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A multi-kinase inhibitor, lenvatinib, plus an immune checkpoint inhibitor, pembrolizumab, became a viable therapeutic option for advanced or recurrent endometrial cancer in Japan by the end of 2021. The Japanese population has a relatively unique genetic background. Hence, the safety profile and effectiveness of lenvatinib plus pembrolizumab may differ between the Japanese and other populations. This single-center, retrospective study aimed to evaluate the treatment efficacy of lenvatinib plus pembrolizumab and the safety profile of the associated adverse events. The clinical records of 15 patients, who received lenvatinib plus pembrolizumab for advanced or recurrent endometrial cancer at the Tohoku University Hospital, were reviewed. Best overall response and disease control rates were 40.0% and 73.3%, respectively. Treatment was discontinued owing to disease progression and adverse events in six patients, respectively. As of the end of July 2023, treatment was ongoing in the remaining three patients. The median treatment and progression-free survival durations were 118 and 258 days, respectively. Relative dose intensity of lenvatinib was not positively associated with progression-free survival, neither during the first 4 weeks after treatment initiation nor during the entire treatment period. All patients experienced one or more adverse events, the most common of which were hypothyroidism (90%) and hypertension (83.3%). Among the 15 patients, 13 required lenvatinib dose reduction owing to adverse events. One patient developed grade 4 interstitial pneumonia requiring intensive care. Our results validate the short-term efficacy of lenvatinib plus pembrolizumab, and indicate that dose optimization of lenvatinib could be individualized without impairing efficacy.

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Extrapulmonary lymphangioleiomyomatosis (LAM) can present as incidental nodal LAM in gynecological surgery specimens, that warrants systemic investigation and follow-up of concurrent and subsequent development of pulmonary and extrapulmonary LAM.

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Advantages of lymphadenectomy for early stage endometrial cancer remain controversial. Lymphadenectomy had been routinely omitted for patients aged ≥ 70 years at our institute if lymph node metastasis was unsuspected due to an increased risk of peri- and postsurgical complications. Since 2013, with the introduction of minimally invasive surgery and considering the heterogeneous medical conditions, we started performing lymphadenectomy in patients who were considered well-tolerated. We retrospectively investigated our clinical database to assess the effect of lymphadenectomy in older patients with early stage endometrial carcinoma. Patients aged ≥ 70 years, preoperatively diagnosed with stage I endometrial carcinoma, and who underwent lymphadenectomy between 2013 and 2021 at Tohoku University Hospital were included in the lymphadenectomy group (n = 33), whereas patients who underwent surgery without lymphadenectomy before the end of 2012 were included in the no-lymphadenectomy group (n = 49). Clinical parameters and patient outcomes, such as disease-free survival (DFS) and disease-specific survival (DSS), were compared. The median age was significantly higher and fewer patients received adjuvant chemotherapy in the no-lymphadenectomy group. Neither DSS nor DFS differed significantly between the two groups. Five-year-DFS rates were 77.2% and 82.5% and 5-year-DSS rates were 89.7% and 97.8% for the lymphadenectomy and no-lymphadenectomy groups, respectively. No significant differences were observed in the subsequent survival analysis by substage, histological subtype, or risk of recurrence. Our results suggest that the indications for lymphadenectomy in older patients should be individually optimized according to the risk of recurrence and postoperative complications.

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The risk factors for venous thromboembolism (VTE) recurrence/exacerbation or a change from a direct oral anticoagulant (DOAC) to another anticoagulant in patients with gynecologic cancer using DOACs have not been thoroughly elucidated. Here, we aimed to investigate the risk factors for a composite primary outcome, including VTE recurrence/exacerbation, or a change from a DOAC to another anticoagulant, in this population. A total of 63 patients were analyzed. Risk factors for a primary outcome within 2 years after DOAC initiation were investigated using multiple logistic regression analysis. Among the 63 patients, 10 developed a primary outcome. Clear cell carcinoma of the ovary (adjusted odds ratio (aOR), 18.9; 95% confidence interval (CI), 2.25-350.74), pulmonary embolism (PE) or proximal deep vein thrombosis without PE (aOR, 55.6; 95% CI, 3.29-11,774.66), and D-dimer levels in the third tertile (≥7.6 µg/dL) when VTE was first diagnosed (aOR, 6.37; 95% CI, 1.17-66.61) were associated with increased odds of a primary outcome in patients with gynecologic cancer using DOACs. Patients with one or more risk factors for a primary outcome require careful follow-up after DOAC initiation for the early recognition of treatment failure.

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Poly(ADP-ribose) polymerase (PARP) inhibitors theoretically promote synthetic lethality in cancer cells with homologous recombination deficiency (HRD). However, clinical evidence indicates that PARP inhibitors are also effective for treating HRD-negative ovarian cancer. The PARP inhibitor olaparib became available in Japan as a maintenance therapy for platinum-sensitive recurrent ovarian cancer regardless of homologous recombination status in April 2018. The purpose of this study was to identify potential clinical biomarkers for olaparib sensitivity in patients with recurrent ovarian cancer. Clinical information about the patients with recurrent ovarian cancer treated with olaparib maintenance therapy (OMT) was retrospectively collected. OMT duration was used as an indicator for olaparib sensitivity. The relationship between OMT duration and clinical parameters was statistically analyzed. We found a positive correlation between OMT duration and progression-free survival (PFS) or treatment free interval (TFI). In some cases, OMT duration exceeded PFS before olaparib introduction. We also found that more than half of the patients with measurable target lesions at the time of OMT introduction showed partial or complete response to OMT. These results validated the effectiveness of OMT and identified PFS and TFI as potential clinical markers for olaparib sensitivity in the patients with recurrent ovarian cancer.

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BACKGROUND: Ovarian cancer is the most lethal gynecologic malignancy due to the tumor's acquisition of chemoresistance to platinum-based chemotherapy. To solve this problem, we conducted RNAi-based large-scale screening and determined that tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) is a key molecule involved in the platinum resistance of ovarian cancer cells. Recently, a variety of studies have investigated that small extracellular vesicles (sEVs) contribute to the communication between cancer cells, including the development of chemoresistance in ovarian cancer. The purpose of our study is to determine if sEVs-derived TIE-1 is involved in the chemoresistance of ovarian cancer cells. MATERIALS AND METHODS: TIE-1-overexpressed TOV112D cells, termed TOV112DTIE-1 cells, were established, and sEVs were isolated from TOV112DTIE-1 cells supernatants by ultracentrifugation. We assessed cisplatin sensitivity in recipient cells with TOV112DTIE-1-derived sEVs by cell-Titer Glo kit. We also asked whether sEV-derived TIE-1 suppressed the DNA damage response in recipient cells and evaluated the DNA damage response by counting cells positive for DNA damage foci. RESULTS: TIE-1 was contained within sEVTIE-1 derived from the cellular supernatant of TOV112DTIE-1. We showed that sEV-derived TIE-1 decreased chemosensitivity to cisplatin by suppressing the DNA damage response in recipient cells. CONCLUSION: Our findings suggest that sEV-derived TIE-1 could be a new therapeutic target for refractory ovarian cancer.

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Platinum resistance is one of the most challenging problems in ovarian cancer treatment. High-throughput functional siRNA screening identified tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) as a gene that confers cells resistant to cisplatin. Conversely enforced over-expression of TIE-1 was validated to decrease cisplatin sensitivity in multiple ovarian cancer cell lines and up-regulation of TIE-1 was correlated with poor prognosis and cisplatin resistance in patients with ovarian cancer. Mechanistically, TIE-1 up-regulates the nucleotide excision repair (NER) system mediated by xeroderma pigmentosum complementation group C (XPC), thereby leading to decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake and excretion. Importantly potentiation of therapeutic efficacy by TIE-1 inhibition was selective to DNA-adduct-type chemotherapeutic platinum reagents. Therefore, TIE-1 is suggested to promote XPC-dependent NER, rendering ovarian cancer cells resistant to platinum. Accompanied with novel findings, TIE-1 could represent as a novel therapeutic target for platinum-resistant ovarian cancer.

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c-Myc is a master regulator of various oncogenic functions in many types of human cancers. However, direct c-Myc-targeted therapy has not been successful in the clinic. Here, we explored a novel therapeutic target, which shows synthetic lethality in c-Myc-driven ovarian cancers, and examined the molecular mechanism of the synthetic lethal interaction. By high throughput siRNA screening with a library of 6,550 genes, Furin, a pro-protein convertase, was identified as the top hit gene. Furin inhibition by siRNA or a Furin inhibitor significantly suppressed cell proliferation in high c-Myc-expressing ovarian cancer cells compared with low c-Myc-expressing cells. Conversely, Furin overexpression in the presence of high c-Myc significantly promoted cell proliferation compared with only c-Myc or Furin overexpression. Notch1, one of the Furin substrates, was upregulated by c-Myc, and Notch1 cleaved by Furin increased cell proliferation of high c-Myc-expressing ovarian cancer cells. Notch1 was involved in the cooperative pathway of c-Myc and Furin in cell proliferation. In clinical ovarian cancer specimens, co-expression of c-Myc and Furin correlated with poor survival. In conclusion, we found that c-Myc cooperates with Furin to promote cell proliferation. Furin may be a promising therapeutic target in c-Myc-driven ovarian cancer.

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Ceramides are bioactive lipids that mediate cell death in cancer cells, and ceramide-based therapy is now being tested in dose-escalating phase I clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics, and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL), we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knockdown of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pronecroptotic target for ceramide in ovarian cancer models. Mol Cancer Ther; 17(1); 50-59. ©2017 AACR.

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BACKGROUND: The aim of this study was to investigate cytological features of Brenner tumors according to tumor grade using imprint cytology. CASE: Between 2004 and 2015, intraoperative imprint cytology was performed on 8 patients with Brenner tumors suspected to be malignant neoplasmas on gross examination because of their large size and solid part. These consisted of 1 benign, 3 borderline, and 4 malignant tumors. In patients with benign and borderline tumors, naked nucleus-like stromal cells and tumor cells in a sheet-like arrangement were observed against a clear background. The nuclei were round to oval-shaped with finely granular chromatin patterns and small nucleoli. Papillary cell clusters and high nucleus-to-cytoplasm ratios were only observed in 1 borderline case. In cases with malignancy, the background was necrotic. The tumor cells occurred in large papillary clusters. The nuclei showed a high degree of nuclear atypia. Nuclear grooves were present in 6 of our 8 cases and they were scant in the malignant cases. CONCLUSION: Imprint cytology of Brenner tumors provided no characteristic findings to enable a definitive distinction of benign versus borderline tumors, but it enabled discrimination between malignant and other tumors. Imprint cytology can facilitate intraoperative diagnosis and aid in selecting the appropriate surgical procedure.

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