Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

Ex vivo chemosensitivity assay using primary ovarian cancer organoids for predicting clinical response and screening effective drugs.

Selecting the best treatment for individual patients with cancer has attracted attention for improving clinical outcomes. Recent progress in organoid culture may lead to the development of personalized medicine. Unlike molecular-targeting drugs, there are no predictive methods for patient response to standard chemotherapies for ovarian cancer. We prepared organoids using the cancer tissue-originated spheroid (CTOS) method from 61 patients with ovarian cancer with 100% success rate. Chemosensitivity assays for paclitaxel and carboplatin were performed with 84% success rate using the primary organoids from 50 patients who received the chemotherapy. A wide range of sensitivities was observed among organoids for both drugs. All four clinically resistant organoids were resistant to both drugs in 18 cases in which clinical response information was available. Five out of 18 cases (28%) were double-resistant, the response rate of which was compatible with the clinical remission rate. Carboplatin was significantly more sensitive in serous than in clear cell subtypes (P = 0.025). We generated two lines of organoids, screened 1135 drugs, and found several drugs with better combinatory effects with carboplatin than with paclitaxel. Some drugs, including afatinib, have shown an additive effect with carboplatin. The organoid sensitivity assay did not predict the clinical outcomes, both progression free and overall survival.

Heterogenous chemosensitivity of a panel of organoid lines derived from small cell neuroendocrine carcinoma of the uterine cervix.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare disease with a poor prognosis. The lack of established disease models has hampered therapy development. We generated a panel of cancer tissue-originated spheroid (CTOS) lines derived from SCNEC of the uterine cervix using a method based upon cell-cell contact throughout the preparation and culturing processes. Using 11 CTOS lines, we assessed the sensitivity of various drugs used in clinical practice. Drug sensitivity assays revealed significant heterogeneous inter-CTOS chemosensitivity. Microarray analyses were then performed to identify sensitivity-related gene signatures. Specific gene sets were identified which likely contribute to the sensitivity to the tested drugs. We identified a line (Cerv54) that was exceptionally sensitive to irinotecan. Cerv54 had increased levels of CES1, which catalyzes the conversion of irinotecan to the active form, SN38, although in Cerv54 cells, SN38 was undetectable, CES1 expression and activity were markedly low compared to the liver, and a CES1 inhibitor had no effect on irinotecan sensitivity. These results suggested a novel irinotecan mode of action in Cerv54. Our CTOS lines may be useful for understanding the variation and mechanism of drug sensitivity, contributing to the understanding and development of chemotherapeutic drugs.

The Evaluation of Laparoscopic Surgery on Pregnant Patients with Ovarian Cysts and Its Effects on Pregnancy over the Past 5 Years.

STUDY OBJECTIVE: Study Objective: In this research paper, we demonstrate how to increase the success rate of laparoscopic surgery on pregnant patients with an ovarian cyst using rectal probe, SAND balloon, and lowering the insufficient level. DESIGN: The study design wasa retrospective study. SETTING: The study was conducted at Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan. PATIENTS: Pregnant patients with an ovarian cyst who underwent laparoscopic surgeries at our institution during the period from January 2011 to December 2016. MATERIALS AND METHODS: We reviewed 14 cases of pregnant women with ovarian cysts that underwent laparoscopic surgery during the study period by observing and analyzing the patient's characteristics, hospitalization practices, surgical complications, operational procedures, and obstetric outcomes. MAIN RESULTS: Three cases were emergency surgeries and 11 cases were elective surgeries. In the 14 cases, the gestational age at the time of the surgeries ranged from 6 to 20 weeks. In our studies, we found no systemic complications after the surgery and none of the cases reported any fetal malformation or any fetal growth restriction. CONCLUSION: In our review, laparoscopic surgery for ovarian cyst during pregnancy was very safe and successful, without any adverse effects on pregnancy outcome.

Transient elevations of liver enzymes and ovarian vein thrombosis arising after total laparoscopic hysterectomy.

Ovarian vein thrombosis in non-pregnant patient is a rare clinical entity. Among 170 patients who underwent total laparoscopic hysterectomy (TLH) in our hospital from December 2011 to December 2015, we have one case of ovarian vein thrombosis (0.0059%). A 42-year-oId woman had a fever of 39 °C on the fourth day after TLH. A blood test revealed elevations of liver enzymes and D-dimer (AST 1157 U/L, ALT 942 U/L and D-dimer >30 µg/L). Computed tomography (CT) scan with intravenous contrast agent demonstrated right ovarian vein thrombosis which caused decline in blood flow to liver and acute liver dysfunction. Low-molecular weight heparin was initiated and liver enzymes reduced rapidly. On the seventeenth day after TLH, CT scan revealed a recanalization of the ovarian vein. We report the clinical outcomes of the case attempted with a small review of the literature.