59回 page： O41 - 2 2021.10

Dilatation of the Endolymphatic Space in the Ampulla of the Posterior Semicircular Canal: A New Clinical Finding Detected on Magnetic Resonance Imaging. Reviewed International journal

Masaru Morioka, Satofumi Sugimoto, Tadao Yoshida, Masaaki Teranishi, Masumi Kobayashi, Naoki Nishio, Naomi Katayama, Shinji Naganawa, Michihiko Sone

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Vol. 42 ( 6 ) page： E643 - E647 2021.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: To investigate the clinical features of ears with dilatation of the endolymphatic space in the ampulla of the posterior semicircular canal on magnetic resonance imaging. STUDY DESIGN: Retrospective study. SETTING: A university hospital. METHODS: This study included 1,842 ears from 934 patients who underwent 3-T magnetic resonance imaging with gadolinium to investigate the presence of endolymphatic hydrops. Age, sex distribution, hearing thresholds on pure-tone audiometry, and vestibular symptoms were compared between cases of unilateral and bilateral dilatation of the endolymphatic space in the ampulla of the posterior semicircular canal. RESULTS: Forty-eight ears (17 men and 14 women; mean age 49.9 yrs) showed dilatation of the endolymphatic space in the ampulla of the posterior semicircular canal. Age and the rate of chronic sensorineural hearing loss were significantly higher in the unilateral group (14 ears) than in the bilateral group (34 ears). The average hearing thresholds and rates of vestibular symptoms reported did not differ between unilateral and bilateral cases, but some patients showed positional nystagmus. CONCLUSIONS: Dilatation of the endolymphatic space in the ampulla was observed selectively in the posterior semicircular canal, though its pathogenesis was not clear. Such dilatation is not usually accompanied by vestibular endolymphatic hydrops, and it may be a cause of vertigo and dizziness.

DOI： 10.1097/MAO.0000000000003073

Surgical Classification of Radical Temporal Bone Resection and Transcranial Tympanotomy: A Retrospective Study from the Neurosurgical Perspective. Reviewed International journal

Kenichiro Iwami, Masazumi Fujii, Naoki Nishio, Takashi Maruo, Tadao Yoshida, Nobuaki Mukoyama, Koji Osuka, Keisuke Takanari, Kenta Murotani, Yuzuru Kamei, Michihiko Sone, Yasushi Fujimoto, Kiyoshi Saito

World neurosurgery Vol. 151 page： E192 - E207 2021.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To review the authors' surgical experience with radical temporal bone resection (TBR) with an emphasis on the classification of skull base osteotomy and transcranial tympanotomy (TCT) that is required for middle ear transection. METHODS: We reviewed the records of 25 patients who underwent radical TBR at our facilities between 2011 and 2020. RESULTS: The osteotomy line of radical TBR was divided into 3 segments: anterior (A), medial (M), and posterior (P). Each segment was further classified as follows: A1, through the glenoid fossa (1 patient); A2, in front of the glenoid fossa (23 patients); A3, through the greater wing of the sphenoid bone (1 patient); M1, through the middle ear (16 patients); M2, through the inner ear (9 patients); P1, through the mastoid (9 patients); and P2, through the posterior cranial fossa (16 patients). The M segment was significantly associated with operation time and intraoperative blood loss. In all patients with M1 osteotomy, TCT was performed; TCT was classified into superior and far posterior approaches. A superior approach was performed in all 16 patients, whereas the far posterior approach was performed in only 7 patients with both M1 and P2 osteotomy. CONCLUSIONS: Our newly proposed osteotomy classification of radical TBR is suitable for minute but clinically important adjustment of the osteotomy line. TCT is an indispensable technique for M1 osteotomy; our newly proposed classification expands our understanding of TCT and how to incorporate this technique into radical TBR.

DOI： 10.1016/j.wneu.2021.04.002

Skull Base Invasion Patterns of Malignant Head and Neck Tumors: A Neurosurgical Perspective. Reviewed International journal

Kenichiro Iwami, Masazumi Fujii, Naoki Nishio, Takashi Maruo, Yasushi Fujimoto, Keisuke Takanari, Yuzuru Kamei, Masayuki Yamada, Tetsuya Ogawa, Koji Osuka, Kiyoshi Saito

Journal of neurological surgery. Part B, Skull base Vol. 82 ( Suppl 3 ) page： E120 - E130 2021.7

Language：English Publishing type：Research paper (scientific journal)

Objective Craniofacial resection (CFR) and temporal bone resection (TBR) on malignant head and neck tumors (MHNTs) invading skull base require accurate and precise determination of the tumor invasion. We investigated tumor skull base invasion patterns and surgical results in CFR and TBR cases. Methods We performed either CFR or TBR for 75 selected patients with the possibility of en bloc resection over the period between 2011 and 2018. The medical charts of the selected patients were reviewed. Results Primary tumor onset site (TOS) groups were: (1) nasal cavity/ethmoid sinus, 20 cases; (2) orbit, 10 cases; (3) maxillary sinus, 28 cases; and (4) external ear/temporomandibular joint, 17 cases. Grades for tumor invasion depth (TID) included: (I) extracranial invasion and skull base bone invasion; (II) extradural invasion; or (III) intradural invasion. Patients in groups 1 and 2 had a significantly higher frequency of grade II and III invasions than patients in groups 3 and 4. The main invasion site was nasal cavity superior wall and ethmoid sinus superior wall for group 1 tumors, orbit superior wall, and lateral skull base sphenoid bone for group 2 and 3 tumors, and lateral skull base temporal bone for group 4 tumors. Positive resection margins represented a significant negative prognostic factor. TID and TOS did not affect skull base margin status. Conclusion Skull base invasion of MHNTs exhibits certain fixed patterns in sites susceptible to invasion based on the TOS. The frequencies of extradural and intradural invasions differed, indicating the importance for accurate preoperative tumor evaluation.

DOI： 10.1055/s-0039-3402034

Surgical strategy and optimal timing of tracheostomy in patients with COVID-19: Early experiences in Japan. Reviewed International journal

Naoki Nishio, Mariko Hiramatsu, Yukari Goto, Yuichiro Shindo, Takanori Yamamoto, Naruhiro Jingushi, Keiko Wakahara, Michihiko Sone

Auris, nasus, larynx Vol. 48 ( 3 ) page： 518 - 524 2021.6

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Tracheostomy is an important surgical procedure for coronavirus disease-2019 (COVID-19) patients who underwent prolonged tracheal intubation. Surgical indication of tracheostomy is greatly affected by the general condition of the patient, comorbidity, prognosis, hospital resources, and staff experience. Thus, the optimal timing of tracheostomy remains controversial. METHODS: We reviewed our early experience with COVID-19 patients who underwent tracheostomy at one tertiary hospital in Japan from February to September 2020 and analyzed the timing of tracheostomy, operative results, and occupational infection in healthcare workers (HCWs). RESULTS: Of 16 patients received tracheal intubation with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, five patients (31%) received surgical tracheostomy in our hospital. The average consultation time for surgical tracheostomy was 7.4 days (range, 6 - 9 days) from the COVID-19 team to the otolaryngologist. The duration from tracheal intubation to tracheostomy ranged from 14 to 27 days (average, 20 days). The average time of tracheostomy was 27 min (range, 17 - 39 min), and post-wound bleeding occurred in only one patient. No significant differences in hemoglobin (Hb) levels were found between the pre- and postoperative periods (mean: 10.2 vs. 10.2 g/dl, p = 0.93). Similarly, no difference was found in white blood cell (WBC) count (mean: 12,200 vs. 9,900 cells /µl, p = 0.25). After the tracheostomy, there was no occupational infection among the HCWs who assisted the tracheostomy patients during the perioperative period. CONCLUSION: We proposed a modified weaning protocol and surgical indications of tracheostomy for COVID-19 patients and recommend that an optimal timing for tracheostomy in COVID-19 patients of 2 - 3 weeks after tracheal intubation, from our early experiences in Japan. An experienced multi-disciplinary tracheostomy team is essential to perform a safe tracheostomy in patients with COVID-19 and to minimize the risk of occupational infection in HCWs.

DOI： 10.1016/j.anl.2020.11.004

Verbalization, Categorization, and Evaluation of Fundamental Surgical Skills: An Expert Consensus in Open Head and Neck Surgery. Reviewed International coauthorship

Mitani S, Nishio N, Kitani T, Ugumori T, Wakisaka H, Tanaka K, Miao B, Chan JYK, Holsinger FC, Hato N

Annals of surgery open : perspectives of surgical history, education, and clinical approaches Vol. 2 ( 2 ) page： e059 2021.6

Photoacoustic Molecular Imaging for the Identification of Lymph Node Metastasis in Head and Neck Cancer using an anti-EGFR Antibody-Dye Conjugate. Reviewed International coauthorship International journal

Naoki Nishio, Nynke S van den Berg, Brock A Martin, Stan van Keulen, Shayan Fakurnejad, Eben L Rosenthal, Katheryne E Wilson

Journal of nuclear medicine : official publication, Society of Nuclear Medicine Vol. 62 ( 5 ) page： 648 - 655 2021.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

The presence of lymph node (LN) metastases is an essential prognostic indicator in patients with head and neck squamous cell carcinoma (HNSCC). This study assessed photoacoustic molecular imaging (PAMI) of the anti-epidermal growth factor receptor (EGFR) antibody (panitumumab) conjugated to a near-infrared fluorescent dye, IRDye800CW (panitumumab-IRDye800CW; pan800) for the identification of occult metastatic LNs in patients with HNSCC (n=7). After in vitro photoacoustic imaging characterization of pan800, PAMI was performed on excised neck specimens of patients infused with pan800 prior to surgery. Freshly obtained neck specimens were imaged with three-dimensional, multiwavelength spectroscopic PAMI (680, 686, 740, 800, 860, 924, and 958 nm wavelengths). Harvested LNs were then imaged with a closed-field near-infrared fluorescence imager and histologically examined by the pathologist to determine their metastatic status. A total of 53 LNs with a maximum diameter of 10 mm were analyzed with photoacoustic and fluorescence imaging, of which four were determined to be metastatic on final histopathology. Photoacoustic signal in the LNs corresponding to accumulated pan800 were spectrally unmixed using a linear least square error classification algorithm. Metastatic LNs had a five-fold higher average thresholded photoacoustic signal intensity corresponding to pan800 compared to benign LNs (2.50 ± 1.09 a.u. vs. 0.53 ± 0.32 a.u., p<0.001). Fluorescence imaging showed that metastatic LNs had a two-fold increase in fluorescence signal compared to benign LNs ex vivo (p<0.01, 0.068 ± 0.027 a.u. vs. 0.035 ± 0.018 a.u.) Moreover, the ratio of the average of the highest 10% photoacoustic signal intensity over total average, representative of degree of heterogeneity of pan800 signal in LNs, showed a significant difference between metastatic LNs vs. benign LNs (11.6 ± 13.4 vs. 1.8 ± 0.7, p<0.01) and an area under the receiver operating characteristic (ROC) curve of 0.96 (95% CI; 0.91-1.00). The data indicate that PAMI of IRDye800-labeled tumor-specific antibody may have the potential to identify occult LN metastasis perioperatively in HNSCC patients.

DOI： 10.2967/jnumed.120.245241

Effect of Formalin Fixation for Near-Infrared Fluorescence Imaging with an Antibody-Dye Conjugate in Head and Neck Cancer Patients. Reviewed International coauthorship International journal

Shrey Kapoor, Guolan Lu, Nynke S van den Berg, Giri Krishnan, Jacqueline Pei, Quan Zhou, Brock A Martin, Fred M Baik, Eben L Rosenthal, Naoki Nishio

Molecular imaging and biology Vol. 23 ( 2 ) page： 270 - 276 2021.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: This study evaluated the effect of formalin fixation for near-infrared (NIR) fluorescence imaging of an antibody-dye complex (panitumumab-IRDye800CW) that was intravenously administered to patients with head and neck squamous cell carcinoma (HNSCC) scheduled to undergo surgery of curative intent. PROCEDURES: HNSCC patients were infused with 25 or 50 mg of panitumumab-IRDye800CW followed by surgery 1-5 days later. Following resection, primary tumor specimens were imaged in a closed-field fluorescence imaging device, before and after formalin fixation. The fluorescence images of formalin-fixed specimens were compared with images prior to formalin fixation. Regions of interest were drawn on the primary tumor and on the adjacent normal tissue on the fluorescence images. The mean fluorescence intensity (MFI) and tumor-to-background ratios (TBRs) of the fresh and formalin-fixed tissues were compared. RESULTS: Of the 30 enrolled patients, 20 tissue specimens were eligible for this study. Formalin fixation led to an average of 10 % shrinkage in tumor specimen size (p < 0.0001). Tumor MFI in formalin-fixed specimens was on average 10.9 % lower than that in the fresh specimens (p = 0.0002). However, no statistical difference was found between the TBRs of the fresh specimens and those of the formalin-fixed specimens (p = 0.85). CONCLUSIONS: Despite the 11 % decrease in MFI between fresh and formalin-fixed tissue specimens, the relative difference between tumor and normal tissue as measured in TBR remained unchanged. This data suggests that evaluation of formalin-fixed tissue for assessing the accuracy of fluorescence-guided surgery approaches could provide a valid, yet more flexible, alternative to fresh tissue analysis. TRIAL REGISTRATION: NCT02415881.

DOI： 10.1007/s11307-020-01553-1

Safety and feasibility of fat injection therapy with adipose-derived stem cells in a rabbit hypoglossal nerve paralysis model: A pilot study. Reviewed International journal

Akihisa Wada, Naoki Nishio, Sayaka Yokoi, Hidenori Tsuzuki, Nobuaki Mukoyama, Takashi Maruo, Mariko Hiramatsu, Tokunori Yamamoto, Momokazu Goto, Yasushi Fujimoto, Michihiko Sone

Auris, nasus, larynx Vol. 48 ( 2 ) page： 274 - 280 2021.4

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The aim of this study is to establish a unilateral tongue atrophy model by cutting the hypoglossal nerve and to evaluate the safety and feasibility of a fat injection of adipose-derived stem cells (ADSCs) to restore swallowing function. METHODS: A total of 12 rabbits were randomized to three groups; the ADSCs+fat group (n=4), the fat group (n=4) and the control group (n=4). All rabbits were treated with denervation of the left hypoglossal nerve and their conditions including body weight and food intake were checked during follow-up periods (8 weeks). At 4 weeks after the transection of the nerve, rabbits received the injection therapy into the denervated side of the tongue with 1.0mL fat tissue premixed with 0.5mL ADSCs in the ADSCs+fat group, 1.0mL fat tissue premixed with 0.5mL PBS in the fat group and 1.5mL PBS in the control group. Rabbits were euthanized 8 weeks post-treatment and resected tongues were collected, formalin-fixed and paraffin embedded. To evaluate the change of the intrinsic muscles of the tongue, muscle fibers around the treatment area was analyzed by evaluating 5 consecutive hematoxylin-eosin slides per rabbit. RESULTS: Food intake did not decrease upon nerve denervation, and none of the rabbits displayed adverse effect such as aspiration, surgical wound dehiscence or infection. No significant body weight changes were found between the three groups at 4 and 8 weeks after nerve transection (p>0.05). In the control group, the denervated side of tongue had significantly smaller muscle fiber areas and diameters compared to the non-denervated side (p<0.05). The ADSCs+fat group demonstrated a larger area of inferior longitudinal muscle fibers compared to the control and the fat groups (582±312µm2 vs. 405±220µm2 and 413±226µm2; p<0.05). A significant thicker lesser diameter of inferior longitudinal muscle fibers was found in the ADSCs+fat group compared to the control and the fat groups (24±8µm vs. 20±6µm and 20±7µm; p<0.05). CONCLUSION: The rabbit tongue atrophy model was found suitable for the assessment of muscle change after nerve transection. Fat injection therapy with ADSCs demonstrated great potential to prevent the muscle atrophy after denervation and to promote the muscle regeneration around the injection area.

DOI： 10.1016/j.anl.2020.08.003

Feasibility of virtual surgical simulation in the head and neck region for soft tissue reconstruction using free flap: a comparison of preoperative and postoperative volume measurement Reviewed

S. Yokoi, N. Nishio, Y. Fujimoto, M. Fujii, K. Iwami, Y. Hayashi, K. Takanari, M. Hiramatsu, T. Maruo, N. Mukoyama, H. Tsuzuki, A. Wada, Y. Kamei, M. Sone

International Journal of Oral and Maxillofacial Surgery Vol. 50 ( 3 ) page： 316 - 322 2021.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

In the head and neck region, preoperative evaluation of the free flap volume is challenging. The current study validated preoperative three-dimensional (3D) virtual surgical simulation for soft tissue reconstruction by assessing flap volume and evaluated fat and muscle volume changes at follow-up in 13 head and neck cancer patients undergoing anterolateral craniofacial resection. Patients received 3D virtual surgical simulation, and the volume of the planned defects was estimated by surgical simulation. Following en bloc resection of the tumor, the defect in the skull base was covered using a rectus abdominis myocutaneous flap. Following surgery, computed tomography scans were acquired at day 1 and at 6 and 12 months. Virtual planned defect was on average 227 ml (range, 154–315) and was 10% smaller than the actual flap volume in patients without skin involvement of the tumor. Between day 1 and 12 months post-surgery, the volume of fat and muscle tissue in the free flap dropped by 9% and 58%, respectively. Our results indicate that 3D virtual surgical simulation provides essential information in determining the accurate volume of the required free flap for surgical defect repair and may thus help improve surgical planning and functional and esthetic outcome.

DOI： 10.1016/j.ijom.2020.07.025

Intraoperative Fluorescence-Guided Surgery in Head and Neck Squamous Cell Carcinoma. Reviewed International coauthorship International journal

Yu-Jin Lee, Giri Krishnan, Naoki Nishio, Nynke S van den Berg, Guolan Lu, Brock A Martin, Stan van Keulen, Alexander D Colevas, Shrey Kapoor, Jonathan T C Liu, Eben L Rosenthal

The Laryngoscope Vol. 131 ( 3 ) page： 529 - 534 2021.3

Language：English Publishing type：Research paper (scientific journal)

The rate of positive margins in head and neck cancers has remained stagnant over the past three decades and is consistently associated with poor overall survival. This suggests that significant improvements must be made intraoperatively to ensure negative margins. We discuss the important role of fluorescence imaging to guide surgical oncology in head and neck cancer. This review includes a general overview of the principles of fluorescence, available fluorophores used for fluorescence imaging, and specific clinical applications of fluorescence-guided surgery, as well as challenges and future directions in head and neck surgical oncology. Laryngoscope, 131:529-534, 2021.

DOI： 10.1002/lary.28822

Safety and Stability of Antibody-Dye Conjugate in Optical Molecular Imaging. Reviewed International coauthorship International journal

Jacqueline Pei, Georgina Juniper, Nynke S van den Berg, Naoki Nisho, Trevor Broadt, Anthony R Welch, Grace S Yi, Roan C Raymundo, Stefania U Chirita, Guolan Lu, Giri Krishnan, Yu-Jin Lee, Shrey Kapoor, Quan Zhou, A Dimitrios Colevas, Natalie S Lui, George A Poultsides, Gordon Li, Kurt R Zinn, Eben L Rosenthal

Molecular imaging and biology Vol. 23 ( 1 ) page： 109 - 116 2021.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients. PROCEDURES: Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis. RESULTS: Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria. CONCLUSIONS: Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.

DOI： 10.1007/s11307-020-01536-2

Lesion-specific prognosis by magnetic resonance imaging in sudden sensorineural hearing loss. Reviewed International journal

Cheng-Jui Yang, Tadao Yoshida, Satofumi Sugimoto, Masaaki Teranishi, Masumi Kobayashi, Naoki Nishio, Shinji Naganawa, Michihiko Sone

Acta oto-laryngologica Vol. 141 ( 1 ) page： 5 - 9 2021.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High signals in the inner ear of idiopathic sudden sensorineural hearing loss (ISSNHL) on magnetic resonance imaging (MRI) have been reported, but no quantitative evaluation has yet been done. OBJECTIVES: To evaluate hearing outcomes and cochlear signal intensities on 3-T heavily T2-weighted three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (hT2W-3D-FLAIR) in patients with ISSNHL. MATERIALS AND METHODS: Twenty-nine patients with ISSNHL were included. Patients underwent hT2W-3D-FLAIR with intravenous gadolinium injection and pure tone audiometry (PTA) at initial visits and 3 months later. Signal intensity ratios (SIRs) were measured in the basal or apical-middle turns of the affected cochlea. A statistical analysis of relationships between SIRs and the average hearing levels (HLs) at low (125, 250, and 500 Hz) and high (2, 4, and 8 kHz) tone frequencies was performed. RESULTS: Hearing improvements at high-tone frequencies in ears with HLs ≥60 dB were significantly worse in those with high SIRs at the basal turns on pre-contrast images. Similarly, hearing improvements at low-tone frequencies in ears with HLs ≥60 dB were significantly worse in those with high SIRs at the apical-middle turns on post-contrast images. CONCLUSIONS AND SIGNIFICANCE: High SIRs on hT2W-3D-FLAIR indicate cochlear disturbances with severe ISSNHL and could provide lesion-specific prognostic information.

DOI： 10.1080/00016489.2020.1827159

EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial. Reviewed International coauthorship International journal

Quan Zhou, Nynke S van den Berg, Eben L Rosenthal, Michael Iv, Michael Zhang, Johana C M Vega Leonel, Shannon Walters, Naoki Nishio, Monica Granucci, Roan Raymundo, Grace Yi, Hannes Vogel, Romain Cayrol, Yu-Jin Lee, Guolan Lu, Marisa Hom, Wenying Kang, Melanie Hayden Gephart, Larry Recht, Seema Nagpal, Reena Thomas, Chirag Patel, Gerald A Grant, Gordon Li

Theranostics Vol. 11 ( 15 ) page： 7130 - 7143 2021

Language：English Publishing type：Research paper (scientific journal)

Rationale: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods: Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo, to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results: No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions: Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.

DOI： 10.7150/thno.60582

Metastatic and sentinel lymph node mapping using intravenously delivered Panitumumab-IRDye800CW. Reviewed International coauthorship International journal

Giri Krishnan, Nynke S van den Berg, Naoki Nishio, Georgina Juniper, Jaqueline Pei, Quan Zhou, Guolan Lu, Yu-Jin Lee, Kimberly Ramos, Andrei H Iagaru, Fred M Baik, Alexander D Colevas, Brock A Martin, Eben L Rosenthal

Theranostics Vol. 11 ( 15 ) page： 7188 - 7198 2021

Language：English Publishing type：Research paper (scientific journal)

Rationale: Sentinel lymph node biopsy (SLNB) is a well-established minimally invasive staging procedure that maps the spread of tumour metastases from their primary site to the regional lymphatics. Currently, the procedure requires the local peri-tumoural injection of radiolabelled and/or optical agents, and is therefore operator dependent, disruptive to surgical workflow and restricted largely to a small subset of malignancies that can be readily accessed externally for local tracer injection. The present study set out to determine whether intravenous (IV) infusion of a tumor-targeted tracer could identify sentinel and metastatic lymph nodes (LNs) in order to overcome these limitations. Methods: We examined 27 patients with oral squamous cell carcinoma (OSCC), 18 of whom were clinically node negative (cN0). Patients were infused intravenously with 50mg of Panitumumab-IRDye800CW prior to surgical resection of their primary tumour with neck dissection and/or SLNB. Lymphadenectomy specimens underwent fluorescence molecular imaging to evaluate tracer distribution to LNs. Results: A total of 960 LNs were analysed, of which 34 (3.5%) contained metastatic disease. Panitumumab-IRDye800CW preferentially localized to metastatic and sentinel LNs as evidenced by a higher fluorescent signal relative to other lymph nodes. The median MFI of metastatic LNs was significantly higher than the median MFI of benign LNs (0.06 versus 0.02, p < 0.05). Furthermore, selecting the highest five fluorescence intensity LNs from individual specimens resulted in 100% sensitivity, 85.8% specificity and 100% negative predictive value (NPV) for the detection of occult metastases and 100% accuracy for clinically staging the neck. In the cN+ cohort, assessment of the highest 5 fluorescence LNs per patient had 87.5% sensitivity, 93.2% specificity and 99.1% NPV for the detection of metastatic nodes. Conclusion: When intravenously infused, a tumour-targeted tracer localized to sentinel and metastatic lymph nodes. Further validation of an IV tumor-targeted tracer delivery approach for SLNB could dramatically change the practice of SLNB, allowing its application to other malignancies where the primary tumour is not accessible for local tracer injection.

DOI： 10.7150/thno.55389

Investigation of parotid gland cancer surgery that preserved the facial nerve Reviewed

Ryoki Hamabata, Nobuaki Mukoyama, Naoki Nishio, Takashi Maruo, Mariko Hiramatsu, Sayaka Yokoi, Michihiko Sone, Yasushi Fujimoto

Japanese Journal of Head and Neck Cancer Vol. 47 ( 3 ) page： 316 - 321 2021

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society for Head and Neck Cancer

Summary There are few reports on the transition and prognosis of postoperative facial nerve paralysis in patients undergoing parotid gland cancer surgery that preserves the facial nerve. The treatment policy for parotid gland cancer in our department is, in principle, combined resection of the facial nerve and one-stage reconstruction of the nerve if there is facial nerve paralysis before surgery, and preservation of the nerve if there is no paralysis regardless of histological type. We examined 31 cases of parotid gland cancer surgery that preserved the facial nerve over the past 15 years. The median observation period was 60 months. Total resection was performed in 24 cases, and lobectomy was performed in 7 cases. The average score of postoperative facial nerve paralysis was 24 points, and the median score was 27 points. The transition of postoperative facial nerve paralysis, although there were cases of transient complete paralysis, eventually recovered to an average of 39.5 points. The recovery period was 6 months after surgery in many cases. The treatment results were good, with 5-year overall survival rate, 5-year disease-free survival rate, and local control rate of 96.0％, 89.5％, and 93.5％, respectively. In cases of parotid gland cancer without facial nerve paralysis, treatment results are considered to be guaranteed even if the nerve is preserved regardless of the pathological type.

DOI： 10.5981/jjhnc.47.316

Endoscopic Fluorescence-Guided Surgery for Sinonasal Cancer Using an Antibody-Dye Conjugate. Reviewed International coauthorship International journal

Zachary P Hart, Naoki Nishio, Giri Krishnan, Guolan Lu, Quan Zhou, Shayan Fakurnejad, Peter John Wormald, Nynke S van den Berg, Eben L Rosenthal, Fred M Baik

The Laryngoscope Vol. 130 ( 12 ) page： 2811 - 2817 2020.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Endoscopic resection of sinonasal squamous cell carcinoma has become the standard of care, but challenges remain in obtaining clear resection margins. The current study evaluated the feasibility of endoscopic fluorescence-guided surgery (FGS) to improve surgical resection in a human sinus surgical model. METHODS: A fluorescence endoscope optimized for near-infrared (NIR) fluorescence detection was evaluated in a phantom study. Various endoscope diameters (4 and 10 mm) and viewing angles (0, 30, and 45 degrees) were evaluated to determine the sensitivity of the system for IRDye800CW detection at various working distances (1-5 cm). Endoscopic FGS was then validated in a three-dimensional human sinus surgical model to which squamous cell tumors derived from mice were inserted. Mice had received intravenous panitumumab-IRDye800CW and upon fluorescence-guided tumor resection, mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were calculated in in situ and ex vivo settings. RESULTS: A significantly higher fluorescence intensity was found when using the 10-mm diameter endoscope compared to the 4mm diameter endoscope (P < .001). No significant difference in MFI was found among the viewing angles of the 4-mm diameter endoscope. Using the human sinus model, the highest MFI and TBR were obtained at a 1-cm working distance compared to longer working distances. CONCLUSION: We demonstrate that clinically acceptable TBRs were obtained with several working distances to discriminate tumor tissue from adjacent normal tissue in a human sinus model, and that endoscopic FGS may have great potential in identifying residual tumor tissue regions during surgery. Laryngoscope, 2019.

DOI： 10.1002/lary.28483

Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates. Reviewed International coauthorship International journal Open Access

Guolan Lu, Naoki Nishio, Nynke S van den Berg, Brock A Martin, Shayan Fakurnejad, Stan van Keulen, Alexander D Colevas, Greg M Thurber, Eben L Rosenthal

Nature communications Vol. 11 ( 1 ) page： 5667 - 5667 2020.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.

DOI： 10.1038/s41467-020-19498-y

FIRST-IN-HUMAN FLUORESCENCE GUIDED SURGERY OF HIGH-GRADE GLIOMAS USING PANITUMUMAB-IRDYE800 International coauthorship International journal

Zhou, Q; van den Berg, N; Nishio, N; Lu, GL; Chirita, S; Raymundo, R; Yi, G; Vogel, H; Cayrol, R; Rosenthal, E; Li, G

NEURO-ONCOLOGY Vol. 22 page： 52 - 52 2020.11

Significance of high signal intensity in the endolymphatic duct on magnetic resonance imaging in ears with otological disorders. Reviewed International journal

Kyoko Morimoto, Tadao Yoshida, Masumi Kobayashi, Satofumi Sugimoto, Naoki Nishio, Masaaki Teranishi, Shinji Naganawa, Michihiko Sone

Acta oto-laryngologica Vol. 140 ( 10 ) page： 818 - 822 2020.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High signal intensity in the endolymphatic duct (ED) is occasionally observed on magnetic resonance imaging (MRI) in ears that have otological disorders. OBJECTIVE: The signal intensity (SI) in the ED on post-contrast MRI was investigated in subjects with various otological disorders, and the meaning of high SI in the ED was evaluated. MATERIAL AND METHODS: 392 patients with otological disorders and 21 controls without otological symptoms underwent 3 T MRI. The SIs of the ED and the cerebellum were measured, the SI ratio (SIR) was calculated, and ears with SIR ≥4 were identified. RESULTS: A high SIR was identified in the ED of 3.7% of ears affected by definite Meniere's disease (dMD), 100% of ears affected by large vestibular aqueduct syndrome (LVAS), and 7.1% of ears with no otological symptoms. On the whole, a significant relationship was found between the existence of vestibular or cochlear EH and the SIR in the ED. CONCLUSION: The MRI finding of high SI in the ED may indicate the mechanism of inner ear disturbances in ears with otological disorders, especially in those with LVAS, and it may suggest an underlying disorder in some ears in which otological symptoms are not apparent.

DOI： 10.1080/00016489.2020.1781927

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