Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H.

Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.

Effectiveness of human papillomavirus vaccine against cervical precancer in Japan: Multivariate analyses adjusted for sexual activity.

Japanese girls aged 12-16 years are offered free human papillomavirus (HPV) vaccination and cervical cancer screening is conducted with cytology and not HPV testing from the age of 20 years. So far, no study has analyzed the effect of HPV vaccination against cervical precancers considering HPV infection status and sexual activity. We aimed to analyze the vaccine effectiveness (VE) against HPV infection and cytological abnormalities, adjusted for sexual activity. This study comprised women aged 20-26 years who underwent cervical screening in Niigata. We obtained HPV vaccination status from municipal records and a questionnaire along with information concerning sexual activity. Of 5194 women registered for this study, final analyses included 3167 women in the vaccinated group (2821 vaccinated women prior to sexual debut) and 1386 women in the unvaccinated group. HPV 16/18 (0.2% vs 3.5%), 31/45/52 (3.4% vs 6.6%), and 31/33/45/52/58 (5.0% vs 9.3%) positive rates were significantly lower in the vaccinated group (P < 0.001). No women vaccinated before sexual debut had HPV 16/18-related cytological abnormalities. VE for HPV 16/18 infection and high-grade cytological abnormalities in women vaccinated prior to sexual debut were 95.8% (95% CI 81.9-99.0%; P < 0.001) and 78.3% (95% CI 11.3-94.7%; P = 0.033), respectively, in multivariate analyses adjusted for age and number of sexual partners. However, analyses of all vaccinated women did not show significant effectiveness against cytological abnormalities. Our results showed the effectiveness of HPV vaccine against high-grade cervical cytological abnormalities and the importance of the vaccination before sexual debut.

Long-term effectiveness of HPV vaccination against HPV infection in young Japanese women: Real-world data.

In Japan, public funding for HPV vaccination began in 2010 for girls aged 13-16 years (birth cohort years 1994-1997) and women born in 1994 who turned 25 in 2019. We aimed to verify the long-term effectiveness of the bivalent HPV vaccine in women aged 25 years. Subjects were women aged 25-26 years who underwent cervical cancer screening and HPV testing in Niigata from 2019 to 2020 (birth cohort years 1993-1994). Information on vaccination status and sexual behavior was obtained from a questionnaire and municipal records. We compared the HPV infection rates of the vaccinated and unvaccinated groups. Of the 429 registrants, 150 (35.0%) and 279 (65.0%) were vaccinated and unvaccinated, respectively. The average period from HPV vaccination to HPV testing was 102.7 months (8.6 years), with a median of 103 months (range 92-109 months). The HPV high-risk infection rate was 21.3% (32/150) in the vaccinated group and 23.7% (66/279) in the unvaccinated group (P = 0.63). The HPV16/18 infection rate was 0% (0/150) in the vaccinated group and 5.4% (15/279) in the unvaccinated group, showing a significant difference (P = 0.0018), and the vaccine effectiveness was 100%. The cross-protective type HPV31/45/52 infection rate in the vaccinated group was significantly lower than that in the unvaccinated group (3.3% vs. 10.0%, P = 0.013). There was no significant difference in the mean age at sexual debut and the number of previous sexual partners between the two groups. We have demonstrated the long-term 9-year effectiveness of the bivalent vaccine against HPV infection for the first time in Japan.

PET/MR imaging for the evaluation of cervical cancer during pregnancy.

BACKGROUND: Malignancy during pregnancy is increasing, and the most common type of malignancy is uterine cervical cancer. When planning the treatment of cervical cancer, it is important to look for signs of metastasis before surgery, especially metastasis to the lymph nodes. In this report, we assessed the diagnostic value of positron emission tomography/magnetic resonance imaging (PET/MRI) for evaluating cervical cancer propagation before surgery, with a focus on pregnant women. CASE PRESENTATION: 18F Fluorodeoxyglucose (FDG)-PET/MRI was performed in seven pregnant cervical cancer patients (28-34 years old) at 9-18 gestational weeks. In case #5, a second PET/MRI was performed at 24 gestational weeks. Of seven FDG-PET/MRI examination series in six cases (cases #1-6), FDG-PET/MR imaging could detect cervical tumors with abnormal FDG accumulation; these tumors were confirmed with a standardized uptake value max (SUV max) titer of 4.5-16. A second PET/MRI examination in case #5 revealed the same SUV max titer as the first examination. In these six imaging series (cases #1-5), there were no signs of cancer metastasis to the parametrium and lymph nodes. However, in case #6, abnormal FDG accumulation in the left parametrial lymph nodes was also detectable. Pathological examination showed lymph node metastasis in case #6. In case #7, PET/MRI could not detect any abnormal FDG accumulation in the cervix and other sites. Cone biopsy demonstrated only micro-invasive squamous cell carcinoma. After treatment for cervical cancer, all seven patients have had no recurrence of disease within the follow-up period (2.8-5.6 years), and their children have developed appropriately. CONCLUSION: PET/MRI is an effective imaging tool to evaluate cervical cancer progression in pregnancy.

Bivalent Human Papillomavirus Vaccine Effectiveness in a Japanese Population: High Vaccine-Type-Specific Effectiveness and Evidence of Cross-Protection.

Background: Proactive recommendations for human papillomavirus (HPV) vaccines in Japan have been suspended for 5 years because of safety concerns. While no scientific evidence exists to substantiate these concerns, one reason given for not reinstating recommendations is the lack of reliable vaccine effectiveness (VE) data in a Japanese population. This study reports the VE of the bivalent HPV vaccine in Japanese women aged 20-22 years. Methods: During cervical screening between 2014 and 2016, women had Papanicolaou smears and HPV tests performed and provided data about their sexual history. Estimates of VE for vaccine-targeted HPV type 16 (HPV16) and 18 and cross-protection against other types were calculated. Results: Overall, 2197 women were tested, and 1814 were included in the analysis. Of these, 1355 (74.6%) were vaccinated, and 1295 (95.5%) completed the 3-dose schedule. In women sexually naive at vaccination, the pooled VEs against HPV16 and 18 and for HPV31, 45, and 52 were 95.5% (P < .01) and 71.9% (P < .01), respectively. When adjusted for number of sex partners and birth year, pooled VEs were 93.9% (P = .01) and 67.7% (P = .01) for HPV16 and 18 and HPV31, 45, and 52, respectively. Conclusions: The bivalent HPV vaccine is highly effective against HPV16 and 18. Furthermore, significant cross-protection against HPV31, 45, and 52 was demonstrated and sustained up to 6 years after vaccination. These findings should reassure politicians about the VE of bivalent HPV vaccine in a Japanese population.

Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium.

STUDY QUESTION: Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium? SUMMARY ANSWER: Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium. WHAT IS KNOWN ALREADY: Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS). STUDY DESIGN, SIZE, DURATION: We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometrium, endometriosis-related ovarian cancer and endometrial cancer. MAIN RESULTS AND THE ROLE OF CHANCE: Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 × 10-11) and normal endometrium (P = 1.4 × 10-7). LIMITATIONS, REASONS FOR CAUTION: The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear. WIDER IMPLICATIONS OF THE FINDINGS: Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the Japan Society for the Promotion of Science KAKENHI grant number JP15H02373 (Grant-in-Aid for Scientific Research A for I.I.), JP16H06267 (Grant-in-Aid for Young Scientists A for K.Y.), JP17K08688 (Grant-in-Aid for Scientific Research C for H.N.) and JP16H06279 (Grant-in-Aid for Scientific Research on Innovative Areas-Platforms for Advanced Technologies and Research Resources for H.N. and K.Y). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Association of statins, aspirin, and venous thromboembolism in women with endometrial cancer.

OBJECTIVE: The anti-thrombogenic effects of statins and aspirin have been reported in various malignancies but have not been well examined in endometrial cancer. This study examined the association between statin and/or aspirin use and venous thromboembolism (VTE) risk in endometrial cancer. METHODS: This is a multi-center retrospective study examining 2527 women with endometrial cancer between 2000 and 2015. Statin and aspirin use at diagnosis was correlated to VTE risk during follow-up on multivariable analysis. RESULTS: There were 132 VTE events with a 5-year cumulative incidence rate of 6.1%. There were 392 (15.5%) statin users and 219 (8.7%) aspirin users, respectively. On multivariable analysis, statin use was associated with an approximately 60% decreased risk of VTE when compared to non-users (5-year cumulative rates 2.5% versus 6.7%, adjusted-hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.19-0.92, P = 0.030) whereas aspirin did not demonstrate statistical significance (2.0% versus 6.5%, adjusted-HR 0.54, 95%CI 0.19-1.51, P = 0.24). There was a trend of joint effect between statin and aspirin although it did not demonstrate statistical significance: VTE risks for dual statin/aspirin user (adjusted-HR 0.27, 95%CI 0.04-2.07), statin alone (adjusted-HR 0.40, 95%CI 0.18-0.93), and aspirin alone (adjusted-HR 0.51, 95%CI 0.16-1.64) compared to non-use after adjusting for patient characteristics, tumor factors, treatment types, and survival events (P-interaction = 0.090). When stratified by statin type, simvastatin demonstrated the largest reduction of VTE risk (5-year cumulative rates 1.1% versus 6.7%, adjusted-HR 0.17, 95%CI 0.02-1.30, P = 0.088). Obesity, absence of diabetes mellitus, type II histology, and recurrent disease were the factors associated with decreased VTE risk with statin use (all, P-interaction<0.05). CONCLUSION: Our study suggests that statin use may be associated with decreased risk of VTE in women with endometrial cancer.

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

Ectopic pregnancy following oral levonorgestrel emergency contraception use.

Levonorgestrel is used worldwide as an emergency oral contraceptive. There have been occasional reports of ectopic pregnancy after oral levonorgestrel use. We present a case of ectopic tubal pregnancy after the use of oral levonorgestrel as an emergency contraceptive in a 37-year-old woman with a history of treatment for Chlamydia trachomatis infection. She conceived after sexual intercourse on menstrual day 14 of the first menstrual cycle following a normal delivery. After salpingectomy for this right tubal pregnancy, her following pregnancy was an ectopic pregnancy in the contralateral tube, which was treated with laparoscopic salpingectomy. Histopathological examination revealed endometriosis. We should be aware of ectopic pregnancy even after emergency contraceptive use, especially in patients with risk factors, such as Chlamydia infection and endometriosis. Because the efficacy of levonorgestrel decreases after ovulation, we should check the stage of the cycle before prescription.

Significance of Lymphovascular Space Invasion by the Sarcomatous Component in Uterine Carcinosarcoma.

OBJECTIVE: The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS: This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I-IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS: Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36-2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39-2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION: In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.

Proposal for a Risk-Based Categorization of Uterine Carcinosarcoma.

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

Significance of abnormal peritoneal cytology on survival of women with stage I-II endometrioid endometrial cancer.

OBJECTIVE: To examine survival of women with stage I-II endometrioid endometrial cancer whose peritoneal cytology showed malignant or atypical cells (abnormal peritoneal cytology). METHODS: This is a multi-center retrospective study examining 1668 women with stage I-II endometrioid endometrial cancer who underwent primary hysterectomy with available peritoneal cytology results between 2000 and 2015. Abnormal peritoneal cytology was correlated to clinico-pathological characteristics and oncological outcome. RESULTS: Malignant and atypical cells were seen in 125 (7.5%) and 58 (3.5%) cases, respectively. On multivariate analysis, non-obesity, non-diabetes mellitus, cigarette use, and lympho-vascular space invasion were independently associated with abnormal peritoneal cytology (all, P<0.05). Abnormal peritoneal cytology was independently associated with decreased disease-free survival (hazard ratio 3.07, P<0.001) and cause-specific survival (hazard ratio 3.42, P=0.008) on multivariate analysis. Abnormal peritoneal cytology was significantly associated with increased risks of distant-recurrence (5-year rates: 8.8% versus 3.6%, P=0.001) but not local-recurrence (5.2% versus 3.0%, P=0.32) compared to negative cytology. Among women with stage I disease, abnormal peritoneal cytology was significantly associated with an increased risk of distant-recurrence in the low risk group (5-year rates: 5.5% versus 1.0%, P<0.001) but not in the high-intermediate risk group (13.3% versus 10.8% P=0.60). Among 183 women who had abnormal peritoneal cytology, postoperative chemotherapy significantly reduced the rate of peritoneal recurrence (5-year rates: 1.3% versus 9.2%, P=0.039) whereas postoperative radiotherapy did not (7.1% versus 5.5%, P=0.63). CONCLUSION: Our study suggests that abnormal peritoneal cytology may be a prognostic factor for decreased survival in women with stage I-II endometrioid endometrial cancer, particularly for low-risk group.

Significance of venous thromboembolism in women with uterine carcinosarcoma.

OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P=0.012), non-Asian race (HR 6.28, P<0.001), large body habitus (HR per kg/m2 1.04, P=0.014), residual disease at surgery (HR 3.04, P=0.003), tumor size ≥5cm (HR 2.73, P=0.003), and stage IV disease (HR 2.12, P=0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P<0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P=0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%CI 1.05-2.04, P=0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.

Survival outcome of women with stage IV uterine carcinosarcoma who received neoadjuvant chemotherapy followed by surgery.

BACKGROUND AND OBJECTIVES: To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. METHODS: This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. RESULTS: The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. CONCLUSION: Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.

The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy.

OBJECTIVES: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. METHODS/MATERIALS: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. RESULTS: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. CONCLUSIONS: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby.

Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma.

BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma.

OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P<0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P=0.02). When stratified by disease-free interval, women with a disease-free interval ≥6months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P=0.002); conversely, in women with a disease-free interval <6months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P=0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P=0.019). CONCLUSION: Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6months.

Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma.

OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

Tumor Characteristics and Survival Outcome of Endometrial Cancer Arising in Adenomyosis: An Exploratory Analysis.

BACKGROUND: Endometrial cancer arising in adenomyosis (EC-AIA) is a rare entity of endometrial cancer, and its clinical significance has not been well studied. This study aimed to examine the tumor characteristics and survival outcomes of EC-AIA. METHODS: An exploratory analysis was performed to compare EC-AIA and historical control cases. For this study, EC-AIA cases were identified via a systematic literature search using PubMed/MEDLINE with entry keywords "endometrial cancer OR uterine cancer" AND "adenomyosis" (n = 46). The control group comprised consecutive non-EC-AIA cases from four institutions that had hysterectomy-based surgical staging (n = 1294). Patient demographics, pathology results, and survival outcomes were evaluated between the two groups. RESULTS: The EC-AIA group was significantly older than the control group (58.9 vs. 55.3 years; P = 0.032). In terms of tumor characteristics, 56.5% of the EC-AIA cases showed tumor within the myometrium without endometrial extension, and the EC-AIA group was significantly more likely to have tumors with more than 50% myometrial invasion (51.6 vs. 26.6%; P = 0.002) and serous/clear cell histology (22.2 vs. 8.2%, P = 0.002) while less likely to express estrogen receptor (14.3 vs. 84.6%; P < 0.001). Grade and stage distributions were similar (P > 0.05). In the univariate analysis, the EC-AIA group had a significantly poorer disease-free survival than the control group (5-year rate: 71.4 vs. 80.6%; P = 0.014). In the multivariate analysis, with control for age, ethnicity, histology, grade, and stage, EA-CIC remained an independent prognostic factor for decreased disease-free survival (adjusted hazard ratio, 3.07; 95% confidence interval 1.55-6.08; P = 0.001). CONCLUSIONS: The study suggested that endometrial cancer arising in adenomyosis may be an aggressive variant of endometrial cancer.