Publications by authors named "Kaoru Abiko"

72 Publications

Tertiary lymphoid structures are associated with favorable survival outcomes in patients with endometrial cancer.

Cancer Immunol Immunother 2021 Oct 23. Epub 2021 Oct 23.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Immunotherapy has experienced remarkable growth recently. Tertiary lymphoid structures (TLSs) and B cells may play a key role in the immune response and have a survival benefit in some solid tumors, but there have been no reports about their role in endometrial cancer (EC). We investigated the clinicopathological and pathobiological characteristics of the tumor microenvironment (TME) in EC. Patients with EC at Kyoto University Hospital during 2006-2011 were retrospectively included. In 104 patients with EC who met study inclusion criteria, 81 (77.9%) had TLSs, which consisted of areas rich in CD20 B cells, CD8 T cells, CD4 T cells, and CD38 plasma cells. The absence of TLS was independently associated with tumor progression (HR, 0.154; 95% CI, 0.044-0.536; P = 0.003). Patients with TLSs that included CD23 germinal centers had better PFS. All tumor infiltrating lymphocytes were counted in the intratumor site. The number of CD20 B cells was significantly larger in patients with TLSs than in those without TLS (P < 0.001). CD20 B cells numbers were positively correlated with other TLSs. The larger number of CD20 B cell was associated with better PFS (P = 0.015). TLSs and B cell infiltration into tumors are associated with favorable survival outcomes in patients with EC. They may represent an active immune reaction of the TME in endometrial cancer.
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http://dx.doi.org/10.1007/s00262-021-03093-1DOI Listing
October 2021

Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study.

Hypertens Res 2021 Oct 12. Epub 2021 Oct 12.

Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP; <130, 130-139, 140-159, and ≥160 mmHg) or diastolic BP (dBP; <80, 80-89, 90-109, and ≥110 mmHg) at 8-11, 12-15, and 16-19 weeks of gestation. The risk of early-onset superimposed preeclampsia and small-for-gestational-age neonates was assessed in each BP group. Moreover, a subgroup analysis was performed in 144 eligible patients whose BP was measured at both 12-13 and 14-15 weeks of gestation. At 16-19 weeks of gestation, higher sBP significantly increased the incidence of early-onset superimposed preeclampsia (13.3%, 24.6%, 32.2% and 75.0%, respectively) and small-for-gestational-age neonates (6.0%, 13.1%, 16.9% and 50.0%, respectively). Multivariate logistic regression analyses showed that women with sBP < 130 mmHg at 16-19 weeks of gestation had a significantly lower risk of early-onset superimposed preeclampsia than women with sBP of 140-159 mmHg. Subgroup analyses also showed that even at 14-15 weeks of gestation, sBP < 130 mmHg was associated with a significantly lower risk of early-onset superimposed preeclampsia than an sBP of 140-159 mmHg. In conclusion, sBP < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed preeclampsia in women with chronic hypertension.
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http://dx.doi.org/10.1038/s41440-021-00763-6DOI Listing
October 2021

Mesonephric-like adenocarcinoma of the ovary in an elderly woman: A case report and a review of the literature.

J Obstet Gynaecol Res 2021 Sep 27. Epub 2021 Sep 27.

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

Mesonephric-like adenocarcinoma (MLA) is a rare tumor that occurs in the uterine endometrium and ovary. It morphologically and immunohistochemically resembles cervical mesonephric adenocarcinoma (MA). Here, we present a case of MLA of the ovary along with a literature review. An asymptomatic 84-year-old woman presented with a pelvic mass, detected by computerized tomography. Magnetic resonance imaging demonstrated a polycystic mass with a solid component in the left adnexal region. The solid component showed low signal intensity on T2-weighted imaging and high signal intensity on diffusion-weighted imaging. We strongly suspected an ovarian malignant tumor; therefore, surgical resection of the uterus and adnexa was performed. Macroscopically, the tumor was predominantly solid with yellowish-tan cut surface. Microscopically, it showed a tubular pattern with intraluminal colloid-like material resembling MA. The tumor cells were negative for estrogen receptor, calretinin, and CD10 and positive for PAX8 and TTF-1. These findings are consistent with those of MLA.
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http://dx.doi.org/10.1111/jog.15035DOI Listing
September 2021

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

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma.

Cancer Sci 2021 Aug 31. Epub 2021 Aug 31.

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

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.
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http://dx.doi.org/10.1111/cas.15125DOI Listing
August 2021

Lymphoepithelioma-like carcinoma of uterine cervix: Preoperative diagnosis and course in three cases.

J Obstet Gynaecol Res 2021 Aug 10. Epub 2021 Aug 10.

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

Lymphoepithelioma-like carcinoma of the uterine cervix is a rare variant of squamous cell carcinoma. Herein, we describe three cases of lymphoepithelioma-like carcinoma of the uterine cervix and review relevant literature. All three patients initially presented with postmenopausal bleeding. Gross appearances were endophytic with ulcerated mucosa in case 1, exophytic with polypoid morphology in case 2, and unremarkable even using colposcopy and hysteroscopy in case 3. Magnetic resonance imaging demonstrated well-demarcated cervical masses with high-intermediate intensity on T2-weighted images and high intensity on diffusion-weighted images in all three cases. In case 3, biopsy referring to local information from magnetic resonance images was required for preoperative diagnosis. We reviewed the literature of 59 lymphoepithelioma-like carcinoma cases in 19 papers published between 2001 and 2020. Preoperative diagnosis of lymphoepithelioma-like carcinoma is sometimes challenging, although magnetic resonance imaging findings may help determine the location of the tumor and obtain a successful biopsy.
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http://dx.doi.org/10.1111/jog.14969DOI Listing
August 2021

Development of Uterine Leiomyosarcoma During Follow-up After Caesarean Section in a Woman With Uterine Leiomyoma.

Anticancer Res 2021 Jun;41(6):3001-3010

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

Background/aim: During pregnancy, uterine leiomyomas may cause problems and treatment typically entails uterine conservation. However, for cases of leiomyomas larger than a particular size with some clinical symptoms, enucleation should be performed. In clinical practice, the importance of postpartum follow-up of pregnancies with uterine fibroids must be established.

Patients And Methods: A 47-year-old female visited an obstetrics and gynecology clinic with a primary complaint of irregular bleeding. We suspected an 8.4×6.6 cm myoma uteri and recommended immediate surgery. During the next visit, a pregnancy test was positive and the patient requested a follow-up for her myoma uteri diagnosis. Because of a breech presentation, we performed an elective cesarean section (CS) at 38 weeks and 1 day. The patient's myoma uteri was stable throughout the pregnancy, and after delivery, we continued to follow her up as an outpatient.

Results: Two years after the CS, the myoma uterus was 6 cm in size, and 6 months later, it had increased to 10 cm. Magnetic resonance imaging (MRI) supported a diagnosis of uterine leiomyosarcoma and she underwent surgery. Ultimately, she was pathologically diagnosed with uterine leiomyoma, uterine leiomyoma with bizarre nuclei, and uterine leiomyosarcoma following examination of the excised tissue by using molecular pathological examination with anti-cyclin E antibody and anti-Ki-67 antibody.

Conclusion: Notably, this case demonstrated the usefulness of cyclin E and Ki-67 as biomarkers for the malignancy of uterine mesenchymal tumors. Presently, she is being monitored for tumor recurrence and metastases on a quarterly basis. In order to detect the rapid increase in uterine mesenchymal tumor, regular follow-up after birth is important.
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http://dx.doi.org/10.21873/anticanres.15082DOI Listing
June 2021

Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer.

Sci Rep 2021 06 1;11(1):11427. Epub 2021 Jun 1.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8501, Japan.

Based on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n = 19, UMIN000005714), we aimed to identify the biomarkers predictive of response. Tumor gene expression was evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas and a signature established prior for ovarian clear cell carcinoma. Resulting signature scores were statistically assessed with both univariate and multivariate approaches for correlation to clinical response. Analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) patient groups. The clear cell gene signature was scored significantly higher in the CR group, and the proliferative gene signature had significantly higher scores in the PD group where nivolumab was not effective (respective p values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. An applicable clinical response prediction formula was derived. Ovarian cancer-specific gene signatures and related pathway scores provide a robust preliminary indicator for ovarian cancer patients prior to anti-PD-1 therapy decisions.
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http://dx.doi.org/10.1038/s41598-021-91012-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169687PMC
June 2021

Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition.

Clin Cancer Res 2021 Sep 7;27(17):4669-4679. Epub 2021 Apr 7.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Epithelial-mesenchymal transition (EMT) has been shown to play a critical role in tumor development from initiation to metastasis. EMT could be regarded as a continuum, with intermediate hybrid epithelial and mesenchymal phenotypes having high plasticity. Classical EMT is characterized by the phenotype change of epithelial cells to cells with mesenchymal properties, but EMT is also associated with multiple other molecular processes, including tumor immune evasion. Some previous studies have shown that EMT is associated with the cell number of immunosuppressive cells, such as myeloid-derived suppressor cells, and the expression of immune checkpoints, such as programmed cell death-ligand 1, in several cancer types. At the molecular level, EMT transcriptional factors, including Snail, Zeb1, and Twist1, produce or attract immunosuppressive cells or promote the expression of immunosuppressive checkpoint molecules via chemokine production, leading to a tumor immunosuppressive microenvironment. In turn, immunosuppressive factors induce EMT in tumor cells. This feedback loop between EMT and immunosuppression promotes tumor progression. For therapy directly targeting EMT has been challenging, the elucidation of the interactive regulation of EMT and immunosuppression is desirable for developing new therapeutic approaches in cancer. The combination of immune checkpoint inhibitors and immunotherapy targeting immunosuppressive cells could be a promising therapy for EMT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4459DOI Listing
September 2021

Potential Novel Ovarian Cancer Treatment Targeting Myeloid-Derived Suppressor Cells.

Cancer Invest 2021 Apr 15;39(4):310-314. Epub 2021 Feb 15.

National Hospital Organization, Kyoto Medical Center, Kyoto, Japan.

Diagnosis by biopsy is difficult in the ovary since it is located deep in the abdomen. As a result, ovarian cancer is mostly found insidiously during exploratory laparotomy. Consequently, the early diagnosis of ovarian cancer is often difficult. The likelihood of peritoneal dissemination increases with the progress of ovarian cancer. With further progression, ovarian cancer metastasizes to the momentum, retroperitoneal lymph nodes, large intestine, small intestine, diaphragm, spleen, and other organs. Ovarian cancer has been considered a tumor that has a favorable response to chemotherapy, but more effective treatments are still being explored. Tumors use their own immune escape mechanism to evade host immunity. The immune checkpoint (IC) mechanism, one of the immune escape mechanisms, is established by programmed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) communication. It has been shown that inhibiting PD-1/PD-L1 communication in various malignancies produces antitumor effects. However, the antitumor effect of ICI monotherapy on ovarian cancer is limited in actual clinical practice. In this review, we describe a novel cancer immunotherapeutic agent that targets myeloid-derived suppressor cells (MDSCs).
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http://dx.doi.org/10.1080/07357907.2020.1871487DOI Listing
April 2021

A Novel Direct Approach to the Deep Uterine Vein in Laparoscopic Radical Hysterectomy.

J Minim Invasive Gynecol 2021 08 23;28(8):1444-1445. Epub 2020 Dec 23.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine (Drs. Horie, Sunada, Kitamura, Yamanoi, Horikawa, Yamaguchi, Hamanishi, Kondoh, and Mandai).

Study Objective: To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy.

Design: Demonstration of the laparoscopic technique with narrated video footage.

Setting: Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein.

Interventions: Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures.

Conclusion: Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed.
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http://dx.doi.org/10.1016/j.jmig.2020.12.018DOI Listing
August 2021

Right-sided Sigmoid Colon Revealed during Laparoscopic Sacrocolpopexy.

J Minim Invasive Gynecol 2021 07 17;28(7):1267-1268. Epub 2020 Sep 17.

Department of Gynecology and Obstetrics, National Hospital Organization Kyoto Medical Center, Kyoto, Japan (all authors).

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http://dx.doi.org/10.1016/j.jmig.2020.09.009DOI Listing
July 2021

Serum lactate dehydrogenase is a possible predictor of platinum resistance in ovarian cancer.

Obstet Gynecol Sci 2020 Nov 17;63(6):709-718. Epub 2020 Sep 17.

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

Objective: The need for tailoring ovarian cancer treatments to individual patients is increasing. This study aimed to evaluate the prognostic value of pretreatment laboratory test data for predicting the response and survival outcomes of platinumbased chemotherapy in ovarian cancer.

Methods: We enrolled 270 patients with ovarian cancer diagnosed at the Kyoto Medical Center (n=120; group A) and Kyoto University (n=150; group B). Data on 9 blood parameters (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte rate [PLR], C-reactive protein, lactate dehydrogenase [LDH], glucose, total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein, and triglyceride levels), cancer pathology, cancer stage, cytoreduction outcomes, serum cancer antigen 125 levels, platinum-free interval (PFI), disease-free survival (DFS), and overall survival were assessed retrospectively.

Results: NLR, PLR, LDH, and HDL were significantly different in advanced stage patients (P<0.001, <0.001, 0.029, and <0.001, respectively). The Kaplan-Meier curves revealed that high LDH level (≥250 U/L) was associated with reduced PFI (P=0.037 and 0.012) and DFS (P=0.007 and 0.002) in groups A and B, respectively. High NLR (≥4) was associated with reduced DFS in both groups (P=0.036 and 0.005, respectively). LDH showed higher area under the curve (AUC) values in predicting platinum resistance with a PFI of less than 6 months and 12 months (AUC=0.606 and 0.646, respectively) than NLR. In the multivariate analysis, LDH remained significant (P=0.019) after adjusting for the 9 blood parameters.

Conclusion: Serum LDH level may possibly predict platinum resistance and prognosis in ovarian cancer and may be useful when developing precision medicine for individual patients.
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http://dx.doi.org/10.5468/ogs.20117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677069PMC
November 2020

Highly conserved binding region of ACE2 as a receptor for SARS-CoV-2 between humans and mammals.

Vet Q 2020 Dec;40(1):243-249

National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

Several cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS-CoV-2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. A tiger from a zoo in New York, USA, was also reportedly infected with SARS-CoV-2. It is believed that SARS-CoV-2 was transmitted to tigers from their caretakers, who were previously infected with this virus. On May 25, 2020, the Dutch Minister of Agriculture, Nature and Food Quality reported that two employees were infected with SARS-CoV-2 transmitted from minks. These reports have influenced us to perform a comparative analysis among angiotensin-converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide "353-KGDFR-357 ( ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS-CoV-2 spike receptor binding domain (RBD). Multiple sequence alignments of the ACE2 proteins by ClustalW, whereas the three-dimensional structure of its binding region for the spike glycoprotein of SARS-CoV-2 was assessed by means of Spanner, a structural homology modeling pipeline method. In addition, evolutionary phylogenetic tree analysis by ETE3 was used. ACE2 works as a receptor for the SARS-CoV-2 spike glycoprotein between humans, dogs, cats, tigers, minks, and other animals, except for snakes. The three-dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS-CoV-2 spike RBD of the mink ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (401 residues of the mink ACE2 available sequence vs 805 residues of the human ACE2). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353-KGDFR-357 with humans, dogs, cats, tigers, minks, and other animals, except for snakes. Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS-CoV-2 transmission from animals to humans.
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http://dx.doi.org/10.1080/01652176.2020.1823522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580767PMC
December 2020

Low-Grade Endometrial Stromal Sarcoma with a Nodule-in-Nodule Appearance in Preoperative Magnetic Resonance Images.

Case Rep Obstet Gynecol 2020 30;2020:8973262. Epub 2020 Jul 30.

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

Low-grade endometrial stromal sarcoma (LG-ESS) is a rare malignant disease and demonstrates various patterns in preoperative imaging. Therefore, accurate diagnosis is important. Given its unique form, we report a case of LG-ESS with a nodule-in-nodule appearance on preoperative imaging. A 41-year-old woman was referred to our department for further examination of a 45 mm diameter uterine corpus mass. Preoperative magnetic resonance imaging (MRI) revealed several small nodules within a larger nodule. T2-weighted images showed moderate-to-high signal intensity with focal bands of low signal intensity in the small nodules. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathological findings of the small nodules showed densely concentrated endometrial stromal cells reminiscent of a proliferative phase endometrium with a concentric arrangement of small spiral arteriole-like vessels. The small nodules exhibited an expansile growth pattern and were surrounded by less densely concentrated endometrial stromal cells intermingled with the normal uterine myometrium. LG-ESS with smooth muscle differentiation and sex cord-like elements was partially observed. In summary, LG-ESS demonstrating a unique nodule-in-nodule appearance on preoperative imaging histopathologically comprised tumor cells of varying densities. Our current case suggests that preoperative diagnostic imaging with MRI may be useful.
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http://dx.doi.org/10.1155/2020/8973262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414370PMC
July 2020

UGT1A1 polymorphism has a prognostic effect in patients with stage IB or II uterine cervical cancer and one or no metastatic pelvic nodes receiving irinotecan chemotherapy: a retrospective study.

BMC Cancer 2020 Aug 5;20(1):729. Epub 2020 Aug 5.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8501, Japan.

Background: Uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) is a predictive biomarker for the side-effects of irinotecan chemotherapy, which reduces the volume of tumors harboring UGT1A1 polymorphisms. We aimed to determine whether UGT1A1 polymorphisms can predict progression-free survival in patients with local cervical cancer treated with irinotecan chemotherapy.

Methods: We retrospectively analyzed the data of 51 patients with cervical cancer treated at a single institution between 2010 and 2015. All patients were diagnosed with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IB1, IB2, IIA, or IIB squamous cell carcinoma, underwent radical hysterectomy, and received irinotecan chemotherapy as neoadjuvant and/or adjuvant treatment. All patients were examined for irinotecan side effects using UGT1A1 tests. Conditional inference tree and survival analyses were performed considering the FIGO stage, age, the UGT1A1 status, and the number of metastatic lymph nodes to determine primary factors associated with progression-free survival.

Results: The tree-structured survival model determined high recurrence-risk factors related to progression-free survival. The most relevant factor was ≥2 metastatic lymph nodes (p = 0.004). The second most relevant factor was UGT1A1 genotype (p = 0.024). Among patients with ≤1 metastatic lymph node, those with UGT1A1 polymorphisms benefited from irinotecan chemotherapy and demonstrated significantly longer progression-free survival (p = 0.020) than those with wild-type UGT1A1.

Conclusions: Irinotecan chemotherapy might be beneficial in patients with cervical cancer, UGT1A1 polymorphisms, and ≤ 1 metastatic lymph nodes.
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http://dx.doi.org/10.1186/s12885-020-07225-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405427PMC
August 2020

Uterine cervical squamous cell carcinoma without p16 (CDKN2A) expression: Heterogeneous causes of an unusual immunophenotype.

Pathol Int 2020 Jul 17;70(7):413-421. Epub 2020 Apr 17.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Immunohistochemically p16 (CDKN2A)-negative uterine cervical squamous cell carcinoma (SCC) is uncommon, and there are few reports about its pathological features. This study explored the causes of p16 negativity in such cases. We analyzed diagnostic tissue samples of five cases of p16-negative cervical SCC among 107 patients who underwent hysterectomy at Kyoto University Hospital between January 2010 and December 2015. The samples were subjected to immunohistochemical staining, in situ hybridization and a genetic analysis. Two of five cases were positive for human papilloma virus (HPV) by genotyping. One was positive for HPV56 with promoter hypermethylation of CDKN2A and co-existing Epstein-Barr virus infection. Another was positive for HPV6 categorized as low-risk HPV with condylomatous morphology. Among the remaining three cases, one had amplification of the L1 gene of HPV with promoter hypermethylation of CDKN2A and TP53 mutation, and one of the other two HPV-negative cases had a homozygous CDKN2A deletion, while the other was positive for p53 and CK7. p16-negativity of cervical SCC is often associated with an unusual virus infection status and CDKN2A gene abnormality.
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http://dx.doi.org/10.1111/pin.12930DOI Listing
July 2020

Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment.

Br J Cancer 2020 03 14;122(6):778-788. Epub 2020 Jan 14.

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

Background: The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy.

Methods: The frequencies of immune cell populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. The expression profiles of both the proteins and genes in the resistant tumours were analysed. The impact of granulocyte-monocyte colony-stimulating factor (GM-CSF) expression on myeloid-derived suppressor cell (MDSC) function in the resistant tumours was evaluated.

Results: We found a marked increase and reduction in the number of Gr-1 + MDSCs and CD8 + lymphocytes in the resistant tumour, and the MDSCs preferentially infiltrated the hypoxic region. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. GM-CSF promoted migration and differentiation of MDSCs, which inhibited the CD8 + lymphocyte proliferation. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case.

Conclusions: The anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers.
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http://dx.doi.org/10.1038/s41416-019-0725-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078258PMC
March 2020

Acquisition of a side population fraction augments malignant phenotype in ovarian cancer.

Sci Rep 2019 10 2;9(1):14215. Epub 2019 Oct 2.

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

Side population (SP) cells harbor malignant phenotypes in cancer. The aim of this study was to identify genes that modulate the proportion of ovarian cancer SP cells. Using a shRNA library targeting 15,000 genes, a functional genomics screen was performed to identify genes whose suppression increased the SP percentage. The biological effects caused by alteration of those identified genes were investigated in vitro and in vivo. We found that suppression of MSL3, ZNF691, VPS45, ITGB3BP, TLE2, and ZNF498 increased the proportion of SP cells. Newly generated SP cells exhibit greater capacity for sphere formation, single cell clonogenicity, and in vivo tumorigenicity. On the contrary, overexpression of MSL3, VPS45, ITGB3BP, TLE2, and ZNF498 decreased the proportion of SP cells, sphere formation capacity and single cell clonogenicity. In ovarian cancer cases, low expression of MSL3, ZNF691 and VPS45 was related to poor prognosis. Suppression of these six genes enhanced activity of the hedgehog pathway. Cyclopamine, a hedgehog pathway inhibitor, significantly decreased the number of SP cells and their sphere forming ability. Our results provide new information regarding molecular mechanisms favoring SP cells and suggest that Hedgehog signaling may provide a viable target for ovarian cancer.
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http://dx.doi.org/10.1038/s41598-019-50794-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775117PMC
October 2019

The efficacy of secondary cytoreductive surgery for recurrent ovarian, tubal, or peritoneal cancer in Tian-model low-risk patients.

J Gynecol Oncol 2019 Nov;30(6):e100

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

Objective: In patients with recurrent ovarian cancer (ROC) in whom surgery is likely to render them disease-free, it is unclear whether secondary cytoreductive surgery (SCS) combined with chemotherapy is superior to chemotherapy alone. The aim of this study was to evaluate the 2 treatment options in Tian-model low-risk patients.

Methods: We retrospectively reviewed 118 ROC cases treated in our hospital between 2004 and 2016. Of these, 52 platinum-sensitive cases were classified as low-risk (complete resection anticipated) using the Tian model. Prognostic factors were assessed with univariate and multivariate analysis using Cox's regression model. Progression-free survival (PFS) and overall survival (OS) were compared in patients treated with SCS plus chemotherapy (SCS group) and those treated with chemotherapy alone (chemotherapy group), using a propensity-score-based matching method.

Results: By multivariate analysis, the only factor associated with better OS was SCS. PFS and OS were significantly longer in the SCS group compared to the chemotherapy group in the matched cohort (median PFS: 21.7 vs. 15.1 months, p=0.027 and median OS: 91.4 vs. 33.4 months, p=0.008, respectively). In cases with multiple-site recurrence, the SCS group also showed significantly longer OS than the chemotherapy group (median 91.4 vs. 34.8 months, p=0.022). In almost all SCS cases, cooperation was required from other departments, and operation time was lengthy (median 323 minutes); however, no serious complications occurred.

Conclusion: SCS combined with chemotherapy results in better PFS and OS than chemotherapy alone in first platinum-sensitive ROC patients categorized as low-risk by Tian's model.
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http://dx.doi.org/10.3802/jgo.2019.30.e100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779625PMC
November 2019

Primary signet ring cell carcinoma of uterine cervix and related disease: two case reports and a review.

Int Cancer Conf J 2019 Oct 17;8(4):157-163. Epub 2019 May 17.

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Primary signet ring cell carcinoma of uterine cervix (SRCCC) is extremely rare. We present two cases of primary SRCCC that were treated with robot-assisted laparoscopic radical hysterectomy (RALRH). Case 1 had stage IB2 cervical adenocarcinoma, in which signet ring cell (SRC) was predominant. As adjuvant chemotherapy was not successful, she twice underwent surgical excision of recurrent tumors in pararectal lymph node and periureteral space 11 months and 27 months after RALRH, respectively. There were only SRCs observed in recurrent tumors. Case 2 had stage IB1 cervical adenocarcinoma, in which SRCs were detected only in the biopsy specimen, and no relapse occurred at 15 months after RALRH. PET/CT was useful for tumor detection in both cases, and the amount of SRC components was associated with the prognostic outcome. Considering the high recurrence rate and few complications at secondary surgery, minimally invasive surgery would be preferred as the primary surgery for SRCCC.
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http://dx.doi.org/10.1007/s13691-019-00375-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744541PMC
October 2019

Phosphorylation of STAT1 serine 727 enhances platinum resistance in uterine serous carcinoma.

Int J Cancer 2019 09 22;145(6):1635-1647. Epub 2019 Jun 22.

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

Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum-cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin-mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine-727 (pSTAT1-Ser727), but not on tyrosine-701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1-Ser727 by dominant-negative plasmid elevated cisplatin-mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1-Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1-Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC.
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http://dx.doi.org/10.1002/ijc.32501DOI Listing
September 2019

Hysteroscopic morphological pattern reflects histological grade of endometrial cancer.

J Obstet Gynaecol Res 2019 Aug 9;45(8):1479-1487. Epub 2019 May 9.

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

Aim: To examine the hysteroscopic morphological features in each histological grade of endometrial cancer, and to distinguish high- and low-grade cancer and low-grade cancer and atypical endometrial hyperplasia (AEH), using hysteroscopy.

Methods: In total, 135 patients who underwent hysterectomy after hysteroscopy were analyzed. They were divided into four categories: benign lesion; AEH; low-grade cancer, including endometrioid carcinoma grades 1 and 2 (G1/2); and high-grade cancer, including endometrioid carcinoma grade 3 and other high-grade carcinomas (G3/others). Three blinded gynecologic oncologists independently evaluated hysteroscopic video images for abnormal vessels, surface smoothness, papillary structure and polypoid structure. Prevalence rates of each finding were compared between the four categories. The accuracy of blind biopsy in outpatient settings and hysteroscopic endometrial biopsy in the four categories were also investigated.

Results: The number of patients with benign lesions, AEH, G1/2 and G3/others was 8, 7, 84 and 36, respectively. Patients with G3/others exhibited more polypoid (86% vs 61%, P = 0.0095) and less papillary (59% vs 80%, P = 0.023) structures than those exhibited by patients with G1/2. AEH and G1/2 were indistinguishable using hysteroscopy. Hysteroscopic biopsy was more accurate than outpatient biopsy in patients with G3/others (84% vs 52%, respectively, P = 0.010). Both biopsies were not sufficiently accurate to diagnose AEH (outpatient; 0%, hysteroscopic; 57%).

Conclusion: Hysteroscopic papillary and polypoid structures can help distinguish between high- and low-grade cancer. Hysteroscopic differentiation between AEH and low-grade cancer is difficult. These findings are considerable in preoperative assessment to determine adequate surgical strategies.
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http://dx.doi.org/10.1111/jog.13998DOI Listing
August 2019

Solitary fibrous tumor arising from pelvic retroperitoneum: A report of two cases and a review of the literature.

J Obstet Gynaecol Res 2019 Jul 7;45(7):1391-1397. Epub 2019 Apr 7.

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

Solitary fibrous tumors (SFT) rarely arise in the pelvis. Here, we report two cases of SFT arising from the pelvic retroperitoneum. The first case involves a 64-year-old woman diagnosed with a 5-cm pelvic mass. Magnetic resonance imaging revealed a solid and cystic mass with marked enhancement, but limited water restriction. During surgery, intraligamental tumor arising near the round ligament was resected. Pathologically, the tumor comprised dilated vessels and spindle-shaped cells positive for STAT6 and CD34. The second case involves a 53-year-old woman diagnosed with a 4.5-cm pelvic mass through computed tomography. Magnetic resonance imaging demonstrated a solid mass with multiple cysts with strong enhancement and slight water restriction. During surgery, the tumor was found in the retroperitoneum. Pathologically, spindle-shaped tumor cells positive for STAT6 and CD34 had proliferated around the prominent hyalinized vessels. Although rare in the pelvis, SFT should be suspected when a mass with strong enhancement is found.
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http://dx.doi.org/10.1111/jog.13965DOI Listing
July 2019

Aggressive adult granulosa cell tumor of the ovary without a FOXL2 mutation: A case report.

J Obstet Gynaecol Res 2019 Jul 5;45(7):1404-1409. Epub 2019 Apr 5.

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

We report a case of aggressive adult granulosa cell tumor (AGCT) of the ovary. On presentation, the tumor was localized in the right ovary; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and partial omentectomy were performed. While some areas of the tumor represented typical AGCT, other areas showed enlarged and hyperchromatic nuclei with numerous mitoses (>10/high-power field) with marked necrosis. The results of immunohistochemical analysis were compatible with AGCT, except that, in the necrotic portion, p53 was strongly positive, and the Ki-67 index was high. Four months after laparotomy, recurrent tumors developed in the bones, liver, lungs and dura mater. The patient responded well to chemotherapy consisting of five cycles of paclitaxel and carboplatin, but later, the tumors rapidly proliferated, and the patient died of disease 11 months after laparotomy. FOXL2 examination demonstrated that both portions of the primary tumor did not have a point mutation (402C→G) specific to AGCT.
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http://dx.doi.org/10.1111/jog.13969DOI Listing
July 2019

Invasive Paget's disease of the vulva treated with a combination of surgery and concurrent chemoradiotherapy: A case report.

Mol Clin Oncol 2018 Nov 17;9(5):489. Epub 2018 Sep 17.

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.

Invasive Paget's disease of the vulva (IP) is rare among patients with vulvar cancer. Radiation therapy and chemotherapy are not considered as radical, whereas surgical resection of the tumor with abdominal lymphadenectomy is highly invasive. Thus, more effective and less invasive treatments for IP are required. The present study reports a case of a 64-year-old woman with IP, who was treated with a combination of surgery and concurrent chemoradiotherapy (CCRT). The patient was diagnosed with IP with suspected lymph node metastases to the inguinal and pelvic lymph nodes, after having suffered from pruritus vulvae for 7 years. Following mapping biopsy, wide local excision, bilateral inguinal lymph node resection and laparoscopic pelvic lymphadenectomy were successfully performed. The vulva was reconstructed with a local fat flap. Postoperative pathological examination revealed metastases to the bilateral superficial inguinal and the left obturator and lateral suprainguinal lymph nodes. Adjuvant CCRT (whole pelvic irradiation, 50.4 Gy with weekly cisplatin, 40 mg/m) was completed without notable complications. Therefore, laparoscopic pelvic lymphadenectomy may be useful in determining the irradiation field for adjuvant CCRT in patients with advanced IP.
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http://dx.doi.org/10.3892/mco.2018.1719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200998PMC
November 2018

VISTA expressed in tumour cells regulates T cell function.

Br J Cancer 2019 01 9;120(1):115-127. Epub 2018 Nov 9.

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

Background: V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune-checkpoint protein. VISTA expression on tumour cells and the associated regulatory mechanisms remain unclear. We investigated VISTA expression and function in tumour cells, and evaluated its mechanism and activity.

Methods: VISTA in tumour cells was assessed by tissue microarray analysis, immunohistochemical staining and western blot. A series of in vitro assays were used to determine the function of tumour-expressed VISTA. In vivo efficacy was evaluated in syngeneic models.

Results: VISTA was highly expressed in human ovarian and endometrial cancers. Upregulation of VISTA in endometrial cancer was related to the methylation status of the VISTA promoter. VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro, and decreased the tumour-infiltrating CD8+ T cells in vivo. Anti-VISTA antibody prolonged the survival of tumour-bearing mice.

Conclusions: This is the first demonstration that VISTA is highly expressed in human ovarian and endometrial cancer cells, and that anti-VISTA antibody treatment significantly prolongs the survival of mice bearing tumours expressing high levels of VISTA. The data suggest that VISTA is a novel immunosuppressive factor within the tumour microenvironment, as well as a new target for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41416-018-0313-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325144PMC
January 2019

Four cases of endometrioid borderline ovarian tumour: case reports and literature review.

BJR Case Rep 2018 21;4(1):20170062. Epub 2017 Oct 21.

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

Endometrioid borderline tumours (EBTs) of the ovary are uncommon tumours of low malignant potential. They consist of atypical endometrioid cells lacking destructive stromal invasion. As the prognosis of EBT is excellent, excessive treatment should be avoided and preoperative diagnosis is important. Here we report four cases of ovarian EBTs along with imaging findings and a review of literature. The average patient age was 52 years. They presented with abdominal discomfort or abnormal vaginal bleeding. The final diagnoses for all four cases were EBT Stage IA with endometriosis. Pathologically, one case was an adenofibromatous type tumour, and three cases were intracystic type tumours. Two patients had concurrent endometrial cancer. MRI of the tumours showed enhanced solid components. The intracystic type tumours presented a dendritic structure in the cyst; fine papillary branches surrounded a low-signal trunk on weighted imaging. Positron emission tomography demonstrated marked fluorodeoxyglucose uptake in the solid component. One case with MRI 3 years before diagnosis indicated that the tumour arose in ovarian endometriotic cyst. EBT cases were difficult to distinguish from malignant ovarian tumours preoperatively. Intraoperative frozen section analysis may aid to determine treatment. Prognoses were excellent. Care should be taken for co-existing endometrial cancer.
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http://dx.doi.org/10.1259/bjrcr.20170062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159154PMC
October 2017

Antitumor Effect of Nivolumab on Subsequent Chemotherapy for Platinum-Resistant Ovarian Cancer.

Oncologist 2018 11 29;23(11):1382-1384. Epub 2018 Aug 29.

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

Platinum-resistant recurrent ovarian cancer is generally refractory to chemotherapy. Programmed cell death-1 (PD-1) signaling is a new target for antitumor therapy. The anti-PD-1 antibody nivolumab had a 10% durable complete response rate in our phase II clinical trial. However, how nivolumab affects sensitivity to subsequent chemotherapy remains unclear. We encountered several cases of unexpected antitumor response among patients who underwent palliative chemotherapy in the follow-up study of our phase II nivolumab trial (UMIN000005714). Several agents had an unexpected antitumor response in patients who were resistant or refractory to standard chemotherapeutic agents. In one patient, both pegylated liposomal doxorubicin (PLD) and nedaplatin (CDGP) resulted in partial response. In another patient, PLD and CDGP resulted in partial response and stable disease, respectively. These two patients remained alive on the cutoff date. These two cases raise the possibility that nivolumab might improve sensitivity to adequate chemotherapy for ovarian cancer.
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http://dx.doi.org/10.1634/theoncologist.2018-0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291322PMC
November 2018
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