Publications by authors named "Tomoyasu Kato"

140 Publications

Prevention of delirium with agitation by yokukansan in older adults after cancer surgery.

Jpn J Clin Oncol 2022 Jul 30. Epub 2022 Jul 30.

Department of Psycho-Oncology, National Cancer Center Japan, Tokyo, Japan.

Objective: Preventing postoperative delirium with agitation is vital in the older population. We examined the preventive effect of yokukansan on postoperative delirium with agitation in older adult patients undergoing highly invasive cancer resection.

Methods: We performed a secondary per-protocol analysis of 149 patients' data from a previous clinical trial. Patients underwent scheduled yokukansan or placebo intervention 4-8 days presurgery and delirium assessment postoperatively. Delirium with agitation in patients aged ≥75 years was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the Japanese version of the Delirium Rating Scale-Revised-98. We assessed odds ratios for yokukansan (TJ-54) compared with placebo for the manifestation of postoperative delirium with agitation across patients of all ages (n = 149) and those aged ≥65 years (n = 82) and ≥ 75 years (n = 21) using logistic regression.

Results: Delirium with agitation manifested in 3/14 and 5/7 patients in the TJ-54 and placebo groups, respectively, among those aged ≥75 years. The odds ratio for yokukansan vs. placebo was 0.11 (95% confidence interval: 0.01-0.87). An age and TJ-54 interaction effect was detected in patients with delirium with agitation. No intergroup differences were observed in patients aged ≥65 years or across all ages for delirium with agitation.

Conclusions: This is the first study investigating the preventive effect of yokukansan on postoperative delirium with agitation in older adults. Yokukansan may alleviate workforce burdens in older adults caused by postoperative delirium with agitation following highly invasive cancer resection.
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http://dx.doi.org/10.1093/jjco/hyac123DOI Listing
July 2022

Salvage image-guided freehand interstitial brachytherapy for pelvic sidewall recurrence after hysterectomy for uterine malignancies.

Brachytherapy 2022 Jun 21. Epub 2022 Jun 21.

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: Pelvic sidewall recurrence after hysterectomy for uterine malignances has a poor prognosis, and the salvage therapy for this type of recurrence is still challenging. The purpose of this study was to investigate the efficacy of freehand high-dose-rate interstitial brachytherapy (HDR-ISBT) through the perineum using transrectal ultrasonography for this disease.

Methods And Materials: We retrospectively evaluated 42 patients with pelvic sidewall recurrence after hysterectomy for uterine cervical and endometrial cancers. We investigated patients' characteristics, the 2-year local control and survival rates, and late adverse events of the rectum and bladder.

Results: The 2-year overall survival, local control, and progression-free survival rates were 73.7% (95% confidence interval [CI], 60.8-89.3%), 69.4% (95% CI, 55.4-80.1%), and 37.3% (95% CI, 24.6-56.5%), respectively. In Cox multivariate analysis, tumor size at recurrence (<45 mm vs. ≥45 mm) (p = 0.04) and disease-free periods after hysterectomy (<10 months vs. ≥10 months) (p < 0.01) were significant prognostic factors for overall survival. Lymph node metastasis at recurrence (p < 0.01) was also a significant prognostic factor for progression-free survival. Three patients experienced Grade 3-4 late proctitis (7%).

Conclusions: Transperineal freehand salvage HDR-ISBT using transrectal ultrasonography was demonstrated to be a curative treatment option for patients with pelvic sidewall recurrence following hysterectomy. Based on the findings of this study, we emphasize the importance of HDR-ISBT for pelvic sidewall recurrence.
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http://dx.doi.org/10.1016/j.brachy.2022.04.009DOI Listing
June 2022

Now is it time to implement spacers in cervical cancer brachytherapy?

J Radiat Res 2022 Jul;63(4):696-698

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.

Although the international study on MRI-guided brachytherapy in cervical cancer (EMBRACE-I) demonstrated excellent local control regardless of the T stage, up to 14.6% of grade 3-5 late radiation-related toxicities were observed, which is unacceptable. While the efficacy of hydrogel spacers has been established in prostate radiotherapy, its implementation speed in cervical cancer brachytherapy is relatively slow, despite the fact that several articles have reported its efficacy in cervical cancer brachytherapy. The authors believe that using a spacer in cervical cancer brachytherapy and brachytherapy for other gynecologic malignancies will reduce late radiation-related toxicity and improve patients' quality of life; therefore, its rapid implementation is required.
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http://dx.doi.org/10.1093/jrr/rrac031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303596PMC
July 2022

Microcystic stromal tumor of the ovary: a recurrent case with somatic CTNNB1 missense mutation.

Virchows Arch 2022 Jun 14. Epub 2022 Jun 14.

Department of Gynecology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Microcystic stromal tumors (MCSTs) of the ovary are rare sex cord-stromal tumors that are considered benign neoplasms because almost all cases display unilateral, localized lesions and have benign outcomes, except for one recurrent case with familial adenomatous polyposis and another initial metastatic case with a CTNNB1 mutation. We report herein a sporadic case that relapsed as intra-abdominal spread 9 years and 1 month after primary left salpingo-oophorectomy for torsion of the ovarian tumor pedicle. The tumor relapsed as multiple disseminations at the subabdominal wall, Douglas pouch, and omentum. Histologically, the tumor cells formed microcysts and infiltrated the surrounding adipose tissue, similar to the invasive implants of ovarian epithelial borderline tumors. Mutation analysis of the recurrent tumor revealed a somatic CTNNB1 p.S33Y activated missense mutation and a germline KDR p.Q472H variant. In conclusion, long-term clinical follow-up may be needed to detect any recurrence of MCST, irrespective of familial adenomatous polyposis.
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http://dx.doi.org/10.1007/s00428-022-03360-1DOI Listing
June 2022

Effect of Hyaluronate Acid Injection on Dose-Volume Parameters in Brachytherapy for Cervical Cancer.

Adv Radiat Oncol 2022 May-Jun;7(3):100918. Epub 2022 Feb 6.

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: Hyaluronate gel has been injected as a spacer into the rectovaginal fossa and vesicouterine fossa during brachytherapy for patients with cervical cancer at our institution. The effect of hyaluronate gel injection (HGI) on dose-volume parameters was investigated in this study.

Methods And Materials: Between July 2008 to January 2020, a total of 104 patients (non-HGI group: 52 patients; HGI group: 52 patients) who underwent curative radiation therapy for cervical cancer were selected. The total doses of external beam radiation therapy and brachytherapy for high-risk clinical target volume (CTV) D, bladder D, and rectal D were converted to the equivalent dose in 2 Gy fractions (EQD2) and were analyzed for association with HGI.

Results: Median CTV D (EQD2) in the non-HGI group was 76.0 Gy (63.7-99.5 Gy), and in the HGI group it was 79.4 Gy (52.6-97.5 Gy) ( = .017). The median bladder D and rectal D (EQD2) were 62.9 Gy and 56.0 Gy in the non-HGI group and 63.7 Gy and 54.8 Gy in the HGI group, which had no significant difference.

Conclusions: In cases with HGI, a significant CTV D dose increase was obtained with sufficient bladder and rectal doses suppression.
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http://dx.doi.org/10.1016/j.adro.2022.100918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133393PMC
February 2022

Large volume was associated with increased risk of acute non-hematologic adverse events in the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer: preliminary results of prospective phase I/II clinical trial.

Jpn J Clin Oncol 2022 Aug;52(8):851-860

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objective: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer.

Methods: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%.

Results: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036).

Conclusion: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial.
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http://dx.doi.org/10.1093/jjco/hyac072DOI Listing
August 2022

Usage of cadavers in surgical training and research in Japan over the past decade.

Anat Sci Int 2022 Jul 5;97(3):241-250. Epub 2022 Apr 5.

The Japan Surgical Society, CST Promotion Committee, World Trade Center Building South Tower 11F, 2-4-1, Hamamatsu-cho, Minato-ku, Tokyo, 105-5111, Japan.

The "Guidelines for Cadaver Dissection in Education and Research of Clinical Medicine" drafted by the Japan Surgical Society (JSS) and the Japanese Association of Anatomists in 2012 helped dispel legal concerns over cadaver surgical training (CST) and the usage of donated human bodies for research and development (R&D) in the country. Subsequently, in the fiscal year 2018, the Ministry of Health, Labour and Welfare increased the funding for CST, prompting its wider implementation. This study analyzed data obtained in 2012-2021 through the reporting system of the JSS-CST Promotion Committee to map the usage of cadavers for clinical purposes, specifically education and R&D, in Japan. We found that the number of medical universities using cadavers for CST and R&D programs was just 5 in 2012, and it reached 38 for the decade. Thus, about half of Japan's medical universities implemented such programs over the period. Meanwhile, the total number of programs was 1,173. In the clinical field, the highest number of programs were implemented in orthopedics (27%), followed by surgery (21%), and neurosurgery (12%). Based on the purpose, the most common objective of the programs (approximately 70%) was acquiring advanced surgical techniques. Further, the highest number of programs and participants were recorded in 2019 (295 programs, 6,537 participants). Thus, the guidelines helped expand cadaver usage for clinical purposes in Japan. To further promote the clinical usage of cadavers in medical and dental universities throughout Japan, sharing know-how on operating cadaver laboratories and building understanding among the general public is recommended.
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http://dx.doi.org/10.1007/s12565-022-00659-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980794PMC
July 2022

Aberrant Activation of Cell-Cycle-Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma.

Clin Cancer Res 2022 05;28(10):2147-2159

Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan.

Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates.

Experimental Design: Transcriptome analysis was performed using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis (IPA) was used to identify potential therapeutic target genes for uterine leiomyosarcoma. Afterward, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using SK-UT-1, SK-LMS-1, and SKN cell lines.

Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The IPA revealed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI-2536 or prexasertib) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest. In SK-UT-1 tumor-bearing mice, BI-2536 monotherapy remarkably suppressed tumorigenicity. Moreover, the prexasertib and cisplatin combination therapy inhibited tumor proliferation and prolonged the time to tumor progression.

Conclusions: We identified upregulated expressions of PLK1 and CHEK1; their kinase activity was activated in uterine leiomyosarcoma. BI-2536 and prexasertib demonstrated a significant anticancer effect. Therefore, cell-cycle-related kinases may present a promising therapeutic strategy for the treatment of uterine leiomyosarcoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-0100DOI Listing
May 2022

Clinical impact of genetic alterations of CTNNB1 in patients with grade 3 endometrial endometrioid carcinoma.

Cancer Sci 2022 May 24;113(5):1712-1721. Epub 2022 Mar 24.

Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

To identify prognostic factors in patients with grade 3 (high-grade) endometrial endometrioid carcinoma, we evaluated the spectrum of genomic alterations and examined whether previously reported molecular subtypes of endometrial carcinoma were adapted to clinical outcome prediction. Seventy-five Japanese patients with grade 3 endometrial endometrioid carcinoma, who underwent a potentially curative resection procedure between 1997 and 2018 at the National Cancer Center Hospital, were included. We classified the patients into four risk groups of the disease based on the Proactive Molecular Risk Classifier for Endometrial Cancer. Genomic alterations in PTEN, ARID1A, TP53, and PIK3CA were detected in more than 30% of the patients. Overall survival and recurrence-free survival of patients with genomic alterations in CTNNB1 were poorer than those of patients with wild-type CTNNB1 (p = 0.006 and p = 0.004, respectively). Compared with that of alterations prevalent in Caucasians, the frequency of genomic alterations in POLE and TP53 was higher in our study than in The Cancer Genome Atlas dataset (p = 0.01 and p = 0.01, respectively). The tendency for recurrence-free survival in the POLE exonuclease domain mutation group was better than that in the TP53 mutation and mismatch repair-deficient groups (p = 0.08 and p = 0.07, respectively), consistent with the Proactive Molecular Risk Classifier for Endometrial Cancer risk classifier definition. The CTNNB1 mutation is a potential novel biomarker for the prognosis of patients with grade 3 endometrial endometrioid carcinoma, and prognosis classification using Proactive Molecular Risk Classifier for Endometrial Cancer may help screen Japanese patients with the disease.
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http://dx.doi.org/10.1111/cas.15328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9128156PMC
May 2022

Treatment specialty-specific characteristics and outcomes in women with vulvo-vaginal melanoma: A JGOG-JSCS joint study.

J Surg Oncol 2022 06 3;125(8):1333-1337. Epub 2022 Mar 3.

Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan.

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http://dx.doi.org/10.1002/jso.26835DOI Listing
June 2022

Bartholin's glands commonly express NKX3.1: reconsideration of "prostatic differentiation" in gynaecological pathology.

Histopathology 2022 05 22;80(6):1013-1015. Epub 2022 Mar 22.

Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1111/his.14638DOI Listing
May 2022

Bevacizumab increases late toxicity in re-irradiation with image-guided high-dose-rate brachytherapy for gynecologic malignancies.

J Contemp Brachytherapy 2022 Feb 18;14(1):52-59. Epub 2022 Feb 18.

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Introduction: Patients with recurrent gynecologic malignancies having had pelvic irradiation, generally have limited salvage options. This study investigated patients with gynecologic malignancies, who had a history of pelvic irradiation and received salvage re-irradiation using image-guided high-dose-rate brachytherapy (IG-HDR-BT).

Material And Methods: Patients with gynecologic malignancies, who had a history of previous irradiation and received re-irradiation using IG-HDR-BT for disease recurrences from June 2014 to March 2020 were included in this study.

Results: A total of 37 patients were included in this retrospective analysis. Primary tumor was uterine cervical cancer in 31 patients, endometrial cancer in 5 patients, and vaginal cancer in 1 patient. Median follow-up period of patients who were alive at the time of analysis was 15.4 months (range, 4.1-61.4 months). Two-year overall survival, progression-free survival, and local control were 68.9%, 49.3%, and 67.5%, respectively. Severe late toxicities ≥ grade 3, which were related to re-irradiation, were observed in 9 patients (24.3%). Usage of bevacizumab in the entire course of treatment was associated with development of late ≥ grade 3 fistula formation, bowel perforation, or vaginal ulcer (50% vs. 6.9%, = 0.013). Tumor size ≥ 2.5 cm was associated with development of late ≥ grade 3 of rectum, bladder, or vaginal toxicities (0% vs. 28%, = 0.047).

Conclusions: If the recurrent disease was found in small size and there was no history of bevacizumab usage, re-irradiation with IG-HDR-BT could be considered, even in patients with a previous history of pelvic irradiation.
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http://dx.doi.org/10.5114/jcb.2022.113549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867241PMC
February 2022

DNA methylation marker to estimate ovarian cancer cell fraction.

Med Oncol 2022 Feb 23;39(5):78. Epub 2022 Feb 23.

Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Evaluation of a cancer cell fraction is important for accurate molecular analysis, and pathological analysis is the gold standard for evaluation. Despite the potential convenience, no established molecular markers for evaluation are available. In this study, we aimed to identify ovarian cancer cell fraction markers using DNA methylation highly specific to ovarian cancer cells. Using genome-wide DNA methylation data, we screened candidate marker genes methylated in 30 ovarian cancer FFPE samples and 12 high-grade serous ovarian cancer cell lines, and unmethylated in two female leucocytes and two normal fallopian epithelial cell samples. Methylation levels of two genes, SIM1, and ZNF154, showed high correlation with pathological cancer cell fractions among the 30 ovarian cancer FFPE samples (R = 0.61 for SIM1, 0.71 for ZNF154). For cost-effective analysis of FFPE samples, pyrosequencing primers were designed, and successfully established for SIM1 and ZNF154. Correlation between a pathological cancer cell fraction and methylation levels obtained by pyrosequencing was confirmed to be high (R = 0.53 for SIM1, 0.64 for ZNF154). Finally, an independent validation cohort of 29 ovarian cancer FFPE samples was analyzed. ZNF154 methylation showed a high correlation with the pathological cancer cell fraction (R = 0.77, P < 0.0001). Therefore, the ZNF154 methylation level was considered to be useful for the estimation of ovarian cancer cell fraction, and is expected to help accurate molecular analysis.
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http://dx.doi.org/10.1007/s12032-022-01679-yDOI Listing
February 2022

How should we appropriately classify low-risk uterine cervical cancer patients suitable for de-intensified treatment?

J Radiat Res 2022 Mar;63(2):312-313

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.

We suggested de-escalation would be possible for cervical cancer like human papillomavirus (HPV)-related oropharyngeal cancer. However, the classification was based on tumor shrinkage that can be obtained after half of the treatment was finished. Our other article found adverse factors which can be obtained prior to treatment, and they might classify patients earlier.
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http://dx.doi.org/10.1093/jrr/rrab130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944302PMC
March 2022

The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma.

Commun Biol 2022 01 11;5(1):39. Epub 2022 Jan 11.

Division of Medical AI Research and Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

High-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths. However, it is still unclear how genetic dysregulations and biological processes generate the malignant subtype of HGSOC. Here we show that expression levels of microtubule affinity-regulating kinase 3 (MARK3) are downregulated in HGSOC, and that its downregulation significantly correlates with poor prognosis in HGSOC patients. MARK3 overexpression suppresses cell proliferation and angiogenesis of ovarian cancer cells. The LKB1-MARK3 axis is activated by metabolic stress, which leads to the phosphorylation of CDC25B and CDC25C, followed by induction of G2/M phase arrest. RNA-seq and ATAC-seq analyses indicate that MARK3 attenuates cell cycle progression and angiogenesis partly through downregulation of AP-1 and Hippo signaling target genes. The synthetic lethal therapy using metabolic stress inducers may be a promising therapeutic choice to treat the LKB1-MARK3 axis-dysregulated HGSOCs.
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http://dx.doi.org/10.1038/s42003-021-02992-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752757PMC
January 2022

Molecular Pathology of Human Papilloma Virus-Negative Cervical Cancers.

Cancers (Basel) 2021 Dec 17;13(24). Epub 2021 Dec 17.

Department of Gynecology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Cervical cancer is the fourth most common cancer in women worldwide and is predominantly caused by infection with human papillomavirus (HPV). However, a small subset of cervical cancers tests negative for HPV, including true HPV-independent cancers and false-negative cases. True HPV-negative cancers appear to be more prevalent in certain pathological adenocarcinoma subtypes, such as gastric- and clear-cell-type adenocarcinomas. Moreover, HPV-negative cervical cancers have proven to be a biologically distinct tumor subset that follows a different pathogenetic pathway to HPV-associated cervical cancers. HPV-negative cervical cancers are often diagnosed at an advanced stage with a poor prognosis and are expected to persist in the post-HPV vaccination era; therefore, it is important to understand HPV-negative cancers. In this review, we provide a concise overview of the molecular pathology of HPV-negative cervical cancers, with a focus on their definitions, the potential causes of false-negative HPV tests, and the histology, genetic profiles, and pathogenesis of HPV-negative cancers.
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http://dx.doi.org/10.3390/cancers13246351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699825PMC
December 2021

Genetic features of endometrioid-type endometrial carcinoma arising in uterine adenomyosis.

Virchows Arch 2022 Jul 17;481(1):117-123. Epub 2021 Nov 17.

Department of Gynecology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

This study aimed to clarify the genetic features of endometrioid-type endometrial cancer arising in adenomyosis (EC-AIA) using targeted sequencing and immunohistochemistry (IHC) for both carcinoma and adjacent adenomyosis tissues. We identified three endometrioid-type EC-AIAs in 689 patients with endometrial cancer; two exhibited grade 3 endometrioid carcinoma. IHC revealed retained expression of PMS2, MSH6, ARID1A, and PAX2. Two of them showed diffuse strong p53 expression only in the carcinoma. PTEN expression was lost in carcinoma of only one of these cases. Carcinoma had many gene mutations than adjacent adenomyosis in all cases. KRAS and TP53 mutations were found in two of them. The other patient had mutations in KRAS, PIK3CA, and PPP2R1A. They were classified as two "p53-mutated" and one "non-specific molecular profile." These molecular alterations in endometrioid-type EC-AIA imply similar carcinogenesis to a subset of endometrial endometrioid carcinoma and might be used as targets of liquid biopsy after further validation.
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http://dx.doi.org/10.1007/s00428-021-03234-yDOI Listing
July 2022

Hotspot mutation profiles of AKT1 in Asian women with breast and endometrial cancers.

BMC Cancer 2021 Oct 21;21(1):1131. Epub 2021 Oct 21.

Department of Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: The V-Akt murine thymoma viral oncogene (AKT) 1 (E17K) is a subfamily of serine/threonine protein kinases that affects the survival, proliferation, and invasion of cancer cells. The clinicopathological features and frequencies in Asian populations with AKT1 mutations in breast and endometrial cancers are unclear. Hence, we aimed to determine the frequencies and relationships between clinicopathological features and AKT1 mutations in Asian women with cancer.

Methods: We extracted DNA from 311 and 143 samples derived from patients with breast and endometrial cancers to detect the AKT1 point mutation (hotspot), E17K. We examined correlations between clinicopathological features and AKT1 mutation status.

Results: The frequency of AKT1 mutations in breast cancer was 7.4%, and they were found more frequently in human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtypes, although this was not statistically significant (P = 0.08). The frequency of AKT1 mutations in endometrial cancer was 4.1%, and the mutations were histologically detected only in endometrioid types. However, AKT1 mutations did not correlate with relapse-free or overall survival of patients with breast or endometrial cancer.

Conclusions: AKT1 mutations are associated with HER2-negative subtype in breast cancer and in endometrial cancer with endometrioid histology. The frequencies of AKT1 mutations in breast and endometrial cancers were similar between Asian and other regional women. The frequency of mutations is too low in both tumor types to talk about predictive significance.
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http://dx.doi.org/10.1186/s12885-021-08869-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529845PMC
October 2021

Extracellular microRNA profiling for prognostic prediction in patients with high-grade serous ovarian carcinoma.

Cancer Sci 2021 Dec 19;112(12):4977-4986. Epub 2021 Oct 19.

Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan.

High-grade serous ovarian carcinoma is a leading cause of death in female patients worldwide. MicroRNAs (miRNAs) are stable noncoding RNAs in the peripheral blood that reflect a patient's condition, and therefore, they have received substantial attention as noninvasive biomarkers in various diseases. We previously reported the usefulness of serum miRNAs as diagnostic biomarkers. Here, we investigated the prognostic impact of the serum miRNA profile. We used the GSE106817 dataset, which included preoperative miRNA profiles of patients with ovarian malignancies. Excluding patients with other malignancy or insufficient prognostic information, we included 175 patients with high-grade serous ovarian carcinoma. All patients except four underwent surgery and received chemotherapy as initial treatment. The median follow-up period was 54.6 months (range, 3.5-144.1 months). Univariate Cox regression analysis revealed that higher levels of miR-187-5p and miR-6870-5p were associated with both poorer progression-free survival (PFS) and overall survival (OS), and miR-1908-5p, miR-6727-5p, and miR-6850-5p were poor prognostic indicators of PFS. The OS and PFS prognostic indices were then calculated using the expression values of three prognostic miRNAs. Multivariate Cox regression analysis showed that both indices were significantly independent poor prognostic factors (hazard ratio for OS and PFS, 2.343 [P = .015] and 2.357 [P = .005], respectively). In conclusion, circulating miRNA profiles can potentially provide information to predict the prognosis of patients with high-grade serous ovarian carcinoma. Therefore, there is a strong demand for early clinical application of circulating miRNAs as noninvasive biomarkers.
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http://dx.doi.org/10.1111/cas.15154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645733PMC
December 2021

TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer.

Sci Rep 2021 09 28;11(1):19261. Epub 2021 Sep 28.

Department of Gynecology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Targeted sequencing for somatic mutations across the hotspots of 50 cancer-related genes was performed using biopsy specimens to investigate whether clinicopathological factors and genomic alterations correlated with prognosis in locally advanced cervical cancer. Seventy patients diagnosed with International Federation of Obstetrics and Gynecology (FIGO) stage III to IVA cervical cancer underwent radiotherapy or concurrent chemoradiotherapy at the National Cancer Center Hospital between January 2008 and December 2017. Mutations were detected in 47 of 70 [67% of cases; frequency of genetic alterations was as follows: PIK3CA (51%), FBXW7 (10%), PTEN (7.1%), and TP53 (5.7%)]. The Cancer Genome Atlas (TCGA) datasets showed a similar distribution of somatic mutations, but PIK3CA mutation frequency was significantly higher in our cohort than in TCGA datasets (P = 0.028). Patients with TP53 mutation were significantly related to poor progression-free survival (PFS) (hazard ratio [HR] = 3.53, P = 0.042). Patients with tumor diameters > 70 mm were associated with poor prognosis (HR = 2.96, P = 0.0048). Patients with non-HPV16/18 genotypes had worse prognosis than those with HPV16/18 genotypes (HR = 2.15, P = 0.030). Hence, patients with locally advanced cervical cancer, TP53 mutation, large tumor diameter, and non-HPV16/18 genotype were independently correlated with poor PFS, despite concurrent chemoradiotherapy.
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http://dx.doi.org/10.1038/s41598-021-98527-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478905PMC
September 2021

Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance.

Cancer Lett 2021 Aug 19;521:29-38. Epub 2021 Aug 19.

Division of Cancer Differentiation, National Cancer Center Research Institute, Japan. Electronic address:

Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.
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http://dx.doi.org/10.1016/j.canlet.2021.08.018DOI Listing
August 2021

CT, MRI, and FDG-PET imaging findings of low-grade extrauterine endometrial stromal sarcoma arising from the mesentery: A case report.

Radiol Case Rep 2021 Sep 22;16(9):2774-2779. Epub 2021 Jul 22.

Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Endometrial stromal sarcoma is a rare uterine mesenchymal neoplasm, and extrauterine endometrial stromal sarcoma is even rarer, with a limited number of case reports. In the present report, we present a case of low-grade extrauterine endometrial stromal sarcoma originating from the mesentery in a 49-year-old woman, without endometrial stromal sarcoma in the uterus or evidence of endometriosis. The tumor was diagnosed using recombination of the gene by fluorescence in situ hybridization. Computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography showed a 13 cm, primarily polycystic, mass containing a contrast-enhancing solid component with restricted diffusion and mild 18F-fluorodeoxyglucose uptake. A large cystic component may be a characteristic feature of extrauterine endometrial stromal sarcoma, given the low pressure from the surrounding tissues.
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http://dx.doi.org/10.1016/j.radcr.2021.06.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326572PMC
September 2021

Loss of ARID1A Expression as a Favorable Prognostic Factor in Early-Stage Grade 3 Endometrioid Endometrial Carcinoma Patients.

Pathol Oncol Res 2021 25;27:598550. Epub 2021 Mar 25.

Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.

High-risk patients with grade 3 endometrioid endometrial carcinoma (G3EEC) who require adjuvant therapy have not been clearly identified. Therefore, the current study aimed to investigate the prognostic impact of ARID1A, p53, and mismatch repair (MMR) protein expressions, previously reported as prognosticators in some gynecological cancers, in patients with early-stage G3EEC. A total of 67 patients with pathologically confirmed early-stage G3EEC diagnosed between 1997 and 2020 were identified; none received adjuvant chemotherapy. The recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with a log-rank test. The protein expressions of ARID1A, p53, and MMR were examined via immunohistochemistry, and the associations between these biomarkers and clinical outcomes were evaluated. Recurrence was observed in 9 (13%) of the 67 patients with early stage G3EEC. The respective 5-years RFS and OS rates were 87.7% and 93.7%, and 68.6% and 85.7%, respectively for stages I and II. Multivariate analysis showed significantly longer RFS among patients with ARID1A loss (hazard ratio = 8.7; 95% CI, 1.09-69.6, = 0.04). No significant differences were observed in RFS and OS of patients according to p53 and MMR expression status. ARID1A expression status was a prognosticator for patients with early stage G3EEC without adjuvant therapy, whereas p53 and MMR expression status showed no impact on survival outcomes. ARID1A may become a useful biomarker for stratification of adjuvant treatment for early stage G3EEC patients.
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http://dx.doi.org/10.3389/pore.2021.598550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262237PMC
January 2022

Characteristics and outcomes of women with adenocarcinoma versus squamous cell carcinoma of the vulva: A Japanese Gynecologic Oncology Group study.

Eur J Surg Oncol 2021 12 9;47(12):3188-3193. Epub 2021 Jul 9.

Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan.

Objective: Studies on vulvar adenocarcinoma are lacking. Thus, we aimed to compare the characteristics and survival outcomes between vulvar adenocarcinoma and squamous cell carcinoma (SCC).

Methods: This was a preplanned sub-analysis of a previously organized nationwide retrospective observational study in Japan conducted between 2001 and 2010 (JGOG-1075S). Surgically treated women with stage I-IV vulvar invasive adenocarcinoma were compared to those with SCC. Multivariable analysis was performed to identify patient and tumor characteristics related to adenocarcinoma. Inverse probability of treatment weighting was used to balance the background differences, and a Cox proportional hazards regression model was fitted to estimate the effect of the histological type on survival.

Results: Forty-eight women with adenocarcinoma were compared with 537 women with SCC. On multivariable analysis, women with adenocarcinoma were younger (median age, 64.5 vs. 70 years, adjusted odds ratio [OR] per age 0.975, 95% confidence interval [CI] 0.955-0.995, P = 0.016) and had higher positive surgical margin rates (31.2% vs. 18.4%, adjusted OR 2.376, 95% CI 1.188-4.754, P = 0.014) than those with SCC. However, according to the weighted model, the survival outcomes were comparable (hazard ratio for progression-free survival, 1.088, 95% CI 0.740-1.601, P = 0.667 and hazard ratio for overall survival, 1.008, 95% CI 0.646-1.573, P = 0.973). Similar associations were observed when the cohort was stratified by age (≤70 or >70 years), stage (I-II or III-IV), and surgical margin (negative or positive) (all, P > 0.05).

Conclusion: Vulvar adenocarcinoma is characterized by a younger age at diagnosis and higher positive surgical margin rates than SCC, but the survival outcomes are comparable.
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http://dx.doi.org/10.1016/j.ejso.2021.07.002DOI Listing
December 2021

Analysis of factors affecting the diagnostic yield of image-guided percutaneous core needle biopsy for peritoneal/omental lesions.

Abdom Radiol (NY) 2021 09 28;46(9):4499-4508. Epub 2021 May 28.

Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: To evaluate the diagnostic yield, safety, and factors associated with the diagnostic yield of percutaneous core needle biopsy (PNB) for peritoneal/omental lesions.

Methods: Consecutive 297 patients (67 men, 230 women; median age, 64 years [range 15-87]) who underwent a PNB for 311 peritoneal/omental lesions at a single center from April 2010 to March 2020 were evaluated retrospectively. The preprocedural CT findings, diagnostic yield, sensitivity, specificity, PPV, NPV, technical success rate, and adverse events were analyzed. Surgical or clinical diagnosis with follow-up was the diagnostic reference standard. Adverse events were evaluated using the Society of Interventional Radiology guidelines.

Results: The median anteroposterior (AP) diameter and CT value of the target lesion were 24 mm (range 5-78) and 46 HU (range - 75 to 140), respectively. Ascites was interposed on the puncture route in 106 patients (34.1%). The technical success rate was 100%. The diagnostic yield, sensitivity, specificity, PPV, and NPV were 93.9%, 93.8%, 100%, 100%, and 20.8%, respectively. Minor complications were observed following five procedures (1.6%). The diagnostic yield was lower for fat-dominant lesions than for other lesions (82.6% vs. 95.8%, p = 0.002). The diagnostic PNB group had a greater AP diameter than did the non-diagnostic PNB group (27.3 ± 13.0 vs. 20.7 ± 8.4 mm, p = 0.037).

Conclusion: PNB for peritoneal/omental lesions provided a sufficiently high diagnostic yield and minimal adverse events. Lesions with a greater AP diameter and a higher density on CT would provide more diagnostic specimens from this technique.
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http://dx.doi.org/10.1007/s00261-021-03088-7DOI Listing
September 2021

Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy.

Sci Rep 2021 05 19;11(1):10567. Epub 2021 May 19.

Department of Radiation Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3-153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.
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http://dx.doi.org/10.1038/s41598-021-90139-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134569PMC
May 2021

Genome-Wide Chromatin Analysis of FFPE Tissues Using a Dual-Arm Robot with Clinical Potential.

Cancers (Basel) 2021 Apr 28;13(9). Epub 2021 Apr 28.

Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

Although chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) using formalin-fixed paraffin-embedded tissue (FFPE) has been reported, it remained elusive whether they retained accurate transcription factor binding. Here, we developed a method to identify the binding sites of the insulator transcription factor CTCF and the genome-wide distribution of histone modifications involved in transcriptional activation. Importantly, we provide evidence that the ChIP-seq datasets obtained from FFPE samples are similar to or even better than the data for corresponding fresh-frozen samples, indicating that FFPE samples are compatible with ChIP-seq analysis. H3K27ac ChIP-seq analyses of 69 FFPE samples using a dual-arm robot revealed that driver mutations in EGFR were distinguishable from pan-negative cases and were relatively homogeneous as a group in lung adenocarcinomas. Thus, our results demonstrate that FFPE samples are an important source for epigenomic research, enabling the study of histone modifications, nuclear chromatin structure, and clinical data.
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http://dx.doi.org/10.3390/cancers13092126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125448PMC
April 2021

Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix.

Cancers (Basel) 2021 Mar 10;13(6). Epub 2021 Mar 10.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (, 32%; , 24%) and distinct (, 20%; , 16%; , 12%; , 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.
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http://dx.doi.org/10.3390/cancers13061215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001835PMC
March 2021

The baseline recurrence risk of patients with intermediate-risk cervical cancer.

Obstet Gynecol Sci 2021 Mar 8;64(2):226-233. Epub 2021 Jan 8.

Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.

Objective: This study aimed to investigate the prognosis of patients with intermediate-risk cervical cancer and to evaluate the necessity of adjuvant therapy.

Methods: We conducted a retrospective chart review of patients with stage IB-II cervical cancer who underwent type III radical hysterectomy with pelvic lymphadenectomy between 2008 and 2017. In our institution, radical hysterectomy is performed as an open surgery and not as a minimally invasive surgery, and adjuvant therapy is not administered to patients with intermediate-risk cervical cancer. The intermediate-risk group included patients with 2 or more of the following factors: tumor size >4 cm, stromal invasion >1/2, and lymphovascular stromal invasion. Intermediaterisk patients with squamous cell carcinoma were included in the I-SCC group, whereas those with endocervical adenocarcinoma, usual type, or adenosquamous carcinoma were included in the I-Adeno group.

Results: There were 34 and 18 patients in the I-SCC and I-Adeno groups, respectively. The 5-year recurrence-free survival (RFS) and overall survival rates in the I-SCC group were 90.5% (95% confidence interval [CI], 85.3-95.7%) and 100% (95% CI, 100%), respectively, whereas those in the I-Adeno group were 54.9% (95% CI, 42.0-67.9%) and 76.1% (95% CI, 63.7-88.4%), respectively. Multivariate analysis revealed that endocervical adenocarcinoma, usual type, or adenosquamous carcinoma, and tumor size >4 cm had worse RFS.

Conclusion: The I-SCC group had good prognosis without adjuvant therapy; therefore, adjuvant therapy may be omitted in these patients. In contrast, the I-Adeno group had poor prognosis without adjuvant therapy; therefore, adjuvant therapy should be considered in their treatment.
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http://dx.doi.org/10.5468/ogs.20243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991004PMC
March 2021
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