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Background: This study assesses the feasibility of minimally invasive surgery (MIS) for well-selected epithelial ovarian cancer (EOC) patients. Methods: We performed a review of data prospectively collected from a single center from 2017 to 2022. Only patients with histologically confirmed EOC, with a tumor diameter of less than 10 cm, were eligible. We also performed a meta-analysis of similar studies comparing the outcomes of laparoscopy and laparotomy. We used MINORS (Methodological Index for Non-Randomized Studies) to assess the risk of bias and calculated the odds ratio or mean difference. Results: Eighteen patients were included; 13 in re-staging group, four in PDS group, and one in IDS group. All achieved complete cytoreduction. One case was converted to laparotomy. The median number of removed pelvic lymph nodes was 25 (range 16–34), and 32 (range 19–44) for para-aortic nodes. There were two (15.4%) intraoperative urinary tract injuries. The median follow-up was 35 months (range 1–53). Recurrence was observed in one case (7.7%). Thirteen articles for early-stage ovarian cancer were included in our meta-analysis. Analysis of the pooled results found that MIS had a higher frequency of spillage (OR, 2.15; 95% CI 1.27–3.64). No differences were observed in recurrence, complications, or up-staging. Conclusions: Our experience supports the possibility of conducting MIS for EOC in well-selected patients. Except for spillage, our meta-analysis findings are consistent with previous reports, the majority of which were also retrospective. Ultimately, randomized clinical trials will be needed to authenticate the safety. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was to evaluate, using definitive diagnostic criteria, the incidence of lymphocyst formation following pelvic lymphadenectomy for gynecological cancer, and to compare rates between the approaches of laparoscopy and laparotomy. Methods: We retrospectively reviewed the medical records of all patients who underwent pelvic lymphadenectomy for cervical or endometrial cancer between March of 2010 and March of 2016. We defined a lymphocyst as a circumscribed collection of fluid within the pelvic cavity, with a diameter of 2 cm or more, as diagnosed with ultrasound or computed tomography. Results: During the six-year observational period, a pelvic lymphadenectomy was conducted in 196 women with clinical stage I uterine cancer; 90 cases underwent laparoscopy, 106 underwent laparotomy. The minimally invasive laparoscopic group had a lower estimated blood loss (p < 0.01), shorter hospital stay (p < 0.01). Lymphocysts were observed in 14.4% (13/90) of the laparoscopy cases, and in 15.1% (16/106) of the laparotomy cases which means no significant difference of lymphocyst (p = 1.00). The median size of symptomatic lymphocyst was significantly larger in laparotomy group than in laparoscopy group (4.8 cm v.s. 2.8 cm, median) (p = 0.04). Symptomatic lymphocysts were more common in laparotomy [7/90 (7.8%) vs 14/106 (13.2%) (p = 0.253)]. Conclusions: In a retrospective analysis with a strict diagnostic criteria, we could find no statistical difference in lymphocyst occurrence between laparoscopy and laparotomy. The median size of the lymphocyst was bigger and lymphocyst was likely to be symptomatic in the laparotomy group. [ABSTRACT FROM AUTHOR]

We investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSC) in the induction of cancer stem-like cells (CSC) and programmed death ligand 1 (PD-L1) expression in ovarian cancer. CSC were defined as tumor cells expressing high levels of aldehyde dehydrogenase 1 (ALDH 1). We inoculated G-CSF-expressing or Mock-expressing ovarian cancer cells into mice, and the frequencies of MDSC and CSC in tumors of these models were compared by flow cytometry. To directly demonstrate the role of MDSC in the induction of CSC and the increase in PD-L1 expression, we performed in vitro co-culture. MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression. [ABSTRACT FROM AUTHOR]

Summary: Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin on cervical cancer with a special focus on its effects on cancer stem cells (CSCs). Methods Using two cervical cell lines (ME180 and CaSki cells), the antitumor effects of lurbinectedin were assessed in vitro using the MTS assay and colony formation assay. The growth inhibitory effects of paclitaxel and cisplatin were also evaluated as controls. By employing ALDH1 activity as a marker of CSCs, the antitumor effects of lurbinectedin on cervical CSCs and non-CSCs were individually evaluated. Finally, we investigated the mechanisms by which lurbinectedin eliminated cervical CSCs. Results Lurbinectedin had significant antitumor activity toward cervical cancer cells at low nanomolar concentrations in vitro. Mouse xenografts of cervical cancer revealed that lurbinectedin significantly inhibits tumor growth. The growth-inhibitory effect of lurbinectedin was greater than that of cisplatin and paclitaxel. ALDH-high CSCs were observed in both cervical cancer cell lines (4.4% and 2.4% in ME180 and CaSki cells, respectively). Lurbinectedin downregulated stem cell-related gene expression (Oct4, Nanog, and SOX2), inhibited HDAC1 activity, and effectively eliminated ALDH-high CSCs. Conclusions Lurbinectedin is highly effective on uterine cervical cancer because it eliminates CSCs, and lurbinectedin is a promising agent to overcome platinum resistance in cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose: Development of new treatment strategies for endometrial cancer that has become refractory or resistant to taxane/platinum is a critical need. The present study was a phase I/II study of gemcitabine, levofolinate, irinotecan, and 5-fluorouracil (5-FU) (GLIF) combination chemotherapy to determine optimal dosages, safety, and efficacy.Methods: Taxane/platinum-resistant or -refractory endometrial disease was defined as tumor progression within 6 months after a taxane/platinum-based regimen. Maximum tolerated dose was investigated by a 3 + 3-designed phase I study. The phase II study was conducted using the recommended doses determined in the phase I study.Results: The dosages recommended for the phase II trial were determined, in the phase I trial, to be: gemcitabine 800 mg/m2, levofolinate 100 mg/m2, irinotecan 80 mg/m2, and 5-FU 1000 mg/m2. Thirty patients were enrolled, including the three patients who received GLIF therapy at the same dose as the recommended phase II dose in the phase I study. Two patients were excluded at this point due to study protocol violations, and the remaining 28 patients were included for analysis. Phase II revealed that the response and disease control rates were 7.1% (2/28) and 39.3% (11/28), respectively, and that the median PFS and OS were 3 months [95% confidence interval (CI) 3-7] and 12 months (95% CI 9-17), respectively. Febrile or grade 4 neutropenia was observed in 14% (4/28) of the cases. Grade 3 or 4 thrombocytopenia was not observed.Conclusion: We found that GLIF combination chemotherapy is potentially a useful treatment option for endometrial cancers refractory or resistant to taxane/platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.Methods: Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m2, respectively; level 2: 100 and 1000 mg/m2) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.Results: A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m2 irinotecan and 1000 mg/m2 gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1-6.0 months) and 17.4 months (95% CI 9.9-21.9 months), respectively, while the 1-year survival rate was 58.6%.Conclusions: Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study is to identify the risk factors associated with recurrent/persistent disease and cervical stenosis after conization. Methods: Five hundred twenty-two (522) cases of high-grade intraepithelial lesions treated by conization were retrospectively reviewed. Risk factors associated with recurrent/persistent disease were analyzed by univariate and multivariate analysis using a Cox hazard regression model. Factors that could potentially affect the risk of cervical stenosis were examined by univariate and by multivariate analysis using the χ test and logistic regression, respectively. Results: Recurrent/persistent diseases and cervical stenosis occurred in 4.8% and 5.4% of the patients, respectively. Age ≥46 years [hazard ratio (HR) 3.6, 95% CI 1.36-10.3, p = 0.0092] and surgical margin involvement (HR 13.44, 95% CI 5.07-46.37, p < 0.001) were independent predictors for recurrent/persistent diseases. Age ≥46 years [odds ratio (OR) 4.27, 95% CI 1.88-10.07, p < 0.001] and shortened interval after childbirth to conization (within 12 months) (OR 5.42, 95% CI 1.42-17.41, p = 0.016) were independent risk factors for cervical stenosis. Conclusion: Elderly patients (aged ≥46 years) are at high risk of recurrence and cervical stenosis, which may lead to unsatisfactory follow-up. Subsequent hysterectomy is beneficial to patients aged 46 or older with surgical margin involvement. Clinicians should recognize the possibility of cervical stenosis after conization during the breastfeeding period, leading to secondary infertility or hematometra. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the significance of lymphatic space invasion (LSI) and tumor VEGF-C expression in the lymphatic spread of ovarian cancer. By performing immunostaining using human ovarian cancer specimens, we first investigated the association between the extent of LSI and tumor VEGF-C expression, tumor lymphangiogenesis, or the lymphatic metastasis. Moreover, by performing in vitro and in vivo experiments, we elucidated the role of VEGF-C in tumor lymphangiogenesis and lymph node metastasis as well as its role as a therapeutic target in ovarian cancer. The presence of LSI was associated with lymph node metastasis in patients with ovarian cancer. VEGF-C overexpression was significantly associated with the increased LSI and LVD in ovarian cancer. VEGF-C stimulated the lymphangiogenesis in vitro, induced the new lymph vessel formation, and increased the lymph node metastasis in mice models of ovarian cancer. The attenuation of VEGF-C expression by the treatment with mTORC1 inhibitor significantly inhibited lymphangiogenesis, and decreased lymph node metastasis in mice models of ovarian cancer. The presence of LSI is an indicator of nodal metastasis and is associated with higher tumor VEGF-C expression and worse clinical outcome of ovarian cancer patients. VEGF-C plays a crucial role in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer. [ABSTRACT FROM AUTHOR]

Purpose: We retrospectively analyzed oncologic and reproductive outcomes of fertility-seeking premenopausal women with complex atypical hyperplasia (CAH) or Grade 1 endometrial adenocarcinoma (G1EA) who underwent medical management with high-dose medroxyprogesterone acetate (MPA) therapy. Methods: Patients were given a dose of 400-600 mg of MPA orally on a daily basis. They had histologically confirmed CAH or G1EA at presumed stage IA and wished to preserve fertility. Endometrial tissue sampling was carried out by dilation and curettage before and after the treatment and the pathologic response to MPA treatment was assessed. Results: A total of 27 premenopausal patients received MPA therapy. The median follow-up time was 39.2 months (3.4-153.8 months). Complete response was achieved in 81.8 % (9/11) of CAH cases and 68.8 % (11/16) of G1EA. Although no recurrences were found in CAH patients, nine G1EA patients (81.8 %) eventually recurred and underwent total hysterectomy. Neither therapeutic death nor irreversible toxicities were observed during the follow-up periods. Five patients (4 CAH and 1 G1EA) became pregnant and had nine live births. Conclusion: The high efficacy of fertility-sparing treatment with MPA was shown demonstrated. MPA therapy can be considered acceptable for the purpose of enabling patients to preserve their fertility. However, the rate of recurrence was high in patients with G1EA. Even in responders, close follow-up is required and a total hysterectomy needs to be considered without delay. Patients should be aware of the risks and limitations of this conservative treatment. [ABSTRACT FROM AUTHOR]

CD95 (also called Fas and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant, raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers and many cancer cells express large quantities of CD95 and are highly sensitive to CD95-mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L. These data raise the possibility that CD95 could actually promote the growth of tumours through its non-apoptotic activities. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and Jun. These results demonstrate that CD95 has a growth-promoting role during tumorigenesis and indicate that efforts to inhibit its activity rather than to enhance it should be considered during cancer therapy. [ABSTRACT FROM AUTHOR]

Paclitaxel resistance is a critical challenge in ovarian cancer treatment. This study aimed to identify microRNAs (miRNAs) that modulate paclitaxel resistance for use as potential therapeutic targets in such settings. Paclitaxel-resistant cell lines were established using two ovarian cancer cell lines: SKOV3ip1 and HeyA8. The evaluation of miRNA polymerase chain reaction (PCR) arrays indicated that the expression of miR-522-3p was downregulated in paclitaxel-resistant cells. The restoration of miR-522-3p sensitized the resistant cells to paclitaxel, and its downregulation desensitized the parental cells. Using PCR arrays, we focused on E2F2, with the luciferase reporter assay revealing that it was a direct target for miR-522-3p. The paclitaxel-resistant cells showed stronger E2F2 expression than the parental cells, while E2F2 inhibition sensitized the resistant cells to paclitaxel. Forced E2F2 expression in the parental cells led to the acquisition of paclitaxel resistance, while miR-522-3p inhibited E2F2 expression and was associated with retinoblastoma protein phosphorylation attenuation, which resulted in G0/G1 arrest. The effects of miR-522-3p and E2F2 in ovarian cancer were examined using public databases, revealing that low miR-522-3p expression and high E2F2 expression were associated with significantly poorer overall survival. In conclusion, miR-522-3p attenuated the degree of paclitaxel resistance in vitro through the downregulation of E2F2; miR-522-3p supplementation may be a therapeutic target for paclitaxel-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Hormone replacement therapy (HRT) is effective treatment for postmenopausal bone loss and osteoporosis. However, postmenopausal women with low bone mass fail to respond after a few years of HRT and some postmenopausal women show no bone response to HRT. In these cases, additive therapy is necessary. Bisphosphonates are highly effective in postmenopausal osteoporosis. We investigated the effects of adding etidronate, a bisphosphonate, to HRT. The addition of etidronate to HRT improved bone density (4.40±1.12% increase per year) in patients showing no increase or even a decrease after at least 1 year of HRT (5.39±2.40% decrease per year). [ABSTRACT FROM AUTHOR]

A correction to the article to the receptor protein CD95 that promotes tumor growth that was published in a previous 2012 issue is presented.

A correction to the article "CD95 promotes tomour growth" that was published in the 2010 issue is presented.