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Simple Summary Ovarian clear cell carcinoma (CCC) exhibits unique characteristics, including slow growth, glycogen accumulation in the cytoplasm, and poor prognosis for stress resistance. Several molecular targeting agents have failed to treat ovarian CCC. Recent reports have identified metabolic alterations through HNF1B, which is highly expressed in ovarian CCC. The Warburg effect, GSH synthesis, and mitochondrial regulation occur in CCC. The metabolic behaviors of ovarian CCC resemble the evolution of life to survive in stressful environments. Understanding the fundamental biology of ovarian CCC might help in the development of novel therapeutic strategies. Abstract Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in AT-rich interacting domain-containing protein 1A and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit alpha genes may contribute to the carcinogenesis of ovarian CCC, whereas hepatocyte nuclear factor-1-beta (HNF1B) plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments.

Background We examined the efficacy and safety of neoadjuvant chemotherapy (NAC) with the CPT-11 + CDDP regimen in combination with radical hysterectomy. Subjects and methods The subjects were 42 patients with stages IB2 to IIIB squamous cell carcinoma of the uterine cervix with a bulky mass. CDDP at 70 mg/m2 was intravenously administered on day 1 and CPT-11 at 70 mg/m2 was intravenously administered on days 1 and 8 of a 21-day cycle. In principle, two cycles were administered followed by radical hysterectomy. We examined antitumor efficacy, adverse events, completion rate of radical hysterectomy, operative time, surgical blood loss, progression-free survival (PFS), and overall survival (OS). Results The antitumor effect was complete response in 7 patients, partial response in 28, stable disease in 6, and progressive disease in 1; the response rate was 83.3 % (95 % confidence interval, 68.6–93.0). Grade 3 or more severe neutropenia, anemia, and platelet count decreases were noted in 23 (54.8 %), 4 (9.5 %), and 1 (2.4 %) patient, respectively. Grade 3 nausea occurred in 3 patients (7.1 %), vomiting in 1 (2.4 %), and grade 3 febrile neutropenia in 2 (7.1 %). The completion rate of radical hysterectomy was 88.1 %. The median operative time and surgical blood loss were 260 min (range, 210–334) and 500 ml (range, 393–898), respectively. The 5-year PFS rate was 67.2 %, and the 5-year OS rate was 68.0 %. In multivariate analysis, lymph node metastasis before NAC [hazard ratio (HR), 34.88] and non-response to NAC (HR 30.58) were significant prognostic factors. Conclusion NAC with the CDDP/CPT-11 regimen achieves a high antitumor efficacy with moderate adverse reactions, allowing safe radical hysterectomy, and is thus considered to be a useful therapeutic method that can improve prognosis.