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Endometrial biopsy is generally performed with a metal uterine curette sonde; however, recently, many types of vacuum aspirators are available, including the manual vacuum aspiration (MVA) system. We used the women's MVA system for endometrial sampling and evaluated its effectiveness in determining the presence of endometrial malignancy.Forty-seven samples were examined using the following procedures after measuring endometrial thickness by transvaginal ultrasonography: fractional curettage biopsy (Bx; 20 samples), total curettage under general anesthesia (T/C; 13 samples), and MVA (14 samples). The quality of the endometrial samples was classified into four types: 1-4, where 1 denoted poor and 4, good quality.The mean score of the MVA group was significantly higher than that of the partial curettage biopsy group (p = 0.0065). No differences were observed between the MVA and total curettage groups (p = 1.00). When patients were divided into two groups according to endometrial thickness (10 mm or ≥10 mm) and analyzed, both the MVA and T/C groups did not show a significant difference in their scores compared to the Bx group when the endometrial thickness was10 mm. However, when the endometrial thickness was ≥10 mm, the MVA and T/C groups had significantly better scores than the Bx group (p = 0.0225 and p = 0.0244, respectively). Vagal reflex, as an adverse event, was observed only in two patients in the Bx group (2/20, 10%).Considering its quality and safety, Karman-type MVA for endometrial sampling could be an alternative to fractional curettage using a metallic uterine curette sonde.

Histone modification is the key epigenetic mechanism that regulates gene expression. Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that catalyzes dimethylation of histone H3 (H3R17) at arginine 17. Lately, it has been suggested that CARM1 is associated with human carcinogenesis, and the CARM1-selective inhibitor, TP-064, has been shown to be a potential therapeutic agent for multiple myeloma. However, the physiological significance of CARM1 in endometrial cancer remains unclear. Therefore, we aimed to explore the role of CARM1 and the effect of TP-064 in endometrial cancer. To this end, we analyzed CARM1 expression in endometrial cancer using quantitative real-time polymerase chain reaction and examined the antitumor mechanism with CARM1 knockdown endometrial cancer cells. Moreover, we evaluated the therapeutic capability of TP-064 in endometrial cancer cells. CARM1 was remarkably overexpressed in 52 endometrial cancer tissues compared to normal endometrial tissues. The growth of CARM1 knockdown endometrial cancer cells was suppressed and CARM1 knockdown induced apoptosis. TP-064 also inhibited endometrial cancer cell growth and declined the number of endometrial cancer cell colonies. These data suggest that CARM1 may be a powerful therapeutic target for endometrial cancer.

Introduction Previous studies have shown that individuals with human papillomavirus (HPV)‐related cervical lesions have different prognoses according to the HPV genotype. However, these studies failed to account for possible diagnostic misclassification. In this retrospective cohort study, we aimed to clarify the natural course of cervical lesions according to HPV genotype to account for any diagnostic misclassification. Materials and Methods Our cohort included 729 patients classified as having cervical intraepithelial neoplasia (CIN). HPV was genotyped in all patients, who were followed up or treated for cervical lesions at the University of Tokyo Hospital from October 1, 2008 to March 31, 2015. Hidden Markov models were applied to estimate the diagnostic misclassification probabilities of the current diagnostic practice (histology and cytology) and the transitions between true states. We then simulated two‐year transition probabilities between true cervical states according to HPV genotype. Results Compared with lesions in patients with other HPV genotypes, lesions in HPV 16‐positive patients were estimated to be more likely to increase in severity (i.e., CIN3/cancer); over 2 years, 17.7% (95% confidence interval [CI], 9.3%–29.3%) and 27.8% (95% CI, 16.6%–43.5%) of those with HPV 16 progressed to CIN3/cancer from the true states of CIN1 and CIN2, respectively, whereas 55%–70% of CIN1/2 patients infected with HPV 52/58 remained in the CIN1/2 category. Misclassification was estimated to occur at a rate of 3%–38% in the current diagnostic practice. Conclusion This study contributes robust evidence to current literature on cervical lesion prognosis according to HPV genotype and quantifies the diagnostic misclassification of true cervical lesions.

The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

Purpose: Pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) frequently lowers the quality of life of ovarian cancer patients. Wrist and ankle cooling, having a limited preventive effect, has been the commonest supportive HFS care. In this study, we retrospectively assessed the primary preventive effect of a combination of cooling and oral dexamethasone therapy (cooling + oral Dex) on HFS. Methods: This study is a single-arm retrospective, observational study. Recurrent ovarian cancer patients were administered PLD ± bevacizumab. We retrospectively examined the efficacy of hands and feet cooling (from the start of PLD to the end) + oral Dex (day 1-5: 8 mg/day, day 6, 7: 4 mg/day) for primary HFS prevention. Results: This study included 74 patients. The initial dose of PLD was 50 mg/m2 and 40 mg/m2 for 32 (43.2%) and 42 (56.8%) patients, respectively. HFS of Grade ≥ 2 and Grade ≥ 3 developed in five (6.8%) and one (1.4%) patient(s), respectively. The incidence of ≥ Grade 2 and ≥ Grade 3 HFS was much lower than those reported in previous studies. Dose reduction was required in 13 patients (17.6%) mainly because of neutropenia or mucositis; there was no HFS-induced dose reduction. Meanwhile, PLD therapy was discontinued mainly because of interstitial pneumonia (4 patients) and HFS (one patient). Conclusions: We demonstrated the efficacy of cooling and oral Dex as primary prevention for PLD-induced HFS. This combination therapy can be considered primary prevention for HFS in ovarian cancer patients on PLD.

With the development of machine learning and deep learning models, artificial intelligence is now being applied to the field of medicine. In oncology, the use of artificial intelligence for the diagnostic evaluation of medical images such as radiographic images, omics analysis using genome data, and clinical information has been increasing in recent years. There have been increasing numbers of reports on the use of artificial intelligence in the field of gynecologic malignancies, and we introduce and review these studies. For cervical and endometrial cancers, the evaluation of medical images, such as colposcopy, hysteroscopy, and magnetic resonance images, using artificial intelligence is frequently reported. In ovarian cancer, many reports combine the assessment of medical images with the multi-omics analysis of clinical and genomic data using artificial intelligence. However, few study results can be implemented in clinical practice, and further research is needed in the future.

A diagnostic biopsy for endometrial cancer is performed via dilation and curettage (D&C). However, D&C may miss endometrial cancer lesions due to of its ‘blind’ approach. Hysteroscopy is a useful method that can be used to detect endometrial cancer lesions. In addition, office hysteroscopy is easy to be scheduled and does not require anesthesia. The patient was a 40-year-old woman with suspected endometrial cancer; however, it could not be diagnosed by D&C and biopsy using hysteroscopy during hospitalization. Office hysteroscopy during the proliferative phase indicated that the suspicious endometrial cancerous lesion was minimal at the isthmus of the uterus with atypical vessels and a white spot, for which biopsy was performed. Pathological diagnosis was endometrioid carcinoma with squamous differentiation, G1. Therefore, total laparoscopic hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy were performed. In this case, it was difficult to detect minimal lesion in the secretory phase because the endometrial thickness hid the endometrial cancer. It is easy to perform office hysteroscopy in the proliferative phase. This case indicated that office hysteroscopy is a useful method to diagnose and perform biopsy for minimal lesions.

In 5% of female patients with malignant melanoma (MM), MM develops from the genital tract. MM of the cervix is particularly rare. In the present case report, a 73-year-old woman with stage ⅢC cervical MM underwent modified radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymph node dissection. A total of 4 months after surgery, multiple metastases were found in the brain, lung, liver, lymph nodes and bone. The patient underwent γ-knife surgery of the brain and received treatment with anti PD-1 antibodies (nivolumab) and anti-CTLA4 antibodies (ipilimumab); however, they were ineffective and the patient subsequently died. To the best of our knowledge, this is the first report of treatment using two types of immune checkpoint inhibitors administered to a patient with cervical MM. Taken together with previous reports, this case suggests that immune checkpoint inhibitors may be less effective in cervical MM than in cutaneous MM; however, the number of cases is small. Further development of biomarkers to stratify efficacy is required.

We encountered HPV6‐positive cervical papillary squamous cancer (PSCC) that was difficult to diagnose. The case was initially diagnosed and treated for condyloma. To the best of our knowledge, this is the first report of HPV6 infection in PSCC.

Although the incidence of febrile neutropenia (FN) is relatively higher for doxorubicin and cisplatin combination regimen than for other regimens in endometrial cancer, evidence regarding the efficacy of pegfilgrastim in this regimen is lacking.We retrospectively reviewed the data of 58 patients with endometrial cancer who were treated with doxorubicin plus cisplatin. The patients were divided into primary prophylaxis and non-prophylaxis groups. We compared the incidence of FN and neutropenia as well as the chemotherapy relative dose intensity (RDI) and usage of antibiotics between the groups.The rates of FN (8.0% vs. 34.8%) and grade 4 neutropenia (12.0% vs. 87.0%) were significantly lower in the primary prophylaxis group. Although there was no difference in the RDI between the groups, the primary prophylaxis group had a lower rate of antibiotic prescriptions.Prophylaxis with pegfilgrastim efficiently prevented FN in patients treated with doxorubicin and cisplatin.

Background Pseudomyxoma peritonei is a rare disease condition mainly caused by primary mucinous tumors from the appendix and rarely from the ovary, such as when mucinous ovarian tumors arise from within a teratoma. Molecular analyses of pseudomyxoma from the appendix showed that KRAS and GNAS pathogenic variants are common genetic features of pseudomyxoma peritonei. However, the origin of the tumors is difficult to be identified via genetic variants alone. This study presents a case of pseudomyxoma peritonei of ovarian origin, which was diagnosed by comprehensive genomic profiling with ploidy analysis in a series of primary, recurrent, and autopsy tumor specimens. Case presentation A 40-year-old woman was diagnosed with Stage IC2 mucinous ovarian tumor of borderline malignancy with mature cystic teratoma, upon clinical pathology. Immunohistochemical analysis suggested that the mucinous tumor was derived from the intestinal component of an ovarian teratoma. Three years later, intraperitoneal recurrence was detected, which subsequently progressed to pseudomyxoma peritonei. Genomic analysis detected KRAS (G12D), GNAS (R201C), and FBXW7 (R367*) variants in the primary tumor. In addition, the tumor showed aneuploidy with loss of heterozygosity (LOH) in all its chromosomes, which suggested that the primary ovarian tumor was derived from germ cells. Existence of one Barr body suggested the existence of uniparental disomy of the tumors throughout the genome, instead of a haploid genotype. All three pathogenic variants remained positive in the initial recurrent tumor, as well as in the paired DNA from the whole blood in pseudomyxoma peritonei. The pathogenic variant of KRAS (G12D) was also identified in the autopsy specimen of the appendix by droplet digital polymerase chain reaction. Conclusions This study pathologically and genetically confirmed that the primary ovarian borderline tumor was derived from the intestinal component of an ovarian teratoma, and that the subsequent pseudomyxoma peritonei progressed from the primary ovarian tumor. Integrative genomic analysis was useful to identify cellular origin of tumors, as well as to precisely interpret the process of disease progression.

PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2.cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry.Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs (P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P 0.001 in OVISE, and P = 0.038 in RMG-I) without severe body weight loss. Immunohistochemistry from the xenograft tumors showed that the combination treatment significantly reduced vascularity and cell proliferation, with an increase of apoptotic cell death.A combination therapy targeting the PI3K pathway and MDM2 might be a promising therapeutic strategy in CCOC.

The programmed cell death 1/programmed cell death 1 ligand 1 pathway was successfully targeted in cancer immunotherapy. Elevated interleukin‐17 (IL‐17), which is known in autoimmune diseases, has recently been recognized in cancer patients. We investigated the role of IL‐17 in the regulation of expression of programmed cell death 1 ligand 1 in ovarian cancer by evaluating changes in the number of IL‐17‐producing cluster of differentiation 4 helper T cells (Th17) and γδT cells (γδT17) in PBMC of 52 gynecological cancer patients (including 30 ovarian cancer patients) and 18 healthy controls. The occupancy ratio of Th17 and γδT17 was higher in ovarian cancer and endometrial cancer patients than in controls, determined by multi‐color flow cytometry (Th17: P

Laparoscopic port site endometriosis is less common in abdominal wall endometriosis, and malignant transformation of abdominal wall endometriosis is rare. We reported a case of mixed endometrioid and clear cell carcinoma arising from port site endometriosis. The patient was a 49-year-old woman with a history of laparoscopic excision of ovarian endometrioma. Physical examination revealed a subcutaneous solid tumor around the laparoscopic surgical scar. Imaging showed a suspicious malignancy. She underwent radical marginal resection of the abdominal wall tumor, flap reconstruction of the abdominal wall, hysterectomy, bilateral salpingo-oophorectomy and omental biopsy. Histological examination revealed mixed endometrioid and clear cell carcinoma. Computed tomography scan showed no evidence of recurrence after six cycles of chemotherapy. This is the first case of malignant transformation from laparoscopic trocar site endometriosis.

Cervical intraepithelial neoplasia (CIN), a precursor lesion to cervical cancer, is caused by high-risk human papillomavirus (HPV), high-grade CIN lesions (CIN2-3) are precancerous and require treatment. No globally approved therapy is available for CIN2-3 treatment. This study is a placebo-controlled randomized clinical trial of GLBL101c treatment for CIN2 in 40 patients with HPV16-positive CIN2 who were 1:1 randomized to receive GLBL101c (1 g/daily) or placebo for 5 days at 1, 2, 4, and 8 weeks. No differences were noted between the GLBL101c and placebo groups for patient background and adverse events. Moreover, no statistically significant difference was noted between the two groups at the primary endpoint, pathological regression after 16 weeks of the first oral dose, however, only in the GLBL101c group, two patients had complete regression (CR, regression to normal within 16 weeks). IFNγ production was significantly correlated with the number of spots identified by the interferon gamma enzyme-linked immunospot (IFNγ-ELISPOT) assay using cervical lymphocytes (CxLs) or peripheral blood mononuclear cells. In the two cases of CR, E7-specific Th1 immune responses were observed at week 16. Therefore, we concluded as a novel Lactobacillus-based vaccine with stronger immunogenicity than GLBL101c should be developed.

Radiation-based therapy is widely used for advanced cervical cancer. Prior radiation-based therapy is a potential risk factor for febrile neutropenia (FN). However, the effect of irradiation field size on the incidence of FN during recurrent cervical cancer treatment is unclear. This study aimed to investigate the relationship between prior irradiation field size and FN development during recurrent chemotherapy. This retrospective, observational study included cervical cancer patients who received recurrent chemotherapy between November 2006 and June 2020. The patients were classified into two groups based on the area of irradiation fields. The first group included patients with a history of whole pelvis (WP) irradiation (WP group). The second group had patients who underwent WP plus para-aortic lymph node (PAN) irradiation (WP + PAN group). The incidences of hematological toxicities and FN during the recurrent chemoradiotherapy were compared between the two groups. The FN incidence was significantly higher in the WP + PAN group than in the WP group (32.1% vs. 0%, P

Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.

Endometrial cancer is a ubiquitous gynecological disease with increasing global incidence. Therefore, despite the lack of an established screening technique to date, early diagnosis of endometrial cancer assumes critical importance. This paper presents an artificial-intelligence-based system to detect the regions affected by endometrial cancer automatically from hysteroscopic images. In this study, 177 patients (60 with normal endometrium, 21 with uterine myoma, 60 with endometrial polyp, 15 with atypical endometrial hyperplasia, and 21 with endometrial cancer) with a history of hysteroscopy were recruited. Machine-learning techniques based on three popular deep neural network models were employed, and a continuity-analysis method was developed to enhance the accuracy of cancer diagnosis. Finally, we investigated if the accuracy could be improved by combining all the trained models. The results reveal that the diagnosis accuracy was approximately 80% (78.91–80.93%) when using the standard method, and it increased to 89% (83.94–89.13%) and exceeded 90% (i.e., 90.29%) when employing the proposed continuity analysis and combining the three neural networks, respectively. The corresponding sensitivity and specificity equaled 91.66% and 89.36%, respectively. These findings demonstrate the proposed method to be sufficient to facilitate timely diagnosis of endometrial cancer in the near future.

Although a majority of women with high-grade serous ovarian cancer (HGSC) achieve a complete response to first-line platinum- and paclitaxel-based chemotherapy, around thirty percent of patients are identified as incomplete responders. Their diseases typically either does not respond or progresses during treatment (refractory) or recurs within 6 months of completing treatment (resistant), suggesting the inherit or intrinsic characteristics of the tumor. Currently, there are no biomarkers that can predict intrinsic resistance, which can avoid unnecessary treatment and toxicity. MicroRNAs (miRNAs) provide a novel master layer of regulation of gene expression. However, the molecular mechanisms by which miRNAs confer a chemoresistant phenotype in ovarian cancer have not been elucidated. To identify miRNAs that are associated with intrinsic chemoresistance in HGSC, Ion Torrent next-generation sequencing analysis of miRNAs was performed on microdissected chemosensitive and chemorefractory primary HGSC cases. Amongst all the miRNAs that were significantly down-regulated in chemorefractory cases, lower miR-625-3p expression was found to be associated with poorer overall and progression-free survivals. Further functional studies showed that overexpression of miR-625-3p significantly decreased cisplatin and paclitaxel resistance in ovarian cancer cells in vitro and in vivo. Online target prediction algorithms together with transcriptome profiling of HGSC cells transfected with miR-625-3p mimics or control mimics identified SSX2IP as a direct target of miR-625-3p, suggesting that SSX2IP may play a role in conferring cisplatin/paclitaxel resistance in HGSC by mediating the effect of miR-625-3p. SSX2IP is a microtubule anchoring and centriolar satellite protein, which plays a critical role in controlling microtubule length and orientation, and centrosome maturation. We demonstrated that HGSC cells transfected with SSX2IP had marked increases in microtubule masses, intracellular multivesicular body trafficking and exosomal cisplatin level; and a decrease in intracellular cisplatin level. In conclusion, down-regulation of miR-625-3p confers cisplatin/paclitaxel resistance in ovarian cancer cells via its novel direct target SSX2IP. SSX2IP alters the microtubule dynamics and subsequently mediates inter-organelle crosstalks between microtubules and multivesicular bodies, which facilitate exosomal export of cisplatin and paclitaxel of HGSC cells. This study is crucial for developing new predictive biomarkers for intrinsic chemoresistance, and new treatment strategies for HGSC based on upregulating miR-625-3p or downregulating SSX2IP expression in ovarian cancer cells, which will enhance cisplatin and paclitaxel sensitivity, and improve patient survival rates. Citation Format: Chi Lam Au Yeung, Tetsushi Tsuruga, Kay-Pong Yip, Sammy Ferri-Borgogno, Samuel Mok. miR-625-3p enhances chemosensitivity in ovarian cancer cells through exosomal export of cisplatin and paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1551.

The albumin-to-globulin ratio reflects both the nutrition and inflammation and predicts prognosis in patients with various malignancies. However, in cervical cancer patients who undergo surgery, its significance has yet to be established. A total of 247 cervical cancer patients who received surgical treatment at our institution between 2005 and 2017 were enrolled in this study. Preoperative data, such as the levels of serum albumin and serum globulin as well as the albumin-to-globulin ratio along with the other clinicopathological characteristics were retrospectively assessed, and their association with the overall survival was analyzed. Overall, 49 cases of recurrence and 26 deaths were observed during the median follow-up time of 58.6 months. A low albumin-to-globulin ratio (

Previous studies have suggested that histone methylation can modulate carcinogenesis and cancer progression. For instance, the histone methyltransferase SET and MYND domain containing 2 (SMYD2) is overexpressed in several types of cancer tissue. The aim of the present study was to determine whether SMYD2 could serve a therapeutic role in ovarian clear cell carcinoma (OCCC). Reverse transcription-quantitative PCR was used to examine SMYD2 expression in 23 clinical OCCC specimens. Moreover, OCCC cell proliferation and cell cycle progression were also examined following small interfering RNA-mediated SMYD2 silencing or treatment with a selective SMYD2 inhibitor. SMYD2 was significantly upregulated in clinical OCCC specimens, compared with normal ovarian tissue. In addition, SMYD2 knockdown decreased cell viability as determined via a Cell Counting Kit-8 assay. Moreover, the proportion of cells in the sub-G1 phase increased following SMYD2 knockdown, suggesting increased apoptosis. Treatment with the SMYD2 inhibitor LLY-507 suppressed OCCC cell viability. These results suggested that SMYD2 could promote OCCC viability, and that SMYD2 inhibition induced apoptosis in these cells. Thus, SMYD2 inhibitors may represent a promising molecular targeted approach for OCCC treatment.

Aim Carboplatin is a key drug for gynecologic cancers. However, hypersensitivity reactions (HSR) are major adverse effects that might necessitate carboplatin discontinuation. Desensitization is an effective method in patients who developed initial HSR and further required carboplatin treatment. Here, we aimed to evaluate our experience with the use of the carboplatin desensitization protocol in five patients at the University of Tokyo Hospital. Methods We established a four-step, 5-h desensitization protocol for our hospital. Observational and retrospective analyses were performed. Additionally, we have shared the patients' clinical information with the emergency department to ensure the safety of this protocol. Results Five patients with recurrent gynecological cancer were treated using this protocol. Four of the five patients were treated effectively and 28 of 29 desensitization protocols were completed successfully. In one patient, we switched to olaparib successfully after two courses of our protocol. One patient who developed grade 4 HSR during initial carboplatin administration developed grade 2 HSR and we discontinued the protocol. Conclusion The carboplatin desensitization protocol is very efficient. The outcome of our protocol was on a par with other protocols. To the best of our knowledge, this is the first study to indicate that switching to olaparib can be considered a suitable option in patients who develop HSR to carboplatin.

Background Soluble Fms-like tyrosine kinase-1 (sFLT1) as an anti-angiogenic factor is abundantly expressed in placental trophoblasts. Choriocarcinoma, a malignant tumor derived from trophoblasts, is known to be highly angiogenic and metastatic. However, the molecular mechanism underlying angiogenesis in choriocarcinoma pathogenesis remains unclear. We aimed to investigate the mRNA expression and DNA methylation status of the FLT1 gene in human choriocarcinoma cells and trophoblast cells. Methods qRT-PCR, Western blotting and ELISA were conducted to evaluate the mRNA and protein expression levels of sFLT1. 5-aza-2′-deoxycytidine (5azadC) treatment and bisulfite sequencing were used to study the FLT1 gene promoter methylation. The effect of sFLT1 on choriocarcinoma growth and angiogenesis was evaluated in a xenograft mouse model. Results Expression of the FLT1 gene was strongly suppressed in choriocarcinoma cell lines compared with that in the primary trophoblasts. Treatment of choriocarcinoma cell lines with 5azadC, a DNA methyltransferase inhibitor, markedly increased in mRNA expression of three FLT1 splice variants and secretion of sFLT1 proteins. Bisulfite sequencing revealed that the CpG hypermethylation was observed at the FLT1 promoter region in choriocarcinoma cell lines and a human primary choriocarcinoma tissue but not in human trophoblast cells. Interestingly, in 5azadC-treated choriocarcinoma cell lines, sFLT1 mRNA expression and sFLT1 production were further elevated by hypoxic stimulation. Finally, as expected, sFLT1-expressing choriocarcinoma cells implanted into nude mice showed significantly slower tumor growth and reduced microvessel formation compared with GFP-expressing control choriocarcinoma cells. Conclusions Inhibition of sFLT1 production by FLT1 silencing occurs via the hypermethylation of its promoter in choriocarcinoma cells. The stable expression of sFLT1 in choriocarcinoma cells resulted in the suppression of tumor growth and tumor vascularization in vivo. We suggest that the FLT1 gene may be a cell-type-specific tumor suppressor in choriocarcinoma cells.

Aim Although the procedure of abdominal trachelectomy has been remarkably improved, preventing subsequent cervical stenosis remains challenging. In this study, we analyzed the clinicopathological risk factors for cervical stenosis to explore the appropriate surgical procedures for the prevention of cervical stenosis following trachelectomy. Methods Thirty-two patients who underwent abdominal extended and radical trachelectomy were assessed retrospectively (median follow-up period = 33 months). To evaluate the risk factors, the clinicopathological factors were analyzed by univariate and multivariate analyses. The reconstructed uterine length (UtL), that is, the length between the vaginal end of the neo-cervix and the uterine fundus, was measured by transvaginal ultrasound after surgery. The cut-off value for the UtL was assessed by a receiver operating characteristic (ROC) curve analysis. Results Cervical stenosis of any grade was observed in 12 patients (grade 1 = 9, grade 3b = 3). Among the various clinicopathological factors, the UtL and cervical length (CL) were significantly related to cervical stenosis following trachelectomy. The multivariate analysis revealed that the UtL, but not CL, is an independent risk factor for stenosis. The ROC curve analysis revealed that stenosis was significantly more likely to occur in patients with a UtL shorter than 53 mm (area under the ROC curve = 0.902). UtL in the patients who became pregnant was longer than that in the patients who did not. No evidence of recurrent cancer was observed during the follow-up period. Conclusion Our proposed method may provide a functional reconstructed uterus with preserving fertility by remaining UtL more than 53 mm.

Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability of transitions between multiple states according to the genotypes of high-risk human papillomavirus (HPV). This retrospective cohort comprised 6022 observations in 737 patients (195 normal, 259 CIN1, and 283 CIN2 patients at the time of entry in the cohort). Patients were followed up or treated at the University of Tokyo Hospital between 2008 and 2015. Our model captured the prevalence trend satisfactory, particularly for up to two years. The estimated probabilities for 2-year transition to CIN3 or more were the highest in HPV 16-positive patients (13%, 30%, and 42% from normal, CIN1, and CIN2, respectively) compared with those in the other genotype-positive patients (3.1%&ndash, 9.6%, 7.6%&ndash, 16%, and 21%&ndash, 32% from normal, CIN1, and CIN2, respectively). Approximately 40% of HPV 52- or 58-related CINs remained at CIN1 and CIN2. The Markov model highlights the differences in transition and progression patterns between high-risk HPV-related CINs. HPV genotype-based management may be desirable for patients with cervical lesions.

Background Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1), a histone methyltransferase, has been found to be upregulated and its expression to be correlated with expression of enhancer of zeste homolog 2 (EZH2) in several cancers. In this study, we evaluated the role of WHSC1 and its therapeutic significance in ovarian clear cell carcinoma (OCCC). Methods First, we analyzed WHSC1 expression by quantitative PCR and immunohistochemistry using 23 clinical OCCC specimens. Second, the involvement of WHSC1 in OCCC cell proliferation was evaluated by MTT assays after siRNA-mediated WHSC1 knockdown. We also performed flow cytometry (FACS) to address the effect of WHSC1 on cell cycle. To examine the functional relationship between EZH2 and WHSC1, we knocked down EZH2 using siRNAs and checked the expression levels of WHSC1 and its histone mark H3K36m2 in OCCC cell lines. Finally, we checked WHSC1 expression after treatment with the selective inhibitor, GSK126. Results Both quantitative PCR and immunohistochemical analysis revealed that WHSC1 was significantly overexpressed in OCCC tissues compared with that in normal ovarian tissues. MTT assay revealed that knockdown of WHSC1 suppressed cell proliferation, and H3K36me2 levels were found to be decreased in immunoblotting. FACS revealed that WHSC1 knockdown affected the cell cycle. We also confirmed that WHSC1 expression was suppressed by EZH2 knockdown or inhibition, indicating that EZH2 is upstream of WHSC1 in OCCC cells. Conclusions WHSC1 overexpression induced cell growth and its expression is, at least in part, regulated by EZH2. Further functional analysis will reveal whether WHSC1 is a promising therapeutic target for OCCC. Electronic supplementary material The online version of this article (10.1186/s12885-019-5638-9) contains supplementary material, which is available to authorized users.

Renal hypouricemia is associated with urinary calculi and severe acute renal failure after exercise. The epidemiology of renal hypouricemia is not yet sufficiently understood, and there is no report of it occurring during pregnancy. We report the case of a pregnant woman with renal hypouricemia. At her first pregnancy, she developed preeclampsia with severe features at the 34th week of gestation. After parturition, she developed acute renal failure and was diagnosed with renal hypouricemia. During the second pregnancy, when she was referred to our hospital, care was taken to ensure adequate hydration by infusion of liquids and water at the time of labour. Consequently, she did not have onset of renal hypouricemia. We suggest that acute renal failure may be avoided in pregnant women with renal hypouricemia by preventing dehydration via drinking enough during pregnancy postpartum period and by infusion during labour.

Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer., The tumor microenviroment can influence cancer progression and response to therapy. In this study, the authors show that miR21 is transferred through exosomes from cancer-associated fibroblasts and adipocytes to ovarian cancer cells where it modulates drug resistance by its direct target APAF1.

The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies.