Circulating tumor cells help differentiate benign ovarian lesions from cancer before surgery: A literature review and proof of concept study using flow cytometry with fluorescence imaging.

Current tools are insufficient for distinguishing patients with ovarian cancer from those with benign ovarian lesions before extensive surgery. The present study utilized a readily accessible platform employing a negative selection strategy, followed by flow cytometry, to enumerate circulating tumor cells (CTCs) in patients with ovarian cancer. These counts were compared with those from patients with benign ovarian lesions. CTC counts at baseline, before and after anticancer therapy, and across various clinical scenarios involving ovarian lesions were assessed. A negative-selection protocol we proposed was applied to patients with suspected ovarian cancer and prospectively utilized in those subsequently confirmed to have malignancy. The protocol was implemented before anticancer therapy and at months 3, 6, 9 and 12 post-treatment. A cut-off value for CTC number at 4.75 cells/ml was established to distinguish ovarian malignancy from benign lesions, with an area under the curve of 0.900 (P<0.001). In patients with ovarian cancer, multivariate Cox regression analysis revealed that baseline CTC counts and the decline in CTCs within the first three months post-therapy were significant predictors of prolonged progression-free survival. Additionally, baseline CTC counts independently prognosticated overall survival. CTC counts obtained with the proposed platform, used in the present study, suggest that pre-operative CTC testing may be able to differentiate between malignant and benign tumors. Moreover, CTC counts may indicate oncologic outcomes in patients with ovarian cancer who have undergone cancer therapies.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Hypoxia-associated genetic signature in ovarian steroid cell tumor NOS.

Steroid cell tumors, not otherwise specified (SCT-NOS), are uncommon ovarian neoplasms accompanied by virilization symptoms due to hyperandrogenism, which are malignant in approximately one-third of the cases. Given the rarity of SCT-NOS, their molecular underpinnings have not yet been studied in depth. In this case series, we performed the first comprehensive analysis of the genetic landscape of this rare ovarian tumor. A detailed clinicopathological description of an index case is also provided. Over a 20-year period, a total of eight patients were seen at our institution. Total nucleic acids (RNA and DNA) were extracted from evaluable formalin-fixed, paraffin-embedded tumor specimens (n = 7) and subjected to TruSight Oncology 500 testing and/or exome sequencing. The results identified pathogenic variants in several hypoxia-related genes - including HIF1A, VHL, SDHB, SRC, IDH2, and FOXO4. As the first comprehensive genetic analysis of SCT-NOS, this study shows that dysregulation in the hypoxia signaling pathway is a key molecular feature of this rare tumor. Clinically, long-term follow-up with periodic measurements of androgen levels should be pursued in all cases since recurrences may occur several years after the initial diagnosis.

Starvation-inactivated MTOR triggers cell migration via a ULK1-SH3PXD2A/TKS5-MMP14 pathway in ovarian carcinoma.

ABBREVIATIONS: AMPK: AMP-activated protein kinase; CHX: cycloheximide; RAD001: everolimus; HBSS: Hanks' balanced salt solution; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; MMP14: matrix metallopeptidase 14; MTOR: mechanistic target of rapamycin kinase; MAPK: mitogen-activated protein kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; PtdIns3P: phosphatidylinositol-3-phosphate; PX: phox homology; SH3: Src homology 3; SH3PXD2A/TKS5: SH3 and PX domains 2A; SH3PXD2A-[6A]: S112A S142A S146A S147A S175A S348A mutant; ULK1: unc-51 like autophagy activating kinase 1.

Mutations in circulating tumor DNA detected in the postoperative period predict poor survival in patients with ovarian cancer.

BACKGROUND: We investigated whether mutations in plasma circulating tumor DNA (ctDNA) can provide prognostic insight in patients with different histological types of ovarian carcinoma. We also examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding formalin-fixed paraffin-embedded (FFPE) tumor specimens. METHODS: Between July 2016 and December 2017, 29 patients with ovarian carcinoma were prospectively enrolled. FFPE tumor specimens were obtained from all participants. A total of 187 blood samples for ctDNA analysis were collected before surgery (C0), immediate after surgery before adjuvant chemotherapy (C1), and at six-month intervals. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. RESULTS: The study cohort consisted of 13 (44.8%) patients with high-grade serous carcinomas (HGSC), 9 (31.0%) with clear cell carcinoma, 2 (6.9%) with mucinous carcinomas, 4 (13.8%) with low-grade serous carcinomas, and 1 (3.4%) with endometrioid carcinoma. Twenty-four (82.8%) patients had at least one detectable ctDNA variant. The concordance rate between mutations identified in pretreatment ctDNA and corresponding FFPE tumor specimens was 92.3% for patients with HGSC and 58.6% for the entire cohort. The median follow-up time was 33.15 months (range: 0.79-46.13 months). Patients with an advanced stage disease more likely had detectable ctDNA mutations before surgery (C0) and after surgery at C1, while those with HGSC more likely had ctDNA mutations detected before surgery. The presence of ctDNA mutations at C1 was an independent predictor of worse OS with a hazard ratio of 6.56 (95% confidence interval, (1.07-40.17) for detectable versus undetectable C1 ctDNA variants, p = 0.042). CONCLUSIONS: ctDNA mutations are common in patients with ovarian carcinoma. The presence of ctDNA mutations after surgery was an independent predictor of less favorable PFS and OS.

Letrozole as premedication of high intensity focused ultrasound treatment of uterine fibroids: A retrospective observation study.

Background: No reports on Letrozole as a pretreatment before ablation of uterine fibroid with high intensity focused ultrasound (HIFU), so a retrospective observation study was performed to evaluate the response of different pre-HIFU medication. Methods: We collected patients with single uterine fibroid receiving HIFU ablation from January 2018 to April 2021. All enrolled patients were classified into three group: group A (no pre-HIFU medication use), group B (Pre-HIFU letrozole use), group C (pre-HIFU gonadotrophin releasing hormone analog, GnRHa). Further associated clinical data and treatment response after HIFU treatment were reviewed and evaluated. Results: A total of 39 patients including 21, 7, and 11 in group A, B, and C were collected respectively. After pre-HIFU medication, no difference of fibroid volume was found (A: 251.4, B: 360.6, C: 409.4 cm3, p = 0.250), and GnRHa group had significantly larger volume reduction than Letrozole users (38.6% vs. 16.4%, p = 0.007). The incidence of hypoestrogenic symptoms was higher in GnRHa group than in letrozole users (27.3% vs. 0, p = 0.170). GnRHa group had more sonication time (p = 0.001), treatment duration (p = 0.002), and ablated energy (p = 0.001) than group A and B. The treatment efficiency was higher in letrozole group than that in other 2 groups (4.52 vs. 2.39 vs. 2.34 cm3/min, p = 0.050). For patients with fibroid over 10 cm in diameter, letrozole group had even better energy efficiency (p = 0.067), treatment speed (p = 0.007), treatment efficiency (p = 0.001), NPV per energy (p = 0.005), and NPV per sonication (p = 0.004) than other 2 groups. Conclusion: Letrozole as a pretreatment medication before HIFU treatment might increase the energy efficiency and treatment efficiency of its ablation of uterine leiomyoma, especially for fibroid over 10 cm. Future study of larger patient number is needed to confirm our results.

Analysis of endometrial lavage microbiota reveals an increased relative abundance of the plastic-degrading bacteria Bacillus pseudofirmus and Stenotrophomonas rhizophila in women with endometrial cancer/endometrial hyperplasia.

The pathogenic influences of uterine bacteria on endometrial carcinogenesis remain unclear. The aim of this pilot study was to compare the microbiota composition of endometrial lavage samples obtained from women with either endometrial hyperplasia (EH) or endometrial cancer (EC) versus those with benign uterine conditions. We hypothesized that specific microbiota signatures would distinguish between the two groups, possibly leading to the identification of bacterial species associated with endometrial tumorigenesis. A total of 35 endometrial lavage specimens (EH, n = 18; EC, n = 7; metastatic EC, n = 2; benign endometrial lesions, n = 8) were collected from 32 women who had undergone office hysteroscopy. Microbiota composition was determined by sequencing the V3-V4 region of 16S rRNA genes and results were validated by real-time qPCR in 46 patients with EC/EH and 13 control women. Surprisingly, we found that Bacillus pseudofirmus and Stenotrophomonas rhizophila - two plastic-degrading bacterial species - were over-represented in endometrial lavage specimens collected from patients with EC/EH. Using computational analysis, we found that the functional profile of endometrial microbiota in EC/EH was associated with fatty acid and amino acid metabolism. In summary, our hypothesis-generating data indicate that the plastic-degrading bacteria Bacillus pseudofirmus and Stenotrophomonas rhizophila are over-represented within the endometrial lavage microbiota of women with EC/EH living in Taiwan. Whether this may be related to plastic pollution deserves further investigation.

Management and Prognosis of Patients with Recurrent or Persistent/Progressive Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a highly aggressive gynecologic malignancy. Recurrent or persistent/progressive disease is usually fatal. We aimed to investigate the management and prognosis of these patients. Clinical records of UCS patients from June 1987 to April 2020 were retrospectively reviewed. The stage was re-assigned with the FIGO 2009 staging system. Univariate and multivariate analyses were used to identify the independent predictors of survival after recurrence (SAR) and cancer-specific survival (CSS). Of the 168 patients, 98 experienced treatment failure. The median time to treatment failure (TTF) was 8.1 months (range: 0.0-89.1). The median follow-up time of censored patients was 32.0 months (range: 16.8-170.7). The 5-year SAR rates of those with recurrent or persistent/progressive disease were 7.6%. On multivariate analysis, salvage therapy mainly using radiotherapy (HR 0.27, 95% CI: 0.10-0.71) or chemotherapy (HR 0.41, 95% CI: 0.24-0.72) or chemoradiotherapy (CRT) (HR 0.33, 95% CI: 0.15-0.75) were associated with improved SAR, whereas disseminated recurrence was associated with significantly worse SAR (HR 3.94, 95% CI: 1.67-9.31, p = 0.002). Salvage therapy using radiotherapy or chemotherapy or CRT significantly improved SAR. Surgery significantly improved CSS but not SAR, adjusting for confounding factors.

Towards less invasive molecular diagnostics for endometrial cancer: massively parallel sequencing of endometrial lavage specimens in women attending for an office hysteroscopy.

We aimed to detect endometrial cancer (EC)-associated mutations in endometrial lavage specimens collected in an office setting and to compare the detected mutations with those identified in tissue samples. Participants included 16 women attending for an office hysteroscopy because of suspected EC between July 2020 and October 2021. Massively parallel sequencing was conducted using the targeted 72 cancer-associated genes. Endometrial lavage specimens, endometrial tissue samples, and blood samples were simultaneously sequenced to establish the concordance of genetic alterations. In this study, the vast majority of EC-associated mutations identified in lavage samples (R2 = 0.948) were identical to those detected in endometrial tissues. Of the 13 patients with EC, 12 (92.3%) had at least one mutation identified in endometrial lavage samples. Notably, no mutations in lavage samples were identified in the two patients with a previous history of EC but no actual endometrial lesions, supporting a high negative predictive value of the test. A patient previously diagnosed with EC and with current evidence of atypical hyperplasia showed persisting PTEN, PIK3R1, and KRAS mutations in her endometrial lavage specimen. PTEN was the most commonly mutated gene, followed by PIK3R1, ARID1A, PIK3CA, CTNNB1, and KRAS. In conclusions, our study provides pilot evidence on the actionability of uterine lavage samples sequencing to detect EC-associated mutations in women with suspected endometrial lesions. In a precision medicine framework, the high mutational concordance between uterine lavage samples and tissue specimens may help inform less invasive diagnostic protocols and the need for ongoing surveillance in patients with EC who wished for fertility-preserving treatment. KEY MESSAGES: • Sequencing of uterine lavage samples collected by office hysteroscopy is feasible. • Most EC mutations identified in lavage were identical to endometrial tissues. • Sequencing of uterine lavage samples may help inform diagnostic protocols for EC. • This approach can be used for recurrence surveillance in patients with EC.

MicroRNAs as Predictors of Future Uterine Malignancy in Endometrial Hyperplasia without Atypia.

The histological criteria for classifying endometrial hyperplasia (EH) are based on architectural crowding and nuclear atypia; however, diagnostic agreement among pathologists is poor. We investigated molecular biomarkers of endometrial cancer (EC) risk in women with simple hyperplasia or complex hyperplasia without atypia (SH/CH-nonA). Forty-nine patients with EC preceded by SH/CH-nonA were identified, of which 23 were excluded (15 with complex atypical hyperplasia (CAH), six not consenting, one with a diagnosis <6 months prior, and one lost to follow-up). The EH tissues of these patients were compared with those of patients with SH/CH-nonA that did not progress to EC (control) through microRNA (miRNA) array analysis, and the results were verified in an expanded cohort through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). MiRNA arrays analyses revealed 20 miRNAs that differed significantly (p < 0.05, fold change >4) between the control (n = 12) and case (n = 6) patients. Multiplex RT-qPCR for the 20 miRNAs in the expanded cohort (94 control and 25 case patients) led to the validation of miR-30a-3p (p = 0.0009), miR-141 (p < 0.0001), miR-200a (p < 0.0001), and miR-200b (p < 0.0001) as relevant biomarkers, among which miR-141, miR-200a, and miR-200b regulate the expression of phosphatase and tensin homolog (PTEN). For the prediction of EC, the area under the curve for miR-30a-3p, miR-141, miR-200a, and miR-200b was 0.623, 0.754, 0.783, and 0.704, respectively. The percentage of complete PTEN loss was significantly higher in the case group than in the control group (24% vs. 0%, p < 0.001, Fisher's exact test). A combination of complete PTEN loss and miR-200a provided optimal prediction performance (sensitivity = 0.760; specificity = 1.000; positive predictive value = 1.000; negative predictive value = 0.937; accuracy = 0.947). MiR-30a-3p, miR-141, miR-200a, miR-200b, and complete PTEN loss may be useful tissue biomarkers for predicting EC risk among patients with SH/CH-nonA.

Massively parallel sequencing of endometrial lavage specimens for the detection of cancer-associated mutations in atypical and non-atypical endometrial hyperplasia.

Background: Endometrial hyperplasia (EH), particularly with atypia, is considered an antecedent of endometrial adenocarcinoma. In this study, we aimed to apply massively parallel sequencing of endometrial lavage specimens for the detection of cancer-associated mutations in atypical (AEH) and non-atypical endometrial hyperplasia (NEH). The identified alterations were compared with those detected in tissue samples. Materials and methods: Endometrial lavage specimens and parallel biopsy samples (n = 11 for AEH and n = 9 for NEH) were obtained from 18 women (9 with AEH and 9 with NEH) who received an office hysteroscopy for suspected endometrial lesions. All samples were tested for somatic mutations in hotspot regions of 72 cancer-associated genes by massively parallel sequencing. Results: On analyzing sequencing data, the presence of at least one cancer-associated gene mutation was identified in 72.7 and 44.4% of endometrial lavage specimens obtained from women with AEH and NEH, respectively (p = 0.362, 95% confidence interval = 0.72-3.70). The concordance rates between mutations identified in endometrial lavage specimens and endometrial biopsies were 54.5 and 0% from women with AEH and NEH, respectively (p = 0.014). A patient with NEH harbored mutations in endometrial lavage with the same mutations found in the tissue specimen at low allele frequency below detection cutoff, raising the suspicion of missed focal atypia. Conclusion: Endometrial hyperplasia is characterized by a high burden of cancer-associated mutations, particularly in the presence of atypia. Our study, albeit performed with a relatively small number of samples, indicates that their detection by massively parallel sequencing of endometrial lavage is feasible. Our findings may allow tailoring of endometrial biopsies to the individual risk of AEH; additionally, they can pave the way toward less invasive surveillance protocols in patients with known EH.

Adjuvant and post-surgical treatment in endometrial cancer.

Endometrial cancer (EC) usually presented as a localized disease at diagnosis (67%), 20% of patients diagnosed with regional spread, and distant metastasis accounted for 9%. The standard treatments include hysterectomy, bilateral salpingo-oophorectomy, and pelvic with/without paraaortic lymph node dissection/biopsy. Adjuvant therapy is arranged according to risk factors and stages. Risk group classification varied among different guidelines and studies and evolved with time. Adjuvant modalities include chemotherapy, radiotherapy, chemoradiotherapy, antiangiogenesis agents, immune checkpoint inhibitors, and multi-target agents. We review the recent literature to incorporate important advances in trial results, real-world big data, and knowledge in biomarkers of EC to update appropriate adjuvant therapy and post-surgical treatment of EC patients.

Hyperthermic intraperitoneal chemotherapy for recurrent epithelial ovarian cancer.

BACKGROUND: To investigate outcomes and morbidity of patients undergoing secondary cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent ovarian cancer. MATERIALS AND METHODS: Between April 2014 and January 2019, a total of 51 recurrent ovarian cancer patients receiving secondary CRS and HIPEC were retrospectively reviewed. RESULTS: Among the 51 patients, median peritoneal cancer index score was 13 (range 3-34), and completeness of cytoreduction (CC) score of 0/1 was achieved in 41 patients (78.8%). Regimen of HIPEC included cisplatin and paclitaxel in 39 (75%) cases. The median follow-up duration of survivors was 20.2 months. Sixteen (30.8%) patients remained free of recurrence after HIPEC. The median progression-free survival (PFS) and overall survival (OS) were 11.8 months and 34.5 months respectively. Multivariate analysis showed previous chemotherapy <2 lines (HR 0.24, 0.11-0.52; p = 0.001), chemotherapy-free interval ≥6 months (HR 0.19, 0.09-0.37; p < 0.001) and CA125 < 35 U/mL before HIPEC (HR 0.133, 0.021-0.0832; p = 0.031) were good prognostic factors for PFS. CC0/1 was not significant in multivariate analysis. The most common grade 3/4 toxicity was anemia (17.3%), pleural effusion (11.5%) and renal insufficiency (5.7%). Patients with age ≥50, peritoneal carcinomatosis index (PCI) ≥ 11, operation time ≥10 h and diaphragm surgery had significantly higher incidence of pleural effusion. CONCLUSIONS: The current study showed adding HIPEC to secondary CRS might prolong PFS especially in patients with previous chemotherapy <2 lines, chemotherapy-free interval ≥6 months and CA125 < 35 U/mL before HIPEC.

Magnetic Resonance Spectroscopy for Risk Stratification of Sonographically Indeterminate Ovarian Neoplasms: Preliminary Study.

We aim to assess the additional value of diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) for the risk stratification of sonographically indeterminate ovarian neoplasms. A total of 21 patients with diagnosed adnexal masses between 2014 and 2017 were divided into malignant (four serous cystadenocarcinomas, four endometrioid carcinomas, three clear cell carcinomas, and one carcinosarcoma) and benign (four cystadenomas, two teratomas, one fibroma, one endometrioma, and one corpus luteal cyst) groups. An apparent diffusion coefficient (ADC) value of 1.27 × 10-3 mm2/s was considered as the optimal threshold in distinguishing malignant from benign ovarian tumors (sensitivity and specificity: 100% and 77.8%, respectively). Choline peaks were detected in six of seven O-RADS (Ovarian-Adnexal Imaging-Reporting Data System) 4 lesions and corrected all of the DWI false-negative clear cell carcinoma. Based on the presence of the choline peaks, the diagnostic performance of MRS showed a sensitivity of 77.8%, a specificity of 100%, and an accuracy of 85.7%, respectively. In conclusion, MRS could potentially play a complementary role for DWI in tumor characterization, particularly for O-RADS 4 tumors or clear cell carcinomas.

Adjuvant therapy and prognosis in uterine carcinosarcoma.

PURPOSE: To investigate the prognostic factors and impact of adjuvant treatment on uterine carcinosarcoma (UCS). METHODS: A retrospective review of UCS patients treated between 2005 and 2019 was conducted. International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system was used. Multivariate stepwise Cox proportional hazard regression models were used to identify the independent predictors of overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 138 patients were eligible for descriptive analysis. Excluding 12 patients without surgery, 126 patients with adequate clinicopathologic data were included for prognostic analysis. The median follow-up for survivors was 51.8 months. 5-year OS and PFS rates for FIGO stage I, II, III, IV were 64.5% and 51.8%, 60.8% and 57.7%, 47.7% and 45.9%, 5.1% and 4.1%, respectively. By multivariate analysis, six models each for PFS and OS were formulated including highly correlated variables alternatively. Adjuvant chemoradiation was consistently selected as an independent prognostic factor for OS (hazard ratio [HR] 0.10-0.22, all p < 0.001) and PFS (HR 0.12-0.23, all p < 0.001), while adjuvant chemotherapy (HR 0.33-0.41), age≥58 years (HR 1.80-1.91), stage III/IV (HR 3.36-13.34), and adnexal metastasis (HR 2.06-5.02) in three to four of the six models for OS. Stratified analyses revealed that adjuvant chemoradiation significantly improved outcome compared with adjuvant chemotherapy for stage IA patients with lymphovascular space invasion and stage IB-IV, lymph node metastasis, and adnexal metastasis. CONCLUSION: Adjuvant chemoradiation was confirmed as an independent good prognostic factor, while older age, stage III/IV, and adnexal metastasis were associated with poor outcome in UCS.

Postoperative adjuvant dose-dense chemotherapy with bevacizumab and maintenance bevacizumab after neoadjuvant chemotherapy for advanced ovarian cancer: A phase II AGOG/TGOG trial.

OBJECTIVE: The objective of this study is to evaluate the safety and efficacy of adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) for stage III/IV ovarian, tubal, and primary peritoneal cancer. STUDY DESIGN: This phase II clinical trial using Simon's minimax two-stage design was conducted. At the first stage, 13 subjects were enrolled, and the trial would proceed to second stage if ≤3 subjects discontinued treatment for study-defined significant adverse events (AEs). Patients with stage III/IV ovarian, tubal, and primary peritoneal cancer deemed not feasible for primary cytoreductive surgery were enrolled after 3-4 cycles of NAC and IDS without disease progression. NAC could be either weekly paclitaxel (80 mg/m2) (dose-dense) plus 3-weekly carboplatin (AUC5-6) or 3-weekly conventional schedule. After IDS, postoperative dose-dense adjuvant chemotherapy for 3 cycles at least (best to 6 cycles), and 3-weekly bevacizumab 15 mg/kg was given since postoperative cycle 2. Further 3-weekly maintenance bevacizumab 15 mg/kg was given intravenously for 17 cycles. RESULTS: Of the 22 enrolled subjects, 13 (59.1 %) had no gross lesion after IDS. Of the 13 subjects enrolled on the 1 st stage, one study-defined significant AE occurred, therefore the trial proceeded to the 2nd stage (n = 9). The median progression-free survival (PFS) was 22.1 months (95 % confidence interval [CI], 13.7-30.5), and the median overall survival (OS) was 49.2 months (95 % CI, 33.8-64.6). Peritoneal Cancer Index score at entering abdomen during IDS was significant for PFS (>12 vs ≤ 12: p = 0.003). One of the 22 subjects did not receive any study treatment. In the safety analysis (n = 21), grade 3/4 AEs included thrombocytopenia of 38.1 %, neutropenia 71.4 %, and anemia 28.6 %. Study-defined significant AEs of bowel perforation, poor-healing wound, and hypertension were found in 1 case each, respectively. CONCLUSION: This phase II trial demonstrated adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after NAC was feasible with tolerable toxicity and comparable PFS/OS as compared to other studies using bevacizumab in the NAC phase or dose-dense scheduling throughout.

Role of human papillomavirus status after conization for high-grade cervical intraepithelial neoplasia.

Human papillomavirus (HPV) is the well-established etiologic factor for cervical neoplasia. Cervical conization constitutes an effective treatment for high-grade cervical intraepithelial neoplasia (HG-CIN). We conducted an observational study for long-term outcomes and HPV genotype changes after conization for HG-CIN. Between 2008 and 2014, patients with newly diagnosed HG-CIN before conization (surveillance new [SN] group) and those who had undergone conization without hysterectomy (surveillance previous [SP] group) were enrolled. HPV testing and Pap smear were performed periodically for the SN and SP (collectively S) groups. All other patients receiving conization for HG-CIN during the study period were identified from our hospital database. Those eligible but not enrolled into our study were assigned to the non-surveillance (non-S) group. For the S group (n = 493), the median follow-up period was 74.3 months. Eighty-four cases had recurrent CIN Grade 2 or worse (CIN2+) (5-year cumulative rate: 14.8%), of which six had invasive cancer. Among the 84 patients, 65 (77.4%) exhibited type-specific persistence in the paired HPV results, whereas only 7 (8.3%) harbored new HPV types that belonged to the 9-valent vaccine types. Among the 7397 non-S patients, 789 demonstrated recurrent CIN2+, of which 57 had invasive cancer. The stages distribution of those progressed to invasive cancer in the non-S group were more advanced than the S group (P = .033). Active surveillance might reduce the severity of those progressed to cancer. Because a majority of the patients with recurrent CIN2+ had persistent type-specific HPV infections, effective therapeutic vaccines are an unmet medical need.

Synergistic effects of pazopanib and hyperthermia against uterine leiomyosarcoma growth mediated by downregulation of histone acetyltransferase 1.

Pazopanib-a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects-has shown promise in the treatment of soft-tissue sarcomas. Hyperthermia has been also applied as an adjunctive treatment to chemotherapy for these malignancies. Here, we show that pazopanib and hyperthermia act synergistically in inhibiting uterine leiomyosarcoma (LMS) cell growth. Compared with either treatment alone, the combination of pazopanib and hyperthermia exerted the highest antitumor activity in a xenograft model. Mechanistically, we found that combined treatment with pazopanib and hyperthermia inhibited histone acetyltransferase 1 (HAT1) expression in LMS cells. The Clock element on the HAT1 promoter was critical for pazopanib- and hyperthermia-induced HAT1 downregulation. Inhibition of HAT1-either by pazopanib and hyperthermia or through HAT1 silencing-was mediated by suppression of Clock. Accordingly, Clock protein reconstitution rescued both HAT1 levels and HAT1-mediated histone acetylation. Immunohistochemistry revealed a higher expression of HAT1 in uterine LMS than in leiomyomas (p = 0.007), with high HAT1 expression levels being associated with poor clinical outcomes (p = 0.007). We conclude that pazopanib and hyperthermia exert synergistic effects against LMS growth by inhibiting HAT1. Further preclinical studies on HAT1 as a potential drug target in uterine LMS are warranted, especially in combination with hyperthermia. KEY MESSAGES: Pazopanib and hyperthermia inhibit the growth of leiomyosarcoma. Their combined use inhibits HAT1 expression in leiomyosarcoma cells. The promoter Clock element is required for HAT1 downregulation. HAT1 expression is higher in leiomyosarcoma than in leiomyomas. An increased HAT1 expression is associated with poor clinical outcomes.

Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer.

OBJECTIVE: To analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review. MATERIALS AND METHODS: Patients accepted weekly paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan. RESULTS: Sixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3-10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3-40.5). The median time to response (TTR) was 29.0 days (range 19.6-38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2-34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%). Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed. CONCLUSION: This is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS.

BRCA1/2 mutation status in patients with metachronous breast and ovarian malignancies: clues towards the implementation of genetic counseling.

OBJECTIVE: The characteristics of patients with metachronous breast and ovarian malignancies and the pathogenic role of BRCA1/2 mutations remain poorly understood. We investigated these issues through a review of hospital records and nationwide Taiwanese registry data, followed by BRCA1/2 mutation analysis in hospital-based cases. METHODS: We retrospectively retrieved consecutive clinical records of Taiwanese patients who presented with these malignancies to our hospital between 2001 and 2017. We also collected information from the Data Science Center of the Taiwan Cancer Registry (TCR) between 2007 and 2015. Next-generation sequencing and multiplex ligation-dependent probe amplification were used to identify BRCA1/2 mutations and large genomic rearrangements, respectively. When BRCA1/2 mutations were identified in index cases, pedigrees were reconstructed and genetic testing was offered to family members. RESULTS: A total of 12,769 patients with breast cancer and 1,537 with ovarian cancer were retrieved from our hospital records. Of them, 28 had metachronous breast and ovarian malignancies. We also identified 113 cases from the TCR dataset. Eighteen hospital-based cases underwent BRCA1/2 sequencing and germline pathogenic mutations were detected in 7 patients (38.9%, 5 in BRCA1 and 2 in BRCA2). All BRCA1/2 mutation carriers had ovarian high-grade serous carcinomas. Of the 12 patients who were alive at the time of analysis, 5 were BRCA1/2 mutation carriers. All of them had family members with BRCA1/2-associated malignancies. CONCLUSIONS: Our results provide pilot evidence that BRCA1/2 mutations are common in Taiwanese patients with metachronous breast and ovarian malignancies, supporting the clinical utility of genetic counseling.