論文 - 西原　広史

Clinical utility of comprehensive genomic profiling for advanced pancreatic cancer: insights from real-world data analysis

Eiichiro So, Hideyuki Hayashi, Keitaro Shimozaki, Sara Horie, Shotaro Kishimoto, Akihiko Chida, Yuki Saito, Kai Tsugaru, Kenro Hirata, Shigeki Tanishima, Hiroshi Nishihara, Takanori Kanai, Yasuo Hamamoto

International Journal of Clinical Oncology （Springer Science and Business Media LLC）  2025年02月

査読有り,  ISSN  1341-9625

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CXCL9 and CXCL13 shape endometrial cancer immune-activated microenvironment via tertiary lymphoid structure formation.

Yoshihiro Nagase, Makoto Kodama, Eriko Aimono, Kohei Nakamura, Reika Takamatsu, Keiko Abe, Takuma Yoshimura, Tatsuyuki Chiyoda, Wataru Yamagami, Hiroshi Nishihara

Cancer science 2025年02月

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Immune checkpoint inhibitor (ICI) therapy has been successfully applied to various cancers; however, not all patients respond to ICI therapy. Tumors with an immune-activated environment are highly responsive to ICIs. To identify the cells and molecules essential to the formation of an immune-activated cancer microenvironment, we focused on the tertiary lymphoid structure (TLS) and performed histological and genomic analyses using endometrial cancer material. In the high immunogenic group, numerous TLSs were observed, and CXCL9 and CXCL13 expression was markedly increased. CXCL9-positive antigen-presenting and CXCL13-positive follicular dendritic cells were distributed in the T- and B-cell zones of TLSs, respectively. A group of molecules whose expression was upregulated along with CXCL9 and CXCL13 expression was strongly associated with cellular immunity. These results suggest that CXCL9-expressing antigen-presenting cells and CXCL13-expressing follicular dendritic cells coordinately shape the immune-activated microenvironment through TLS formation. The current findings will contribute to a better understanding of the mechanisms underlying the activated cancer immune microenvironment, thereby advancing the field of precision cancer medicine.

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Clinical value of preoperative circulating tumor DNA before surgery in patients with esophageal squamous cell carcinoma.

Ryota Kobayashi, Satoru Matsuda, Kohei Nakamura, Hirofumi Kawakubo, Keiso Ho, Yosuke Morimoto, Kazuhiko Hisaoka, Yuki Hoshi, Masashi Takeuchi, Kazumasa Fukuda, Jun Okui, Hiroshi Nishihara, Yuko Kitagawa

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 51 （ 5 ） 109625 - 109625 2025年01月

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INTRODUCTION: A precise preoperative tumor monitoring method that reflects tumor burden during neoadjuvant treatment is required to guide individualized perioperative treatment strategies for esophageal squamous cell carcinoma (ESCC). This study examined the clinical significance of preoperative circulating tumor DNA (ctDNA) in the plasma of patients undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy. MATERIALS AND METHODS: Plasma samples were collected longitudinally for ctDNA analysis as well as genomic DNA from primary lesions from patients with histologically confirmed ESCC who received neoadjuvant chemotherapy (NAC) followed by subtotal esophagectomy. Next-generation sequencing was used to identify mutations in both the plasma and primary tumors. We evaluated the relationship between ctDNA alterations and recurrence in patients with locally advanced ESCC. RESULTS: Pretreatment samples from 25 patients (100 %) showed the same mutations in both ctDNA and primary tumors; therefore, they were classified as ctDNA-positive before treatment. In the cohort of 25 patients analyzed, those who tested positive for ctDNA after NAC had a significantly higher risk of recurrence; the 36-month recurrence-free survival rates were 92 % for ctDNA-negative patients and 8 % for ctDNA-positive patients (p < 0.001). CONCLUSIONS: Preoperative ctDNA status may be a promising prognostic biomarker that can be assessed before surgery in patients with ESCC who received NAC. Expanded cohort validation will allow for more personalized multidisciplinary treatment approaches for ESCC tailored to ctDNA analysis.

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Clinical characteristics of gastrointestinal stromal tumors with hypoglycemia.

Akihiko Chida, Kenta Kawasaki, Junko Kuramoto, Hideyuki Hayashi, Toru Kawahara, Satomi Makiuchi, Eiichiro So, Satoko Shimizu, Shotaro Kishimoto, Sara Horie, Yuki Saito, Keitaro Shimozaki, Kai Tsugaru, Kazuhiro Togasaki, Kenro Hirata, Hiroshi Nishihara, Yae Kanai, Takanori Kanai, Yasuo Hamamoto

Oncology letters 28 （ 6 ） 568 - 568 2024年12月

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The development of tyrosine-kinase inhibitors has improved survival rates for patients with gastrointestinal stromal tumors (GISTs). Despite the progress, not all the patients can universally receive the benefit from treatment due to the individual underlying conditions in a real-world setting. The present study focused on the well-known but understudied condition of GIST with hypoglycemia. Hypoglycemia in GIST is characterized by hypoglycemic symptoms such as dizziness, sweating and confusion. It is caused by several factors such as multiple liver metastases, drug adverse effects, postoperative complications and paraneoplastic syndrome [non-islet cell tumor hypoglycemia (NICTH)]. Comprehensive analysis of this condition has been hindered due to its rarity, and has been mostly limited to case reports. In the present study, a single-institution retrospective analysis of GIST with hypoglycemia was conducted to investigate its prevalence and prognosis, and the cause of this condition. The present study identified that the prevalence of hypoglycemic episodes of GIST was 4.1% in all patients with GIST, and recurrent hypoglycemic cases had a poor prognosis. The present study identified 1 case with recurrent hypoglycemia due to NICTH. Since NICTH is a rare hypoglycemic cause and requires further evaluation, an autopsy and genetic sequencing were performed using the available clinical materials. Through this histological and genetic investigation, the histological diversity of NICTH-GIST was revealed and insulin-like growth factor II (IGF-II) amplification was identified. Furthermore, a chronological analysis was performed using multiple resected archived samples from the same case, and revealed that diffuse IGF-II expression may have occurred in the early phase of tumor development. The present study catalogued the characteristics of GIST with hypoglycemia with a focus on NICTH-GIST.

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Characterizing multi-PIK3CA mutations across cancer types: Toward precision oncology.

Kohei Nakamura, Marin Ishikawa, Ryutaro Kawano, Eriko Aimono, Takaaki Mizuno, Sachio Nohara, Shigeki Tanishima, Hideyuki Hayashi, Hiroshi Nishihara

Cancer medicine 13 （ 14 ） e70052 2024年07月

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BACKGROUND: PIK3CA mutations are implicated in various cancers, but the implications of multiple concurrent mutations and their orientations within the gene have not been fully explored. METHODS: In this study, we analyzed multi-PIK3CA mutations across a diverse pan-cancer cohort comprising 3564 tumors. RESULTS: Multi-PIK3CA mutations were present in 10.3% of all PIK3CA-mutant tumors, predominantly occurring in breast and gynecological cancers. Notably, mutations within the helical domain (E542:E545) exclusively occurred in the trans-orientation, contrasting with mutations in the kinase ABD and C2 domains, which mainly appeared in the cis orientation. CONCLUSIONS: The distinct pattern of mutation orientations in PIK3CA suggests variable oncogenic potential, with helical domain mutations in the trans-orientation potentially being less oncogenic. These findings highlight the importance of mutation orientation in the PIK3CA gene as potential biomarkers for targeted therapy. This understanding is crucial for designing clinical trials that leverage PI3K inhibitors, aiming for more effective and precise cancer treatment.

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Clinical and Diagnostic Utility of Genomic Profiling for Digestive Cancers: Real-World Evidence from Japan.

Marin Ishikawa, Kohei Nakamura, Ryutaro Kawano, Hideyuki Hayashi, Tatsuru Ikeda, Makoto Saito, Yo Niida, Jiichiro Sasaki, Hiroyuki Okuda, Satoshi Ishihara, Masatoshi Yamaguchi, Hideaki Shimada, Takeshi Isobe, Yuki Yuza, Akinobu Yoshimura, Hajime Kuroda, Seigo Yukisawa, Takuya Aoki, Kei Takeshita, Shinichi Ueno, Junichi Nakazawa, Yu Sunakawa, Sachio Nohara, Chihiro Okada, Ko Nishimiya, Shigeki Tanishima, Hiroshi Nishihara

Cancers 16 （ 8 ）  2024年04月

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The usefulness of comprehensive genomic profiling (CGP) in the Japanese healthcare insurance system remains underexplored. Therefore, this large-scale study aimed to determine the usefulness of CGP in diagnosing digestive cancers. Patients with various cancer types recruited between March 2020 and October 2022 underwent the FoundationOne® CDx assay at the Keio PleSSision Group (19 hospitals in Japan). A scoring system was developed to identify potentially actionable genomic alterations of biological significance and actionable genomic alterations. The detection rates for potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to companion diagnosis (CDx), as well as the signaling pathways associated with these alterations in each digestive cancer, were analyzed. Among the 1587 patients, 547 had digestive cancer. The detection rates of potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to CDx were 99.5%, 62.5%, and 11.5%, respectively. APC, KRAS, and CDKN2A alterations were frequently observed in colorectal, pancreatic, and biliary cancers, respectively. Most digestive cancers, except esophageal cancer, were adenocarcinomas. Thus, the classification flowchart for digestive adenocarcinomas proposed in this study may facilitate precise diagnosis. CGP has clinical and diagnostic utility in digestive cancers.

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Clinical-histopathological features and cancer gene analysis of cutaneous epithelioid angiosarcoma: A report of 4 cases.

Keiko Tokuchi, Teruki Yanagi, Suguru Kurosawa, Shinya Kitamura, Takuya Maeda, Che Yuan Hsu, Kodai Miyamoto, Hiroshi Nishihara, Hideyuki Ujiie

JAAD case reports 46   45 - 48 2024年04月

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A familial case of extramammary Paget disease: Analysis of whole-exome sequencing

Takuya Maeda, Teruki Yanagi, Shinya Kitamura, Hiroshi Nishihara, Yusuke Ono, Yusuke Mizukami, Shinya Tanaka, Hideyuki Ujiie

EJC Skin Cancer 2024年03月

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14年後に再発したBRAF V600E変異を有するlow-grade gliomaの1例

黒田 花音, 小田 義崇, 岡本 迪成, 村木 岳史, 種井 善一, 王 磊, 津田 真寿美, 高阪 真路, 西原 広史, 田中 伸哉

日本病理学会会誌 （(一社)日本病理学会）  113 （ 1 ） 482 - 482 2024年02月

査読有り,  ISSN  0300-9181

Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data.

Ayaka Saito, Hideki Terai, Tae-Jung Kim, Katsura Emoto, Ryutaro Kawano, Kohei Nakamura, Hideyuki Hayashi, Hatsuyo Takaoka, Akihiko Ogata, Katsuhito Kinoshita, Fumimaro Ito, Lisa Shigematsu, Masahiko Okada, Takahiro Fukushima, Akifumi Mitsuishi, Taro Shinozaki, Keiko Ohgino, Shinnosuke Ikemura, Hiroyuki Yasuda, Ichiro Kawada, Kenzo Soejima, Hiroshi Nishihara, Koichi Fukunaga

Cancer medicine 13 （ 4 ） e7077 2024年02月

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BACKGROUND: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. AIMS: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. MATERIALS AND METHODS: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. RESULTS: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). CONCLUSION: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

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Identifying intense inflammatory subtype of esophageal squamous cell carcinoma using clustering approach.

Satoru Matsuda, Shota Hoshino, Tadahiro Goto, Hirofumi Kawakubo, Masashi Takeuchi, Ryota Kobayashi, Kohei Nakamura, Hiroya Takeuchi, Hiroshi Nishihara, Yuko Kitagawa

General thoracic and cardiovascular surgery 2024年01月

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OBJECTIVE: To establish a risk-stratification system for predicting the postoperative recurrence of esophageal squamous cell carcinoma, this study aimed to evaluate the prognostic value of clusters based on blood inflammation and coagulation markers and investigate their correlation with serum cytokines and genetic alteration. METHOD: This single-center, retrospective cohort study enrolled 491 patients with esophageal cancer who underwent subtotal esophagectomy between 2004 and 2012. For cluster exploration, nonhierarchical cluster analysis and k-means were applied using serum C-reactive protein, albumin, fibrinogen, and platelet-lymphocyte ratio as variables. Then, multivariate survival analysis was conducted to investigate the association of clusters with recurrence-free survival. To characterize the clusters, serum interleukin-6, interleukin-8, and genetic alteration in primary tumors, the PleSSision-Rapid panel, which can evaluate 160 representative driver genes, was used. RESULTS: Patients were classified into clusters 1, 2, and 3, which included 24 (5%), 161 (33%), and 306 (62%) patients, respectively. Compared with cluster 3, cluster 1 or 2 had significantly worse recurrence-free survival. Based on the multivariable analysis using cluster, pStage, and age as covariates, cluster was an independent prognostic factor for recurrence-free survival (hazard ratio, 1.55; 95% confidence interval, 1.08-2.21; P = 0.02). The percentage of serum interleukin-6 and interleukin-8 levels was the highest in cluster 1, followed by clusters 2 and 3. In 23 patients with available genomic profiles, no significant difference in representative genomic alterations was observed. CONCLUSIONS: Non-biased clustering using inflammation and coagulation markers identified the intense inflammatory subtype, which had an independent prognostic effect on recurrence-free survival.

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Germline BRCA2 variant with low variant allele frequency detected in tumor-only comprehensive genomic profiling.

Hideyuki Hayashi, Kei Kunimasa, Shigeki Tanishima, Kohei Nakamura, Marin Ishikawa, Yasutaka Kato, Eriko Aimono, Ryutaro Kawano, Hiroshi Nishihara

Cancer science 2023年12月

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Germline BRCA1/2 variants in comprehensive genomic profiling (CGP) often exhibit variant allele frequency (VAF) exceeding 50%. However, when genomic loss occurs at the ipsilateral allele, including the germline variant in tumor cells, the VAF is low. This case report presents a patient with uterine sarcoma with a pathogenic BRCA2 mutation and low VAF in tumor-only CGP, which was later identified as a germline variant. When genomic alterations in BRCA1/2 are identified in tumor-only CGP, the possible germline origin of the variants should be considered, even if their VAF is very low.

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Eribulin inhibits growth of cutaneous squamous cell carcinoma cell lines and a novel patient-derived xenograft

Che Yuan Hsu, Teruki Yanagi, Takuya Maeda, Hiroshi Nishihara, Kodai Miyamoto, Shinya Kitamura, Keiko Tokuchi, Hideyuki Ujiie

Scientific Reports 13 （ 1 ）  2023年12月

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Advanced cutaneous squamous cell carcinoma (cSCC) is treated with chemotherapy and/or radiotherapy, but these typically fail to achieve satisfactory clinical outcomes. There have been no preclinical studies to evaluate the effectiveness of eribulin against cSCC. Here, we examine the effects of eribulin using cSCC cell lines and a novel cSCC patient-derived xenograft (PDX) model. In the cSCC cell lines (A431 and DJM-1 cells), eribulin was found to inhibit tumor cell proliferation in vitro as assessed by cell ATP levels. DNA content analysis by fluorescence-activated cell sorting (FACS) showed that eribulin induced G2/M cell cycle arrest and apoptosis. In xenograft models of cSCC cell lines, the administration of eribulin suppressed tumor growth in vivo. We also developed a cSCC patient-derived xenograft (PDX) which reproduces the histological and genetic characteristics of a primary tumor. Pathogenic mutations in TP53 and ARID2 were detected in the patient’s metastatic tumor and in the PDX tumor. The cSCC-PDX responded well to the administration of eribulin and cisplatin. In conclusion, the present study shows the promising antineoplastic effects of eribulin in cSCC. Also, we established a novel cSCC-PDX model that preserves the patient’s tumor. This PDX could assist researchers who are exploring innovative therapies for cSCC.

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<i>BRCA1/2</i> reversion mutations in a pan‐cancer cohort

Kohei Nakamura, Hideyuki Hayashi, Ryutaro Kawano, Marin Ishikawa, Eriko Aimono, Takaaki Mizuno, Hajime Kuroda, Yasuyuki Kojima, Naoki Niikura, Aya Kawanishi, Kei Takeshita, Shinsuke Suzuki, Shinichi Ueno, Kosuke Okuwaki, Jiichiro Sasaki, Masatoshi Yamaguchi, Kenta Masuda, Tatsuyuki Chiyoda, Wataru Yamagami, Chihiro Okada, Sachio Nohara, Shigeki Tanishima, Hiroshi Nishihara

Cancer Science （Wiley）  2023年12月

査読有り,  ISSN  1347-9032

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Abstract

Tumor sensitivity to platinum (Pt)‐based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency‐causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan‐cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan‐cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell‐free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single‐nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology‐mediated end‐join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP‐inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt‐based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA‐associated cancers, our findings suggest that reversion mutations due to Pt‐chemotherapy might be correlated with BRCA1/2‐mediated tumorigenesis even in non‐BRCA‐associated histologies.

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Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer.

Shoko Kitazawa, Tatsuyuki Chiyoda, Kohei Nakamura, Kensuke Sakai, Tomoko Yoshihama, Hiroshi Nishio, Yusuke Kobayashi, Takashi Iwata, Kouji Banno, Wataru Yamagami, Hiroshi Nishihara, Daisuke Aoki

International journal of clinical oncology 2023年08月

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BACKGROUND: Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. METHODS: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. RESULTS: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. CONCLUSION: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.

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Tumor Burden Monitoring with Circulating Tumor DNA During Treatment in Patients with Esophageal Squamous Cell Carcinoma.

Yosuke Morimoto, Satoru Matsuda, Hirofumi Kawakubo, Kohei Nakamura, Ryota Kobayashi, Kazuhiko Hisaoka, Jun Okui, Masashi Takeuchi, Eriko Aimono, Kazumasa Fukuda, Rieko Nakamura, Hideyuki Saya, Hiroshi Nishihara, Yuko Kitagawa

Annals of surgical oncology 30 （ 6 ） 3747 - 3756 2023年06月

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BACKGROUND: To guide appropriate treatment strategy, an accurate tumor monitoring modality that reflects tumor burden during neoadjuvant treatment is required for esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinical utility of circulating tumor DNA (ctDNA) in plasma in patients who received neoadjuvant chemotherapy (NAC) followed by esophagectomy. PATIENTS AND METHODS: Longitudinally collected plasma samples for ctDNA combined with genomic DNA from primary lesions were obtained from patients with histologically confirmed ESCC who underwent NAC followed by subtotal esophagectomy. Next-generation sequencing was performed to identify mutations from the plasma and the primary tumor. The relationships between changes in ctDNA and the pathological response and recurrence were assessed in patients with locally advanced ESCC. RESULTS: In pretreatment samples from 13 patients, multiple concordant mutations in ctDNA and primary tumors were observed in 11 patients (85%), who were classified as ctDNA positive before treatment. The ctDNA positive rate after NAC correlated with the pathological response (responders, 25%; nonresponders, 100%; p = 0.007). The risk of recurrence increased significantly in patients with positive ctDNA after surgery in analysis of 16 patients; the 1-year recurrence-free survival rates were 90 and 0% in ctDNA-negative and ctDNA-positive groups, respectively (p = 0.0008). In two patients with postoperative recurrence, ctDNA was detected approximately 5.5 months earlier than the diagnosis using radiographical imaging. CONCLUSIONS: ctDNA is a promising biomarker for predicting pathological response and postoperative recurrence in ESCC. To demonstrate the external validity, we are currently preparing a multicenter prospective study.

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ASO Author Reflections: Can Circulating Tumor DNA Guide Individualized Treatment for Patients with Esophageal Squamous Cell Carcinoma?

Yosuke Morimoto, Satoru Matsuda, Hirofumi Kawakubo, Kohei Nakamura, Ryota Kobayashi, Kazuhiko Hisaoka, Jun Okui, Masashi Takeuchi, Eriko Aimono, Kazumasa Fukuda, Rieko Nakamura, Hideyuki Saya, Hiroshi Nishihara, Yuko Kitagawa

Annals of surgical oncology 30 （ 6 ） 3757 - 3758 2023年06月

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ASO Visual Abstract: Tumor Burden Monitoring with Circulating Tumor DNA During Treatment in Patients with Esophageal Squamous Cell Carcinoma.

Yosuke Morimoto, Satoru Matsuda, Hirofumi Kawakubo, Kohei Nakamura, Ryota Kobayashi, Kazuhiko Hisaoka, Jun Okui, Masashi Takeuchi, Eriko Aimono, Kazumasa Fukuda, Rieko Nakamura, Hideyuki Saya, Hiroshi Nishihara, Yuko Kitagawa

Annals of surgical oncology 30 （ 6 ） 3759 - 3759 2023年06月

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Prognostic role of the innate immune signature CD163 and "eat me" signal calreticulin in clear cell renal cell carcinoma.

Tadatsugu Anno, Nobuyuki Tanaka, Kimiharu Takamatsu, Kyohei Hakozaki, Ryohei Kufukihara, Yuto Baba, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Shuji Mikami, Hiroshi Nishihara, Ryuichi Mizuno, Mototsugu Oya

Cancer immunology, immunotherapy : CII 72 （ 6 ） 1779 - 1788 2023年06月

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The effects of the innate immune status on patients with clear cell renal cell carcinoma (ccRCC) currently remain unknown. We herein provided more extensive information about the inner landscape of immunobiology of ccRCC. In total, 260 ccRCC samples from three different cohorts consisting of 213 primary tumors and 47 metastases were obtained. We focused on five representative innate immune signatures, CD68, CD163, the "eat me" signal calreticulin, the "don't eat me" signal CD47, and signal regulatory protein α, and examined the role of each signature by quantitative immunohistochemistry. We then conducted an integrated genome mutation analysis by next-generation sequencing. Among the five markers, high CD163 and low calreticulin expression levels were prognostic in ccRCC. The application of a new risk model based on CD163 and calreticulin levels, named the innate immune risk group (high risk: high-CD163/low calreticulin, intermediate risk: high-CD163/high calreticulin or low CD163/low calreticulin, low risk: low-CD163/high calreticulin), enabled the sequential stratification of patient prognosis and malignancy. Although organ-specific differences were observed, metastases appeared to have a higher innate immune risk, particularly in the lungs, with 50% of ccRCC metastases being classified into the high-risk group according to our risk score. An analysis of genomic alterations based on the innate immune risk group revealed that alterations in the TP53/Cell cycle pathway were highly prevalent in high-risk ccRCC patients according to two innate immune signatures CD163 and calreticulin. The present results provide insights into the immune-genomic biology of ccRCC tumors for innate immunity and will contribute to future therapies focused on the innate immune system in solid cancers.

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Cancer gene analysis of liquid-based cytology specimens using next-generation sequencing: A technical report of bimodal DNA- and RNA-based panel application.

Toshiaki Akahane, Tomomi Isochi-Yamaguchi, Natumi Hashiba-Ohnuki, Nobuyuki Bandoh, Eriko Aimono, Yasutaka Kato, Hiroshi Nishihara, Hajime Kamada, Akihide Tanimoto

Diagnostic cytopathology 51 （ 8 ） 493 - 500 2023年05月

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BACKGROUND: As liquid-based cytology (LBC) specimens harbor high-quality DNA, genomic analysis using LBC specimens is beneficial for integrative diagnosis. This study aimed to clarify the feasibility of LBC specimens for a bimodal application of DNA- and RNA-based next-generation sequencing (NGS) panels. METHODS: LBC specimens were prepared from cultured human cancer HEC59 cells using commercially available fixatives (Cellprep, CytoRich Red, and SurePath solutions), and were subjected to NGS for a feasibility study. Clinical LBC specimens of thyroid and salivary gland tumors were prepared using CytoRich Red solution. After DNA and RNA extraction, NGS analyses were performed in a single run using combined DNA- and RNA-based custom-made cancer panels for the detection of gene mutations and fusions. RESULTS: High-quality DNA and RNA were obtained, and the expected gene mutations and fusions were detected in HEC59 cells using all types of LBC fixatives. Most available clinical cases (18 out of 20) exhibited pathogenic gene mutations (15 cases) and fusion genes (3 cases) using the bimodal DNA- and RNA-based panels. Overall, 18 cases (90%) showed oncogenic mutations or fusion genes of diagnostic values. CONCLUSION: Simultaneous application of bimodal DNA- and RNA-based gene panels was useful in NGS analysis using residual LBC specimens for integrative diagnosis. Residual LBC specimens for genomic analysis, including fusion gene analysis, are particularly useful for obtaining genomic information before surgical resection.

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