Publications by authors named "Hideki Tokunaga"

76 Publications

Oncological Properties of Intravenous Leiomyomatosis: Involvement of Mesenchymal Tumor Stem-Like Cells.

Curr Issues Mol Biol 2021 Sep 19;43(2):1188-1202. Epub 2021 Sep 19.

National Hospital Organization Kyoto Medical Center, Department of Obstetrics and Gynecology, Kyoto 612-8555, Japan.

Uterine leiomyoma, also known as fibroids, is the most common benign neoplasm of the female genital tract. Leiomyoma is the most common uterine tumor. The leiomyoma subtypes account for approximately 10% of leiomyomas. Intravenous leiomyomatosis, a uterine leiomyoma subtype, is an intravascular growth of benign smooth muscle cells, occasionally with pelvic or extrapelvic extension. Uterine leiomyosarcoma, a malignant tumor, tends to metastasize hematogenously, and distant metastasis to the lungs and liver is common. Therefore, the oncological properties of this intravenous leiomyomatosis resemble those of the malignant tumor uterine leiomyosarcoma. Cancer stem cells migrate to distant organs via intravascular infiltration, leading to micrometastases. We examined the oncological properties of intravenous leiomyomatosis using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. CD44-positive mesenchymal tumor stem-like cells were detected in both patients with intravenous leiomyomatosis and uterine leiomyosarcoma. The oncological properties of intravenous leiomyomatosis were found to be similar to those of uterine leiomyosarcoma. However, in intravenous leiomyomatosis, cyclin E and Ki-67-positive cells were rare and no pathological findings suspecting malignancy were observed. It is expected that establishing a treatment method targeting cancer stem cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis.
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http://dx.doi.org/10.3390/cimb43020084DOI Listing
September 2021

Liquid biopsy with droplet digital PCR targeted to specific mutations in plasma cell-free tumor DNA can detect ovarian cancer recurrence earlier than CA125.

Gynecol Oncol Rep 2021 Nov 17;38:100847. Epub 2021 Aug 17.

Division of Molecular and Cellular Oncology, 5 Division of Cancer Stem cell, and 7 Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, 47-1, Nodayama, Medeshima-Shiode, Natori, Miyagi 981-1293 Japan.

Objective: Ovarian cancer (OC) is an intractable gynecological tumor, and frequent recurrence is experienced within a few years even after the complete eradication of tumor tissues by radical resection and neo-adjuvant chemotherapies. The conventional recurrence marker, CA125, is widely used for follow-up after resection of OC, but CA125 has a long half-life in blood and lacks dynamic responses to tumor recurrence. Recent developments in liquid biopsy procedures are expected to overcome the difficulties in early diagnosis of OC recurrence after surgery.

Methods: We applied droplet digital PCR (ddPCR) technology to detect circulating tumor-derived DNA in OC patients' plasma during follow-up. Exome sequencing of 11 tumor-normal pairs of genomic DNA from consecutive OC patients identified tumor-specific mutations, and ddPCR probes were selected for each sample.

Results: Six of 11 cases showed apparent recurrence during follow-up (mean progression-free survival was 348.3 days) and all six cases were positive in ddPCR analyses. In addition, ddPCR became positive before increased plasma CA125 in five out of six cases. Increased allele frequency of circulating tumor DNA (ctDNA) is associated with increased tumor volume after recurrence. ddPCR detected ctDNA signals significantly earlier than increased CA125 in the detection of OC recurrence by imaging (49 days and 7 days before, respectively: p < 0.05). No ctDNA was detected in the plasma of recurrence-free cases.

Conclusions: Our results demonstrate the potential of identifying ctDNA by ddPCR as an early detection tool for OC recurrence.
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http://dx.doi.org/10.1016/j.gore.2021.100847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446792PMC
November 2021

Surveillance of radical hysterectomy for early-stage cervical cancer in the early experienced period of minimally invasive surgery in Japan.

Int J Clin Oncol 2021 Aug 25. Epub 2021 Aug 25.

Department of Gynecology and Obstetrics, Tohoku University Graduate School of Medicine, Sendai, Japan.

Objective: The purpose of our study was to conduct a detailed survey of radical hysterectomy in Japanese patients with early-stage cervical cancer, and to compare oncologic outcomes between open and minimally invasive radical hysterectomy.

Methods: In Japan during 2015, the medical records of 929 patients with FIGO stage IB1 and IIA disease treated with radical hysterectomy were retrospectively reviewed. We assessed patients' characteristics, disease-free survival (DFS), overall survival (OS) and prognostic factors for survival.

Results: The median patient age was 44 (20-80) years. Most patients (94.4%) had stage IB1 disease. Of the patients who underwent radical hysterectomy, 91.2% underwent open surgery and 8.8% underwent minimally invasive surgery (MIS). The median follow-up period was 40.8 months (range, 0.49-51.1 months). The rate of DFS and OS at 4 years in all patients was 88.3% and 96.4%, respectively. Multivariate analysis identified age (≥ 47), adenocarcinoma histology, tumor size (≥ 2 cm), parametrial invasion, positive lymph node metastasis and institutional accreditation as independent predictors of recurrence, and adenocarcinoma, other cell types, and positive lymph node metastasis as independent predictors of death. Oncologic outcomes in all patients were similar between open and MIS, including DFS and OS.

Conclusion: The survival rate of the Japanese patients underwent radical hysterectomy for early-stage cervical cancer was favorable. No significant differences were observed for DFS and OS between open and MIS performed by a limited number of surgeons at a limited number of facilities in Japan. Further investigations are required to identify the appropriate patients might benefit from MIS.
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http://dx.doi.org/10.1007/s10147-021-02017-4DOI Listing
August 2021

A Single Arm Prospective Pilot Study Examining the Efficacy and Safety of Bevacizumab Single Maintenance Therapy Following Platinum-Based Chemotherapy in Patients with Advanced or Recurrent Cervical Cancer.

Tohoku J Exp Med 2021 07;254(3):145-153

Department of Obstetrics and Gynecology, Tohoku University School of Medicine.

Although the addition of bevacizumab to platinum-based combination chemotherapy has been recommended as a standard regimen for patients with advanced or recurrent cervical cancer, there is no clear evidence regarding the effectiveness of bevacizumab monotherapy as salvage chemotherapy. This study prospectively examined the efficacy and safety of switching from platinum-based chemotherapy combined with bevacizumab to single maintenance therapy in patients with advanced or recurrent cervical cancer. Patients were first treated with standard combination chemotherapy. However, if chemotherapy was discontinued because of an adverse event, bevacizumab monotherapy was continued for patients who agreed to participate in this study and provided written informed consent. The study protocol was approved by the Independent Review Board of Tohoku University School of Medicine (reception number 2017-1-540). A total of 15 patients (median age of 55 years, range 33-69 years) participated in this study. The median number of cycles of bevacizumab single maintenance administration was 8, and the main reasons for discontinuation were disease progression and adverse events. Bevacizumab single maintenance therapy had a disease control rate of 53.3% (CR 40%, PR 6.7%, SD 6.7%). The most frequent grade 3/4 clinical adverse events were proteinuria (5/15) and hypertension (4/15). No treatment-related deaths occurred. Bevacizumab single maintenance therapy was effective as salvage chemotherapy in patients with advanced or recurrent cervical cancer, and the safety profile was generally consistent with those reported in previous studies of bevacizumab monotherapy.
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http://dx.doi.org/10.1620/tjem.254.145DOI Listing
July 2021

Wide-Targeted Metabolome Analysis Identifies Potential Biomarkers for Prognosis Prediction of Epithelial Ovarian Cancer.

Toxins (Basel) 2021 06 30;13(7). Epub 2021 Jun 30.

Advanced Research Center for Innovations in Next Generation Medicine, Tohoku University, Sendai 980-8573, Japan.

Epithelial ovarian cancer (EOC) is a fatal gynecologic cancer, and its poor prognosis is mainly due to delayed diagnosis. Therefore, biomarker identification and prognosis prediction are crucial in EOC. Altered cell metabolism is a characteristic feature of cancers, and metabolomics reflects an individual's current phenotype. In particular, plasma metabolome analyses can be useful for biomarker identification. In this study, we analyzed 624 metabolites, including uremic toxins (UTx) in plasma derived from 80 patients with EOC using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Compared with the healthy control, we detected 77 significantly increased metabolites and 114 significantly decreased metabolites in EOC patients. Especially, decreased concentrations of lysophosphatidylcholines and phosphatidylcholines and increased concentrations of triglycerides were observed, indicating a metabolic profile characteristic of EOC patients. After calculating the parameters of each metabolic index, we found that higher ratios of kynurenine to tryptophan correlates with worse prognosis in EOC patients. Kynurenine, one of the UTx, can affect the prognosis of EOC. Our results demonstrated that plasma metabolome analysis is useful not only for the diagnosis of EOC, but also for predicting prognosis with the variation of UTx and evaluating response to chemotherapy.
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http://dx.doi.org/10.3390/toxins13070461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309959PMC
June 2021

CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents.

PLoS One 2021 23;16(6):e0251079. Epub 2021 Jun 23.

Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251079PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221472PMC
October 2021

Clinico-pathological characteristics of patients with stage IB1-IB2 (FIGO 2018) uterine cervical cancer: a nationwide study in Japan.

Int J Clin Oncol 2021 Aug 9;26(8):1541-1552. Epub 2021 Jun 9.

Department of Obstetrics and Gynecology, Tokai University, 143, Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

Objective: The aim of this retrospective analysis is to reveal clinicopathological findings and clinical outcome of patients with stage IB1/IB2 (FIGO 2018) uterine cervical cancer.

Methods: Based on the database of the Japanese Gynecologic Oncology Group, 2194 patients with stage IB1/IB2 (FIGO 2018), who underwent radical hysterectomy between 1/1/2004-12/31/2008, were identified as eligible for this retrospective study.

Results: Patients with squamous cell carcinoma had significantly frequent lympho-vascular space invasion than those with non-squamous cell carcinoma in both stage IB1 and IB2 (stage IB1; 29.1% vs. 17.1%, p < 0.0001, stage IB2; 50.5% vs. 39.7%, p = 0.0009). Among 1262 patients with stage IB1, 61.2% (772/1262) were low-risk group, 29.4% (371/1262) were intermediate-risk group (single risk: 23.3%, double risks: 6.1%). Of 932 patients with stage IB2, 32.1% (299/932) were low-risk group, 59.1% (551/932) were intermediate-risk group (single intermediate-risk: 31.0%, double intermediate-risk: 28.1%). Disease-free survival rate and overall survival rate of stage IB1 patients were significantly better than those with stage IB2 (5-year DFS; 94.7% vs. 88.6%, p < 0.001, 5-yrs OS; 98.5% vs. 95.1%, p < 0.001). Stage IB1 Patients with double intermediate-risk showed significantly worse survival than those with single intermediate-risk (5-yrs DFS: 96.1% vs. 84.6%, p < 0.001, 5-yrs OS: 98.9% vs. 93.0%, p = 0.029). Multivariate analysis revealed that double intermediate-risk was the independent prognostic factor in stage IB1, but non-squamous cell carcinoma and intermediate-risk in stage IB2.

Conclusion: Non-squamous cell carcinoma and intermediate-risk decreased survival in patients with stage IB2, whereas double intermediate-risk was a negative impact on survival in stage IB1.
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http://dx.doi.org/10.1007/s10147-021-01938-4DOI Listing
August 2021

Establishment of a Diagnostic Method for Pelvic Sentinel Lymph Node Metastasis by Contrast-Enhanced Ultrasound in Uterine Cancer.

Ultrasound Med Biol 2021 08 26;47(8):2107-2116. Epub 2021 May 26.

Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

This study investigated the usefulness of conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) in distinguishing metastasis of pelvic sentinel lymph nodes (SLNs) in patients with gynecological cancer. We examined 74 SLNs of patients with endometrial cancer (n = 26) and cervical cancer (n = 11). Patients underwent US and CEUS followed by SLN biopsy; US and CEUS results were evaluated visually and quantitatively and compared between pathological metastasis-negative and -positive groups. To support CEUS results, the microvessel density of SLNs was evaluated immunohistochemically. Seventeen positive and 40 negative SLNs were evaluable. Margin and enhancement patterns by visual assessment revealed significant differences (p = 0.046 and 0.022, respectively). In quantitative time-intensity curve analyses, the weakest peak intensities (PI), PI ratio and PI difference indicated significant differences (p = 0.045, p < 0.001 and p < 0.001, respectively). The areas under the receiver operating characteristic curves (AUCs) were 0.64, 0.82 and 0.83, respectively. The most effective PI ratio from the AUC was 1.3 (sensitivity = 82%, specificity = 70%), and the PI difference from the AUC was 20 (sensitivity = 88%, specificity = 70%). Microvessel density was significantly lower in metastatic lesions than in other areas. The quantitative analysis of CEUS seemed to be a reasonable method for distinguishing lymph node metastasis in patients with gynecological cancer.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.03.040DOI Listing
August 2021

Docetaxel and carboplatin chemotherapy for treating patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix: a phase II study.

Int J Clin Oncol 2021 Jul 7;26(7):1314-1321. Epub 2021 Apr 7.

Matsue City Hospital, 32-1, Noshira-cho, Matsue, Shimane, 690-8509, Japan.

Background: This phase II study evaluated the efficacy and safety of docetaxel/carboplatin chemotherapy for treating patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix.

Methods: A total of 50 patients with International Federation of Gynecology and Obstetrics stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix were enrolled and administered docetaxel at a dose of 60 mg/m, followed by carboplatin at a dose based on the area under the receiver operating characteristic curve of 6. The treatments were repeated every 21 days until disease progression or unacceptable adverse events. Except for two patients, 48 were eligible for evaluation. Another patient withdrew consent before treatment; adverse events were evaluated in 47.

Results: The response rate was 47.9% with 5 patients achieving complete response, 18 partial response, 14 stable disease, and 6 progressive disease. The disease control rate was 77.1%. With a median follow-up duration of 368 days, the median progression-free survival and overall survival were 6.1 months (95% CI 5.5-8.6) and 15.8 months (95% CI 18.2-28.3), respectively. The most frequent grade 3 and grade 4 hematological toxicity was neutropenia, with 38 patients (81%) having grade 4 and 4 (9%) having grade 3 neutropenia. The non-hematological toxicities were mainly grade 1 or 2 in severity.

Conclusion: Docetaxel/carboplatin chemotherapy was effective, with a higher disease control rate and well-tolerated chemotherapeutic regimen for patients with stage IVB or recurrent non-squamous cell carcinoma of the uterine cervix.
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http://dx.doi.org/10.1007/s10147-021-01903-1DOI Listing
July 2021

The 2020 Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

J Gynecol Oncol 2021 03;32(2):e49

Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

The fifth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was published in 2020. The guidelines contain 6 chapters-namely, (1) overview of the guidelines; (2) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (4) borderline epithelial tumors of the ovary; (5) malignant germ cell tumors of the ovary; and (6) malignant sex cord-stromal tumors. Furthermore, the guidelines comprise 5 algorithms-namely, (1) initial treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (2) treatment for recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) initial treatment for borderline epithelial ovarian tumor; (4) treatment for malignant germ cell tumor; and (5) treatment for sex cord-stromal tumor. Major changes in the new edition include the following: (1) revision of the title to "guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer"; (2) involvement of patients and general (male/female) participants in addition to physicians, pharmacists, and nurses; (3) clinical questions (CQs) in the PICO format; (4) change in the expression of grades of recommendation and level of evidence in accordance with the GRADE system; (5) introduction of the idea of a body of evidence; (6) categorization of references according to research design; (7) performance of systematic reviews and meta-analysis for three CQs; and (8) voting for each CQ/recommendation and description of the consensus.
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http://dx.doi.org/10.3802/jgo.2021.32.e49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930451PMC
March 2021

The validity of the subsequent pregnancy index score for fertility-sparing trachelectomy in early-stage cervical cancer.

Fertil Steril 2021 05 13;115(5):1250-1258. Epub 2021 Feb 13.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan. Electronic address:

Objective: To evaluate timing and a prediction model for pregnancy in early-stage cervical cancer patients who underwent fertility-sparing trachelectomy.

Design: Retrospective cohort.

Setting: Academic multicenter.

Patient(s): Women ages <45 years with clinical stage I-II cervical cancer were enrolled between 2009 and 2013 (n = 393).

Intervention(s): Planned fertility-sparing trachelectomy.

Main Outcome Measure(s): Cumulative incidences and clinicopathological characteristics of those who developed subsequent pregnancy were examined.

Result(s): There were 77 (21.6%) women who had subsequent pregnancies after fertility-sparing trachelectomy with 1-, 2-, and 5-year cumulative pregnancy rates of 2.8%, 6.2%, and 17.4%, respectively. The median time to develop subsequent pregnancy was 3.2 years. In a competing risk analysis, women had a higher risk of recurrent cancer than conception during the first 11 months postsurgery. On multivariable analysis, younger age, being married, and postoperative reproductive treatment were independently associated with an increased chance of developing a subsequent pregnancy. The subsequent pregnancy index (SPI) score to predict the likelihood of having pregnancy was proposed, and it was calculated based on age, marital status, and reproductive treatment (2, 2, and 4 points, respectively). Women with a higher SPI score had significantly higher subsequent pregnancy rates (5-year pregnancy rate; the score was 3 in 4.7% of cases; 4 to 5 in 11.3%; 6 to 7 in 27.4%; and 8 in 50.8%), but they had similar recurrence rates (5.0%).

Conclusion(s): The SPI score proposed in our study is useful in predicting subsequent pregnancy in women with early-stage cervical cancer undergoing fertility-sparing trachelectomy.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.162DOI Listing
May 2021

Lymphadenectomy issues in endometrial cancer.

J Gynecol Oncol 2021 03 7;32(2):e25. Epub 2021 Jan 7.

Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine and Faculty of Medicine, Sapporo, Japan.

Objectives: This review aims to introduce preoperative scoring systems to predict lymph node metastasis (LNM) and ongoing clinical trials to investigate the therapeutic role of lymphadenectomy for endometrial cancer.

Methods: We summarized previous reports on the preoperative prediction models for LNM and evaluated their validity to omit lymphadenectomy in our recent cohorts. Next, we compared characteristics of two ongoing lymphadenectomy trials (JCOG1412, ECLAT) to examine the survival benefit of lymphadenectomy in endometrial cancer, and described the details of JCOG1412.

Results: Lymphadenectomy has been omitted for 64 endometrial cancer patients who met low-risk criteria to omit lymphadenectomy using our scoring system (LNM score) and no lymphatic failure has been observed. Other two models also produced comparable results. Two randomized phase III trials to evaluate survival benefit of lymphadenectomy are ongoing for endometrial cancer. JCOG1412 compares pelvic lymphadenectomy alone with pelvic and para-aortic lymphadenectomy to evaluate the therapeutic role of para-aortic lymphadenectomy for patients at risk of LNM. For quality assurance of lymphadenectomy, we defined several regulations, including lower limit of the number of resected nodes, and submission of photos of dissected area to evaluate thoroughness of lymphadenectomy in the protocol. The latest monitoring report showed that the quality of lymphadenectomy has been well-controlled in JCOG1412.

Conclusion: Our strategy seems reasonable to omit lymphadenectomy and could be generalized in clinical practice. JCOG1412 is a high-quality lymphadenectomy trial in terms of the quality of surgical procedures, which would draw the bona-fide conclusions regarding the therapeutic role of lymphadenectomy for endometrial cancer.
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http://dx.doi.org/10.3802/jgo.2021.32.e25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930450PMC
March 2021

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer.

J Gynecol Oncol 2021 03 6;32(2):e21. Epub 2021 Jan 6.

Department of Gynecology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Objective: The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting.

Methods: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs).

Results: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8-79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease).

Conclusion: The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib.

Trial Registration: ClinicalTrials.gov Identifier: NCT03759587.
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http://dx.doi.org/10.3802/jgo.2021.32.e21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930455PMC
March 2021

Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2).

PLoS One 2021 11;16(1):e0236907. Epub 2021 Jan 11.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799847PMC
April 2021

Prospective evaluation of sentinel node navigation surgery in Japanese patients with low-risk endometrial cancer-safety and occurrence of lymphedema.

Jpn J Clin Oncol 2021 Apr;51(4):584-589

Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan.

Objective: The present study aimed to clarify the occurrence rate of lymphedema and prognosis in patients with endometrial cancer according to sentinel lymph node biopsy alone with intraoperative histopathological examination.

Methods: The study included 45 consecutive patients with endometrial cancer treated at Tohoku University Hospital between October 2014 and August 2017. All patients had endometrial carcinoma with endometrioid histology Grade 1 or Grade 2 confirmed by biopsy and stage I on magnetic resonance imaging and/or computed tomography at their preoperative evaluation. Sentinel lymph node detection was performed by radioisotope and dye. Patients who were diagnosed intraoperatively as negative for sentinel lymph node metastasis did not undergo further systematic pelvic lymphadenectomy. The occurrence rate of lymphedema and prognosis was evaluated.

Results: Bilateral sentinel lymph nodes were detected in 44 of 45 patients (97%). Forty-three patients underwent sentinel lymph node biopsy alone, and only two patients underwent systematic lymphadenectomy. Sentinel lymph node metastases were detected in one patient intraoperatively and two patients postoperatively as ITCs. No patients experienced recurrence. New symptomatic lower-extremity lymphedema was identified in one of 43 patients (2.3%) who underwent sentinel lymph node biopsy alone.

Conclusion: Sentinel lymph node biopsy alone with intraoperative histopathological diagnosis appears to be a safe and effective strategy to detect lymph node metastasis and to reduce the number of patients with lower-extremity lymphedema among patients with endometrial cancer.
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http://dx.doi.org/10.1093/jjco/hyaa252DOI Listing
April 2021

Impact of Histopathological Risk Factors on the Treatment of Stage IB-IIB Uterine Cervical Cancer.

Tohoku J Exp Med 2020 12;252(4):339-351

Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine.

In the past decade, the incidence of adenocarcinoma of the uterine cervix gradually increased. Recent literature revealed that the molecular pathogenesis differs by histological subtype, and the histological subtype should be considered in deciding treatments for patients with uterine cervical cancer. However, no treatment based on histological type or genomic signature has been recommended in various treatment guidelines. The Japanese treatment guidelines recommend either radical hysterectomy or definitive radiotherapy as primary treatment for patients with stage IB-IIB squamous cell carcinoma and a radical hysterectomy-based approach for those with non-squamous cell carcinoma because of its lower radiosensitivity. The impact of histological type on survival outcome of uterine cervical cancer is controversial. Our retrospective studies suggested that the difference in survival outcome by histological subtype might be remarkable with disease progression. Recent literature suggested that usual-type endocervical adenocarcinoma, which is the most common histological type of cervical adenocarcinoma, showed a similar survival outcome to squamous cell carcinoma. In contrast, gastric-type mucinous carcinoma of the uterine cervix, which has aggressive clinical behavior and is not associated with high-risk human papillomavirus infection, showed resistance to chemotherapy and radiotherapy. Importantly, gastric-type mucinous carcinoma is rather common in Japan, compared with Western countries. It is therefore conceivable that the survival outcome of non-squamous cell carcinoma may be affected by regional difference in the frequency of gastric-type mucinous carcinoma. A molecular target to refractory uterine cervical cancer, such as gastric-type mucinous carcinoma of uterine cervix, still remains to be identified.
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http://dx.doi.org/10.1620/tjem.252.339DOI Listing
December 2020

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BMC Cancer 2020 Nov 30;20(1):1169. Epub 2020 Nov 30.

Department of Obstetrics and Gynecology, Tohoku University Hospital, Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.

Background: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT).

Methods: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared.

Results: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort.

Conclusion: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.
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http://dx.doi.org/10.1186/s12885-020-07672-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708164PMC
November 2020

Correction to: Gaussian mixture model-based cluster analysis of apparent diffusion coefficient values: a novel approach to evaluate uterine endometrioid carcinoma grade.

Eur Radiol 2021 Mar;31(3):1780-1781

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Seiryo 1-1, Sendai, 980-8574, Japan.

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http://dx.doi.org/10.1007/s00330-020-07144-6DOI Listing
March 2021

MicroRNA Let-7c Contributes to Paclitaxel Resistance via Aurora-B in Endometrial Serous Carcinoma.

Tohoku J Exp Med 2020 08;251(4):263-272

Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine.

The incidence of endometrial cancer has rapidly risen over recent years. Paclitaxel, a key drug for endometrial cancer treatment, inhibits microtubule depolymerization and induces apoptosis in cancer cells. Endometrial serous carcinoma (ESC) accounts for < 10% of all endometrial carcinomas, but its aggressive nature makes it responsible for close to 40% of cancer deaths. Thus, novel therapeutic targets are required for ESC. To identify microRNAs that promote paclitaxel resistance, we established two paclitaxel-resistant cell lines from USPC1 human ESC cells by exposing paclitaxel to parental cells for 12 weeks. Paclitaxel concentrations were increased every 2 weeks, and after 12 weeks of paclitaxel exposure, two replicate paclitaxel-resistant cell lines were established (USPC1-PTSR1 and USPC1-PTXR2). The microarray analysis was performed using USPC1 cells and USPC1-PTXR1 cells, and eight candidate microRNAs were thus selected as potential mediators of paclitaxel sensitivity. Among these candidate microRNAs, let-7c precursor treatment of paclitaxel-resistant USPC1-PTXR1 cells caused the greatest increase in paclitaxel-mediated cytotoxicity. Let-7c inhibition conversely decreased paclitaxel-induced apoptosis. It is known that let-7a microRNA, a member of the let-7 family, inhibits growth of endometrial carcinoma cells targeting Aurora-B that controls progression through each phase of mitosis. We thus studied whether let-7c mediates Aurora-B expression in ESC cells. The expression levels of Aurora-B mRNA and protein were higher in USPC-PTXR1 cells compared with USPC1 cells. Let-7c inhibition increased Aurora-B expression in USPC1 cells but decreased Aurora-B expression in USPC1-PTXR1 cells. These results indicate that let-7c mediates paclitaxel resistance via inhibition of Aurora-B expression in ESC cells.
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http://dx.doi.org/10.1620/tjem.251.263DOI Listing
August 2020

Gaussian mixture model-based cluster analysis of apparent diffusion coefficient values: a novel approach to evaluate uterine endometrioid carcinoma grade.

Eur Radiol 2021 Jan 28;31(1):55-64. Epub 2020 Jul 28.

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Seiryo 1-1, Sendai, 980-8574, Japan.

Objectives: The purpose of our study was to perform Gaussian mixture model (GMM)-based cluster analysis of the apparent diffusion coefficient (ADC) data of patients with endometrioid carcinoma, and to evaluate the relationship between histological grade and the ratios of the different clusters in each patient.

Methods: This retrospective study enrolled 122 patients (training: n = 63; and validation: n = 59) imaged between May 2015 and February 2020. In the training cohort, manual segmentation was performed on the ADC maps to obtain the ADC data of each patient, and these ADC data were summated to obtain the "All-patient" ADC data. Cluster analysis (three clusters) was performed on this All-patient ADC data, and the ADC ranges of each cluster were defined as follows: cluster 1, 490-699 × 10 mm/s; cluster 2, 700-932 × 10 mm/s; and cluster 3, over 933 × 10 mm/s. In the training and validation cohorts, the ADC data of each patient was classified into three clusters according to these ADC ranges. The cluster ratios of each patient were calculated and compared with histological grade.

Results: In the training cohort, a significant positive correlation was found between the cluster 1 ratio and histological grade (ρ = 0.34, p = 0.0059). The cluster 1 ratios of high-grade lesions (grade 3) were significantly higher than those of low-grade lesions (grades 1 and 2) (p = 0.0084). A similar significant positive correlation was found between the cluster 1 ratio and histological grade in the validation cohort (ρ = 0.44, p = 0.0006).

Conclusions: The cluster 1 ratio containing voxels with low ADC was significantly correlated with the histological grade of endometrioid carcinoma.

Key Points: • We performed Gaussian mixture model (GMM)-based cluster analysis of the apparent diffusion coefficient (ADC) data of patients with endometrioid carcinoma. • The cluster 1 ratio, which included low ADC values, was significantly positive correlated with histological grade in the training and validation cohorts. • The GMM-based cluster analysis of voxel-based ADC data was effective for grading endometrioid carcinoma.
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http://dx.doi.org/10.1007/s00330-020-07047-6DOI Listing
January 2021

Potential of Tyrosine Kinase Receptor TIE-1 as Novel Therapeutic Target in High-PI3K-Expressing Ovarian Cancer.

Cancers (Basel) 2020 Jun 26;12(6). Epub 2020 Jun 26.

Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Tohoku University, Sendai 980-8577, Japan.

Tyrosine kinase receptor TIE-1 plays a critical role in angiogenesis and blood-vessel stability. In recent years, increased TIE-1 expression has been observed in many types of cancers; however, the biological significance and underlying mechanisms remain unknown. Thus, in the present study, we investigated the tumor biological functions of TIE-1 in ovarian cancer. The treatment of SKOV3 ovarian-cancer cells with siRNA against TIE-1 decreased the expression of key molecules in the PI3K/Akt signaling pathway, such as p110α and phospho-Akt, suggesting that TIE-1 is related to the PI3K/Akt pathway. Furthermore, the knockdown of TIE-1 significantly decreased cell proliferation in high-PI3K-expressing cell lines (SKOV3, CAOV3) but not low-PI3K-expressing cell lines (TOV112D, A2780). These results suggested that inhibition of TIE-1 decreases cell growth in high-PI3K-expressing cells. Moreover, in low-PI3K-expressing TOV112D ovarian-cancer cells, TIE-1 overexpression induced PI3K upregulation and promoted a PI3K-mediated cell proliferative phenotype. Mechanistically, TIE-1 participates in cell growth and proliferation by regulating the PI3K/Akt signaling pathway. Taken together, our findings strongly implicate TIE-1 as a novel therapeutic target in high-PI3K-expressing ovarian-cancer cells.
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http://dx.doi.org/10.3390/cancers12061705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352248PMC
June 2020

Cervical cancer screening rates before and after the Great East Japan Earthquake in the Miyagi Prefecture, Japan.

PLoS One 2020 11;15(3):e0229924. Epub 2020 Mar 11.

Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan.

After disasters, issues pertaining to women's health such as irregular periods and bleeding are well surveyed. However, the management of women's health, especially changes in the rate of health checkups, has not been investigated. In the present study, we focused on the change in the cervical cancer screening rates (CCS-Rs) before and after the Great East Japan Earthquake in Miyagi Prefecture, Japan. The earthquake had a magnitude of 9.0, a profound disaster. We examined the CCS-R from 2009 to 2016 in 45 areas of the Miyagi Prefecture. Screening was completed using mobile vans. In the 4 areas impacted by the tsunami after the earthquake, a marked decrease in the CCS-R was observed in 2011 when the earthquake took place (more than a 3% decrease compared with that in the previous year). The CCS-Rs in these 4 regions remained lower in 2016 than in the previous year. In 2009-2016 except for 2014, CCS-Rs in coastal areas (9 areas) were significantly lower than those in the non-coastal areas (36 areas). A delay in seeking healthcare, also known as "patient's delay," is considered as one of the problems of cancer treatment in affected areas. It is possible that a decrease in the CCS-R may lead to low detection of advanced stages of cancer. Therefore, the establishment of a comprehensive medical system including medical screening after a disaster is important for the management of women's health.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065810PMC
June 2020

Clinical experience of pelvic radiotherapy or chemoradiotherapy for postoperative uterine cervical cancer using intensity-modulated radiation therapy.

J Radiat Res 2020 May;61(3):470-478

Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.

The purpose of this study was to reveal treatment outcomes and toxicity after pelvic intensity-modulated radiotherapy (IMRT) for postoperative uterine cervical cancer of Japanese patients. Consecutive patients who were treated with pelvic IMRT for postoperative cervical cancer in our institute were retrospectively analyzed. Relapse-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier estimator, and log-rank tests were used to compare differences. From the database, 62 patients were identified. The pathology was squamous cell carcinoma in 44 patients and other pathology in 18 patients. Of the 62 patients, 35 had high-risk prognostic factors and 27 patients had intermediate-risk prognostic factors. The prescribed radiation doses were 50 Gy in 25 fractions for 58 patients and 50.4 Gy in 28 fractions for 4 patients. One patient received a vaginal cuff boost. Chemotherapy was administered in 36 patients. During the median follow-up period of 50.9 months, there was no locoregional failure. Six patients in the high-risk group relapsed, but none of the patients in the intermediate-risk group relapsed (P = 0.02). The 3-year OS and RFS rates were 98.2% and 90.9%, respectively. Significant factors related to RFS were squamous cell carcinoma pathology (P = 0.02), pathological T stage (P = 0.04), surgical margin status (P < 0.01) and multiple lymph nodes metastases (P < 0.01). Grade 3 or more toxicity occurred in 6 patients. Four patients had obstruction of the intestine, and 2 patients had stenosis of the urinary tract. In clinical practice, the use of pelvic IMRT for postoperative cervical cancer of Japanese patients showed a low rate of toxicity without decreasing the efficacy.
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http://dx.doi.org/10.1093/jrr/rraa004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299262PMC
May 2020

Correlation of World Health Organization 2010 Classification for Gastroenteropancreatic Neuroendocrine Neoplasms with the Prognosis of Ovarian Neuroendocrine Neoplasms: Kansai Clinical Oncology Group-Protocol Review Committee/Intergroup Study.

Neuroendocrinology 2021 25;111(4):320-329. Epub 2020 Feb 25.

Department of Pathology, Osaka Medical College, Takatsuki, Japan.

Background: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis.

Methods: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS).

Results: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01).

Conclusion: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors.
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http://dx.doi.org/10.1159/000506743DOI Listing
February 2020

Clinical status and prognostic factors in Japanese patients with uterine leiomyosarcoma.

Gynecol Oncol 2020 04 23;157(1):115-120. Epub 2020 Jan 23.

Department of Gynecology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Nodame Minami-ku, Fukuoka, Japan. Electronic address:

Objective: Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy for which the currently available treatments do not consistently provide long-term disease control. This study aimed to reveal the current clinical status of uLMS to support future clinical trials.

Methods: This study enrolled patients with uLMS treated at 53 Japanese institutions from 2000 to 2012. Central pathological review (CPR) was performed. All cases were confirmed by CPR, and epidemiological features, treatment, and prognosis were analyzed statistically.

Results: A total of 307 patients were enrolled. A diagnosis of uLMS was confirmed in 266 patients (86.6%) of patients after CPR, of whom data for 259 were analyzed. Of these, 186 (71.8%) patients underwent complete gross resection as primary therapy. Ninety-eight patients received no additional adjuvant therapy, while docetaxel and gemcitabine was the most frequent regimen among 155 patients treated with adjuvant chemotherapy. In all cases, the median overall survival (OS) was 44.2 months. Multivariate analyses of prognostic factors in all cases identified stage III and IV disease, high serum lactate dehydrogenase level, and menopausal status as poor prognostic factors. However, in stage I cases, high serum lactate dehydrogenase level and no adjuvant treatment were identified as poor prognostic factors. The 5-year OS of patients with stage I uLMS treated with adjuvant chemotherapy was significantly better than that of those without adjuvant treatment (67.8% vs 46.7%, P = 0.0461).

Conclusions: Despite complete removal of the primary lesion, the clinical course of patients with uLMS was poor due to recurrence of distant metastasis. The application of a suitable biomarker and effective adjuvant chemotherapy are required to improve the prognosis of patients with uLMS.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.022DOI Listing
April 2020

Perioperative treatments for stage IB-IIB uterine cervical cancer.

Jpn J Clin Oncol 2020 Feb;50(2):99-103

Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Japan Society of Gynecologic Oncology guidelines recommended either radical hysterectomy-based approach or the definitive radiotherapy including concurrent chemoradiotherapy as primary treatment for patients with not only stage IB1/IIA1, but also stages IB2, IIA2 and IIB. Based on pathological findings of surgical specimens, patients who underwent radical hysterectomy are divided into three recurrent-risk groups, low-risk, intermediate, and high-risk groups. Although some authors reported the usefulness of adjuvant chemotherapy for intermediate/high-risk patients, radiotherapy was standard adjuvant treatment for pathological-risk patients after radical hysterectomy. It has been uncertain whether neoadjuvant chemotherapy followed by radical hysterectomy is beneficial for stage IB2-IIB patients. Recently, the randomized phase III study revealed that neoadjuvant chemotherapy followed by radical hysterectomy failed to improve survival of stage IB2-IIB patients compared to concurrent chemoradiotherapy. Majority of stage IB2-IIB patients are required adjuvant radiotherapy after radical hysterectomy. The multimodality strategy consisting of radical hysterectomy followed by adjuvant radiotherapy is associated with not only impaired quality of life, but also conflicting of cost-effectiveness. Thereby, some authors investigated the significance of multimodality strategy consisting of chemotherapy before/after radical hysterectomy for stage IB2-IIB cervical cancer. Multimodality strategy consisting of radical hysterectomy/perioperative chemotherapy needs higher curability of radical hysterectomy, higher response to perioperative chemotherapy and less perioperative complications. Consequently, gynecologic oncologists have to examine the patients strictly before treatment and judge whether radical hysterectomy-based approach or definitive irradiation is appropriate for the patient with stage IB-IIB cervical cancer.
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http://dx.doi.org/10.1093/jjco/hyz200DOI Listing
February 2020

Clinical and reproductive outcomes of fertility-sparing surgery in stage I epithelial ovarian cancer.

Mol Clin Oncol 2020 Jan 22;12(1):44-50. Epub 2019 Nov 22.

Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.

The aim of the present study was to evaluate the oncologic safety and reproductive outcome in patients with stage I epithelial ovarian cancer (EOC) treated with fertility-sparing surgery (FSS). Women aged ≤40 years with stage I EOC who had undergone FSS between 2000 and 2010 were retrospectively reviewed. Survival was examined using the Kaplan-Meier method and statistical significance was analyzed using the log-rank test. A total of 29 EOC patients (stage IA, n=14; stage IC1 n=6; stage IC3, n=9) from seven participating institutions belonging to the Tohoku Gynecologic Cancer Unit were enrolled. After a median follow-up duration of 60.6 months (range, 6-135 months), five patients (17.2%) experienced tumor recurrence. The respective five-year relapse-free survival (RFS) and overall survival (OS) rates were 90.9 and 100% for stage IA/IC1, and 43.8 and 87.5% for stage IC3. Significant differences in RFS were observed between stage IA/IC1 and IC3 patients (P=0.026). However, there was no significant difference in OS between patients with 1A/1C1 and those with 1C3 (P=0.712). After FSS, seven pregnancies occurred in five patients, which resulted in the birth of six healthy children. The results of the present study confirmed that FSS may be an acceptable treatment method for stage IA and IC1 EOC, exhibiting a favorable reproductive outcome. However, the safety of FSS for treating stage IC3 EOC is uncertain and warrants further investigation.
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http://dx.doi.org/10.3892/mco.2019.1954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904870PMC
January 2020

Survival outcome and perioperative complication related to neoadjuvant chemotherapy with carboplatin and paclitaxel for advanced ovarian cancer: A systematic review and meta-analysis.

Eur J Surg Oncol 2020 05 4;46(5):868-875. Epub 2019 Dec 4.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Japan; Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan. Electronic address:

Objective: To compare the effectiveness and safety of neoadjuvant chemotherapy with carboplatin/paclitaxel followed by interval debulking surgery (NACT-IDS) to primary debulking surgery plus postoperative chemotherapy (PDS) for advanced ovarian cancer.

Methods: A comprehensive systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Ovarian Cancer Committee. Multiple public search engines including PubMed/MEDLINE and the Cochrane Database, were searched in March 2019 using the entry keywords "ovarian cancer [all fields]" AND "interval debulking surgery [all fields]", AND "neoadjuvant chemotherapy [all fields]". Key inclusion criteria were prospective clinical trials examining platinum-based NACT for stage II-IV epithelial ovarian cancer. The primary outcome of interest was survival, and the secondary outcome was adverse events with each intervention.

Results: After screening 333 studies, four phase III randomized clinical trials were identified that met the inclusion criteria. These trials included 1692 women (847 receiving NACT-IDS and 845 receiving PDS). It was found that NACT-IDS and PDS had similar overall survival (hazard ratio [HR]: 0.97, 95% confidence interval [CI]: 0.87-1.07, P = 0.53) and progression-free survival (HR: 0.98, 95%CI: 0.90-1.08, P = 0.74). In contrast, NACT-IDS was associated with significantly lower rates of perioperative complications (odds ratio [OR] 0.27, 95%CI: 0.20-0.36, P < 0.001) and perioperative mortality (OR: 0.17, 95%CI: 0.06-0.50, P < 0.001) compared to PDS.

Conclusion: This systematic review and meta-analysis suggests that NACT-IDS with carboplatin and paclitaxel does not negatively impact the survival of women with advanced ovarian cancer compared to PDS, while perioperative complications and mortality are significantly reduced by 70-80%.
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http://dx.doi.org/10.1016/j.ejso.2019.11.520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535131PMC
May 2020

Changes in the Clinicopathological Demographics of Vulvar Cancer in Japan: Increasing Oldest-Old, Stage Shifting, and Decreasing Cohort-Level Survival .

J Clin Med 2019 Nov 29;8(12). Epub 2019 Nov 29.

Department of Obstetrics and Gynecology, Tokai University Hospital, Isehara, Kanagawa 259-1193, Japan.

Background: To examine trends in the clinicopathological characteristics of vulvar cancer in Japan.

Methods: This is a nationwide retrospective study examining consecutive women with vulvar cancer between 2001 and 2010 in Japan ( = 1061). Temporal trends in demographics, tumor characteristics, and survival were assessed by cohort-level analysis. The National Cancer Institute's Surveillance, Epidemiology, and End Result Program was used for external validation ( = 10,154).

Results: The number of oldest-old women aged ≥80 years significantly increased (from 18.0% in 2001 to 30.6% in 2010; 70.5% relative increase) in the study period. A stage shift was observed, with stage I disease decreasing from 43.0% to 34.0% (21.0% relative decrease), and tumors with distant metastases increasing from 23.2% to 35.6% (53.3% relative increase, < 0.05). The number of women who underwent surgical treatment decreased from 84.0% to 69.7% (17.0% relative decrease), whereas utilization of radiotherapy increased from 34.4% to 43.2% (25.7% relative increase) over time ( < 0.05). In the cohort-level analysis, the five-year survival rates significantly decreased from 2001 to 2010 ( < 0.05), specifically, 66.9% to 51.0% for progression-free survival (23.7% relative decrease), 79.5% to 67.9% for cause-specific survival (14.6% relative decrease), and 74.9% to 62.3% for overall survival (16.9% relative decrease). In the patient-level analysis, oldest-old women were less likely to undergo surgical treatment and were independently associated with decreased survival ( < 0.05). In the US cohort, the number of oldest-old women (25.2% to 27.8%) and the five-year cause-specific survival rate (81.8% to 79.9%) remained unchanged during the study period ( > 0.05).

Conclusion: Demographics and outcomes of vulvar cancer in Japan significantly changed during the study period. An increasing oldest-old population and a stage shift to more metastatic disease resulted in a cohort-level decrease in survival rates.
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http://dx.doi.org/10.3390/jcm8122081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947365PMC
November 2019

Fertility-sparing trachelectomy for early-stage cervical cancer: A proposal of an ideal candidate.

Gynecol Oncol 2020 02 23;156(2):341-348. Epub 2019 Nov 23.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Japan. Electronic address:

Objective: To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy.

Methods: This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged <45 years with clinical stage I-II cervical cancer who had planned fertility-sparing trachelectomy and pelvic lymphadenectomy between 2009 and 2013 (n = 393). Ideal candidates were defined to have a tumor size of ≤2 cm, no lymph node metastasis, no deep stromal invasion, and no high-risk histology (n = 284, 69.6%). Less-ideal candidates were defined to have any one of these four characteristics (n = 109, 30.4%). Propensity score inverse probability of treatment weighting was used to assess survival outcomes.

Results: Less-ideal candidates were more likely to undergo hysterectomy conversion (22.9% versus 3.2%), receive postoperative radiotherapy (11.9% versus 0.4%), or chemotherapy (32.1% versus 3.2%) compared with ideal candidates (all, P < 0.05). The weighted model revealed that among those who underwent trachelectomy (ideal candidates, n = 275 and less-ideal candidates, n = 84), less-ideal candidates had significantly decreased disease-free survival (5-year rates: 85.5% versus 95.5%; HR 3.93, 95% CI 1.99-7.74; P < 0.001) and cause-specific survival (92.5% versus 98.6%; HR 5.47, 95% CI 1.68-17.8, P = 0.001) compared with ideal candidates. Similarly, less-ideal candidates were significantly associated with decreased disease-free survival compared with ideal candidates among those who were young age, had small tumors or squamous histology, and underwent surgery alone (all, P < 0.05).

Conclusion: Less-ideal candidates had approximately four-fold higher recurrence risk and cancer mortality compared with ideal candidates. Ideal candidates for fertility-sparing trachelectomy for early-stage cervical cancer proposed in our study may be useful as the future framework for developing guidelines for fertility-sparing trachelectomy in Japan.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526083PMC
February 2020
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