Clinical efficacy of ovarian cancer screening

Various trials of ovarian cancer screening programs have been reported worldwide. In 2011, one of the most famous papers indicated that annual screening using CA125/transvaginal sonography (TVS) did not reduce ovarian cancer mortality in the United States of America (USA). To investigate the validity of ovarian cancer screening, we verified the analyses of previous reports. At first, we obtained the USA datasets that were used for the analyses and identified many patients in whom cancers were accidentally detected several years after the screening period. We thus performed a new prognostic comparison between the screening group (cancers that were detected through screening or within one year after screening) and the control group (cancers that were found more than one year after screening, without screening, or in the original control group). The results showed that the prognoses of the screening group were significantly better than those of the control group (p=0.0017). In addition, the screening group contained significantly fewer stage IV cases than the control group (p=0.005). In another screening in the United Kingdom, ovarian cancer was detected at a relatively earlier stage (stage I/II: 44%), while the rate of stage IV detection was low (4%). Very recently, this team showed significant difference in the rates with and without screening (p=0.021) when prevalent cases were excluded and indicated the delayed effect of screening. These results contrasted with the USA data. In other studies in the USA and Japan, annual screening was also associated with a decreased stage at detection. New histopathological, molecular and genetic studies have recently provided two categories of ovarian carcinogenesis. Type I carcinomas are slow-growing neoplasms that often develop from benign ovarian cysts. Type II carcinomas are high-grade clinically aggressive neoplasms. The rate of type II carcinomas is significantly higher in Europe and the USA than in Asia (p < 0.001). Conversely, type I carcinomas are relatively common in Asia. These data theoretically imply that annual screening would be more effective in Asia

Subtypes of Ovarian Cancer and Ovarian Cancer Screening

Ovarian cancer is the foremost cause of gynecological cancer death in the developed world, as it is usually diagnosed at an advanced stage. In this paper we discuss current issues, the efficacy and problems associated with ovarian cancer screening, and compare the characteristics of ovarian cancer subtypes. There are two types of ovarian cancer: Type I carcinomas, which are slow-growing, indolent neoplasms thought to arise from a precursor lesion, which are relatively common in Asia; and Type II carcinomas, which are clinically aggressive neoplasms that can develop de novo from serous tubal intraepithelial carcinomas (STIC) and/or ovarian surface epithelium and are common in Europe and the USA. One of the most famous studies on the subject reported that annual screening using CA125/transvaginal sonography (TVS) did not reduce the ovarian cancer mortality rate in the USA. In contrast, a recent study in the UK showed an overall average mortality reduction of 20% in the screening group. Another two studies further reported that the screening was associated with decreased stage at detection. Theoretically, annual screening using CA125/TVS could easily detect precursor lesions and could be more effective in Asia than in Europe and the USA. The detection of Type II ovarian carcinoma at an early stage remains an unresolved issue. The resolving power of CA125 or TVS screening alone is unlikely to be successful at resolving STICs. Biomarkers for the early detection of Type II carcinomas such as STICs need to be developed

Ovarian clear cell carcinoma meets metabolism; HNF-1β confers survival benefits through the Warburg effect and ROS reduction.

Ovarian clear cell carcinoma (OCCC) constitutes one of the subtypes of ovarian cancers, but it has unique clinical, histological and biological characteristics, one of which is chemo-resistance. It is also known to develop from endometriotic cyst, a benign ovarian tumor, at relatively high frequency. Recently, it is becoming well known that most of OCCCs express HNF1β, a transcription factor, which is closely associated with the development of liver, pancreas and kidney, as well as occurrence of familial forms of type 2 diabetes. Expression of HNF1β is now regarded as a hallmark of this tumor. Nevertheless, exact biological function of this gene in OCCC has not been clarified. We have shown in previous studies that microenvironment in endometriotic cysts contains severe oxidative stress and OCCC develops under such stressful environment as stress-resistant tumor, which may lead to chemo-resistance. We also showed that increased expression of HNF1β facilitates glucose uptake and glycolysis, which is known as Warburg effect. In the previous issue of this journal, by using comprehensive metabolome analysis, we report that HNF1β actually reduces and protects themselves from internal oxidative stress by dramatically changing cellular metabolism. In this article, we review the relevance and significance of cancer-specific metabolism and how they are associated with biological characteristics of OCCC via expression of HNF1β, along with future clinical implications of targeting cancer-specific metabolism

Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

卵巣がんに対する分子標的薬「ベバシズマブ」の効果を解析 投与終了後に悪化リスクが高まることを確認、最適な投与法を提案. 京都大学プレスリリース. 2023-08-03.[Importance] Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown. [Objective] To investigate time-dependent changes in the outcomes of bevacizumab therapy. [Design, Setting, and Participants] This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed. [Exposures] Bevacizumab treatment vs placebo or no treatment. [Main Outcomes and Measures] Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups. [Results] In the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P < .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P < .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P < .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P < .001; after, 0.71; 95% CI, 0.56-0.90; P < .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P < .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image–based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination–associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression. [Conclusions and Relevance] In ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome

〈Case Reports〉HELLP syndrome at 22 weeks of gestation with resulting stillbirth and a favorable outcome in a subsequent pregnancy: A case report

[Abstract]HELLP syndrome, characterized by hemolysis,elevated liver enzymes, and low platelets,is one of the diseases related to hypertension in pregnancy. If the pregnancy is not terminated soon after HELLP is diagnosed, liver failure or disseminated intravascular coagulopathy (DIC)may occur. HELLP syndrome occurs in 0.2%–0.9% of all pregnancies; Onset before 24 weeks of gestation is extremely rare but is more likely to result in stillbirth. Women who have had a stillbirth often hope for another pregnancy soon after,but there is little information about the risks and outcomes for subsequent pregnancy in women who developed HELLP syndrome in early pregnancy.Thus, it is important to accumulate data on these outcomes in this population. Here, we report a case in which severe HELLP syndrome developed at 22 weeks of gestation, resulting in stillbirth, and was followed six months later by a pregnancy that with early intervention, produced a live birth

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

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, though 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

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC

Effectiveness of adjuvant systemic chemotherapy for intermediate-risk stage IB cervical cancer

Objective: To examine the effectiveness of systemic chemotherapy following radical hysterectomy for women with intermediate-risk stage IB cervical cancer.Materials and Methods: This is a retrospective analysis of a previously organized nation-wide cohort study examining 6,003 women with stage IB-IIB cervical cancer who underwent radical hysterectomy between 2004 and 2008 in Japan. Survival of 555 women with stage IB cervical cancer in the intermediate-risk group (deep stromal invasion > 50%, large tumor size > 4 cm, and lympho-vascular space invasion [LVSI]) were examined based on adjuvant therapy patterns: chemotherapy alone (n = 223, 40.2%), concurrent chemo-radiotherapy (n = 172, 31.0%), and radiotherapy alone (n = 160, 28.8%).Results: The most common intermediate-risk pattern was LVSI with deep stromal invasion (n = 216, 38.5%). The most common chemotherapeutic choice was taxane/platinum (52.2%). Women with adenocarcinoma/adenosquamous histology were more likely to receive chemotherapy (P = 0.03), and intermediate-risk pattern was not associated with chemotherapy use (P = 0.11). Women who received systemic chemotherapy had disease-free survival (5-year rate, 88.1% versus 90.2%, adjusted-hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.52–1.83, P = 0.94) and cause-specific survival (95.4% versus 94.8%, adjusted-HR 0.85, 95% CI 0.34–2.07, P = 0.71) similar to those who received concurrent chemo-radiotherapy on multivariable analysis. Similar results were seen among 329 women with multiple intermediate-risk factors (5-year rates for disease-free survival, chemotherapy versus concurrent chemo-radiotherapy, 87.1% versus 90.2%, P = 0.86; and cause-specific survival 94.6% versus 93.4%, P = 0.82). Cumulative local-recurrence (P = 0.77) and distant-recurrence (P = 0.94) risks were similar across the adjuvant therapy types.Conclusions: Our study suggests that systemic chemotherapy may be an alternative treatment choice for adjuvant therapy in intermediate-risk stage IB cervical cancer

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

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

Suppression of ABHD2, identified through a functional genomics screen, causes anoikis resistance, chemoresistance and poor prognosis in ovarian cancer

Anoikis resistance is a hallmark of cancer, and relates to malignant phenotypes, including chemoresistance, cancer stem like phenotypes and dissemination. The aim of this study was to identify key factors contributing to anoikis resistance in ovarian cancer using a functional genomics screen. A library of 81 000 shRNAs targeting 15 000 genes was transduced into OVCA420 cells, followed by incubation in soft agar and colony selection. We found shRNAs directed to ABHD2, ELAC2 and CYB5R3 caused reproducible anoikis resistance. These three genes are deleted in many serous ovarian cancers according to The Cancer Genome Atlas data. Suppression of ABHD2 in OVCA420 cells increased phosphorylated p38 and ERK, platinum resistance, and side population cells (p<0.01, respectively). Conversely, overexpression of ABHD2 decreased resistance to anoikis (p<0.05) and the amount of phosphorylated p38 and ERK in OVCA420 and SKOV3 cells. In clinical serous ovarian cancer specimens, low expression of ABHD2 was associated with platinum resistance and poor prognosis (p<0.05, respectively). In conclusion, we found three novel genes relevant to anoikis resistance in ovarian cancer using a functional genomics screen. Suppression of ABHD2 may promote a malignant phenotype and poor prognosis for women with serous ovarian cancer