Chemotherapy response score no longer predicts survival outcomes in high-grade serous ovarian cancer patients with BRCA mutation and/or maintenance therapy.

OBJECTIVE: We aimed to revalidate the chemotherapy response score (CRS) system as a prognostic factor for ovarian cancer patients with breast cancer gene (BRCA) mutations or those receiving frontline poly-ADP ribose polymerase (PARP) inhibitors or bevacizumab as maintenance therapy. METHODS: A retrospective analysis was performed using medical records of patients with high-grade serous carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery between January 2007 and December 2021 at 5 tertiary medical institutions in South Korea. At each hospital, pathologists independently assessed each slide of omental tissues obtained from surgery using the CRS system. Progression-free survival (PFS) and overall survival (OS) values were obtained using Kaplan-Meier analysis to evaluate the effect of BRCA mutation, maintenance therapy, and CRS on survival time. RESULTS: Of 466 patients, BRCA mutations were detected in 156 (33.5%) and 131 (28.1%) were treated with maintenance therapy; 98 (21.0%) and 42 (9.0%) were treated with PARP inhibitors or bevacizumab, respectively. Patients with CRS3 had significantly longer PFS than those with CRS1 or 2 (24.7 vs. 16.8 months, p<0.001). However, there was no significant difference in PFS improvement between CRS3 patients and those with CRS1 or 2 with BRCA mutation (22.0 vs. 19.3 months, p=0.193). Moreover, no significant PFS prolongation was observed in CRS3 patients compared to CRS1 or 2 patients treated with PARP inhibitors or bevacizumab (24.3 vs. 22.4 months, p=0.851; 27.5 vs. 15.7 months, p=0.347, respectively). CONCLUSION: CRS may not be a prognostic factor in patients with BRCA mutations and those receiving frontline maintenance therapy.

Survival outcomes of laparoscopic versus open radical hysterectomy in early cervical cancer with incidentally identified high-risk factors.

OBJECTIVE: Previously, we suggested that patients with cervical cancer (CC) with tumors ≤2 cm on preoperative magnetic resonance imaging (MRI) are safe candidates for laparoscopic radical hysterectomy (LRH). Here, we aim to investigate whether LRH deteriorates the prognosis of patients with incidentally identified high-risk factors; lymph node metastasis (LNM) or parametrial invasion (PMI). METHODS: We identified patients with 2009 FIGO stage IB1 CC who underwent Type C LRH or open radical hysterectomy (ORH) at three tertiary hospitals between 2000 and 2019. Those with a tumor ≤2 cm on preoperative MRI who were not suspicious of LNM or PMI preoperatively were included, while those who were indicated to receive adjuvant treatment but did not actually receive it were excluded. Survival outcomes were compared between the LRH and ORH groups in the overall population, then narrowed down to those with LNM, and then to those with PMI. RESULTS: In total, 498 patients were included: 299 in the LRH group and 199 in the ORH group. The LRH and ORH groups showed similar 3-year progression-free survival (PFS) (94.0% vs. 93.6%; P = 0.615) and 5-year overall survival (OS) rates (97.2% vs. 96.8%; P = 0.439). On pathologic examination, 49 (9.8%) and 16 (3.2%) patients had LNM and PMI, respectively, and 10 (2.0%) had both. In the LNM subgroup, 5-year PFS rate was not significantly different between the LRH and ORH groups (73.2% vs. 91.7%; P = 0.169). In the PMI subgroup, no difference in PFS was observed between the two groups (P = 0.893). CONCLUSIONS: LRH might not deteriorate recurrence and mortality rates in CC patients with tumors ≤2 cm when adjuvant treatment is appropriately administered, even if pathologic LNM and PMI are incidentally identified.

Prognostic significance of L1CAM expression in addition to ProMisE in endometrial cancer.

OBJECTIVE: To investigate the prognostic significance of L1 cell-adhesion molecule (L1CAM), ß-catenin, and programmed death-ligand 1 (PD-L1) in endometrial cancer (EC) patients, with a focus on p53 wild-type subgroup, for additional risk stratification. METHODS: This retrospective cohort study included EC patients classified according to Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) who underwent primary surgical treatment at the single center between January 2014 and December 2018. Immunohistochemical staining was performed for four mismatch repair (MMR) proteins, p53, L1CAM, ß-catenin, and PD-L1. DNA polymerase epsilon (POLE) mutation was detected by hot spot sequencing via droplet digital polymerase chain reaction. Survival outcome of each subgroup of L1CAM, ß-catenin, and PD-L1 was measured according to their expression. RESULTS: A total of 162 EC patients were included. Endometrioid histologic type and early-stage disease were 140 (86.4%) and 109 (67.3%), respectively. ProMisE classification assigned 48 (29.6%), 16 (9.9%), 72 (44.4%), and 26 (16.0%) patients to MMR-deficient, POLE-mutated, p53 wild-type, and p53 abnormal subgroups, respectively. L1CAM was identified as an independent poor prognostic factor for progression-free survival (PFS; adjusted hazard ratio [aHR], 3.207; 95% confidence interval (CI), 1.432-7.187; P = 0.005), whereas ß-catenin and PD-L1 positivity were not associated with recurrence (P = 0.462 and P = 0.152, respectively). In p53 wild-type subgroup, L1CAM positivity was associated with worse PFS (aHR, 4.906; 95% CI, 1.685-14.287; P = 0.004). CONCLUSION: L1CAM positivity was associated with poor prognosis in EC and further stratified the risk of recurrence in p53 wild-type subgroup, whereas ß-catenin and PD-L1 were not informative for risk stratification.

Role of systematic lymphadenectomy in patients with intermediate to high-risk early stage endometrial cancer.

OBJECTIVE: To determine the clinical significance of systematic lymph node dissection (LND) and to better define the relevant extent of LND in intermediate- to high-risk early stage endometrial cancer (EC). METHODS: Patients who received surgery as a primary treatment of histologically confirmed EC and preoperatively considered as uterus-confined early stage disease were included in the study population. The rates of lymph node metastasis (LNM) according to the risk groups and anatomic sites were assessed. Univariate and multivariate analyses were performed to evaluate risk factors for recurrence. RESULTS: A total of 804 patients were included in the study analysis. The rates of LNM were significantly different according to the risk group; 1.2% in low-risk, 20.1% in intermediate-risk, and 30.0% in high-risk group. When assessing the rates of LNM in individual anatomic sites, positive LNs were evenly distributed throughout the pelvic and para-aortic regions. In the intermediate to high-risk EC cases, the rates of para-aortic LNM below and above inferior mesenteric artery (IMA) were 11.1% and 12.5%, respectively. On multivariate analysis, LNM was the only independent risk factor for recurrence in the intermediate to high-risk EC (hazard ratio=2.63, 95% confidence interval=1.01-6.82, p=0.047). CONCLUSION: LNM was frequently observed in intermediate- and high-risk early stage EC and it served as an independent risk factor for recurrence. When considering the similar rates of LNM between below and above IMA, nodal assessment needs to be performed up to the infra-renal level, especially for the staging purpose in high-risk EC.

Clinical Outcomes Associated with Endocervical Glandular Involvement in Patients with Cervical Intraepithelial Neoplasia III.

This study aimed to determine whether endocervical glandular involvement (GI) affects the clinical prognosis of patients with cervical intraepithelial neoplasia (CIN) III who underwent the loop electrosurgical excision procedure (LEEP). This retrospective study included 250 patients who underwent LEEP for the treatment of CIN III between August 2005 and May 2020. The medical records of 234 patients were analyzed; 137 (58.5%) patients were GI negative, and 97 (41.5%) were GI positive. Margin involvement of the LEEP specimen was found in 59 (45.4%) patients in the GI-negative group and 54 (58.7%) patients in the GI-positive group (p = 0.051). The additional surgical procedures (repeat conization or hysterectomy) were significantly more performed in GI-positive patients than in GI-negative patients (40.9% vs. 23.1%, p = 0.004). When comparing the LEEP specimens of GI-1 (GI-positive confirmed via cervical biopsy before conization) and GI-2 (GI-positive confirmed via conization), we found that the mean depth was significantly greater in the GI-1 group (10.9 mm) than in the GI-2 group (7.6 mm) (p = 0.024). Surgical margin involvement was more frequently observed in the GI-2 group than in the GI-1 group (p = 0.030). There was no significant difference in the recurrence rates of CIN between the GI-negative and GI-positive groups (p = 0.641). In conclusion, despite no significant differences in residual disease and CIN recurrence between the GI-negative and GI-positive groups, additional surgical treatments were more frequently performed in GI-positive patients. Repeat surgery based on GI positivity should be carefully considered to avoid overtreatment and surgical complications.

Retreatment with progestin for recurrence after complete response with fertility-sparing treatment in patients with endometrial cancer.

OBJECTIVE: To assess the outcomes of retreatment using progestin for recurrence after a complete response with fertility-sparing treatment in patients with early endometrial cancer. METHODS: We retrospectively reviewed the data of patients with presumed stage IA, grade 1 endometrioid endometrial cancer who developed intra-uterine recurrence after a complete response with fertility-sparing treatment using progestin. Oncological and pregnancy outcomes were analyzed after repeated fertility-sparing treatment. Logistic and Cox regression analyses were performed to analyze the prognostic factors associated with a complete response with secondary fertility-sparing treatment and recurrence-free survival after secondary fertility-sparing treatment, respectively. RESULTS: Fifty patients with a median age of 31 years (range 23-40) underwent secondary fertility-sparing treatment. With a median secondary progestin treatment duration of 9 months (range 3-55), the complete response rate was 78% (39/50) and no patients had extra-uterine spread of disease. Among the 26 (67%) patients who attempted to conceive after complete response, 10 became pregnant (3 spontaneous abortions, 7 live births). Eighteen (46.1%) patients had a second recurrence, with a median recurrence-free survival after secondary fertility-sparing treatment of 14 months (range 3-36); 15 patients received tertiary fertility-sparing treatment and nine (60%) achieved a complete response. Polycystic ovary on ultrasound (OR 5.82, 95% CI 1.1 to 30.6, p=0.037) was associated with an increased complete response rate with secondary fertility-sparing treatment. Multivariable analysis revealed that recurrence-free survival after initial hormonal treatment >6 months (HR 0.11, 95% CI 0.02 to 0.51, p=0.005) and pregnancy after secondary fertility-sparing treatment (HR 0.27, 95% CI 0.08 to 0.98; p=0.047) were significantly associated with longer recurrence-free survival after secondary fertility-sparing treatment. CONCLUSIONS: Repeated progestin treatment was associated with a 78% response rate and it was safe in patients with intra-uterine recurrent endometrial cancer. Thus, it might help preserve fertility after first and second recurrences.

Minimally invasive surgery versus open surgery in high-risk histologic endometrial cancer patients: A meta-analysis.

OBJECTIVE: To compare the effects of minimally invasive surgery (MIS) and open surgery (OPS) on the risk of recurrence and mortality in patients with endometrial cancer (EC) of high-risk histology (grade 3 endometrioid adenocarcinoma, papillary serous carcinoma [PS], clear cell carcinoma [CC], and carcinosarcoma) using meta-analysis. MATERIAL AND METHODS: We systematically reviewed published studies comparing MIS and OPS in EC patients with high-risk histology until January 2022. The endpoints were recurrence and mortality rate. Study design features that may have affected participant selection, recurrence/death detection, and manuscript publication were assessed. For pooled estimates of the effect of MIS on recurrence/mortality, the random- or fixed-effects meta-analytical models were used after assessing the cross-study heterogeneity. RESULT: Nine observational studies (eight retrospective and one prospective) fulfilled our search criteria (MIS, 8877 patients; OPS, 5751 patients). The fixed-effects model-based meta-analysis indicated that MIS did not significantly increase the risk of recurrence (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.71-1.05; p = 0.13) and mortality (HR, 0.86; 95% CI, 0.79-0.93; p < 0.001) when compared with OPS. This pattern was also observed in the subgroup analyses based on the stage (early stage vs. all stage), histology (PS and CC), and MIS type (laparoscopy vs. robotic). There was no evidence of publication bias. CONCLUSION: This meta-analysis of observational studies revealed that MIS did not compromise the prognosis of EC patients with high-risk histology. Well-designed randomized controlled trials could verify the results of this uncommon but deadly tumor.

Laparotomic radical hysterectomy versus minimally invasive radical hysterectomy using vaginal colpotomy for the management of stage IB1 to IIA2 cervical cancer: Survival outcomes.

ABSTRACT: This study compared survival outcomes for patients with stage IB1 to IIA2 (International Federation of Gynecology and Obstetrics stage 2009) cervical cancer who underwent open radical hysterectomy (ORH) versus those who underwent minimally invasive radical hysterectomy (MIRH) using vaginal colpotomy (VC).Data for 550 patients who were diagnosed with cervical cancer at our institution during the period August 2005 to September 2018 was retrospectively reviewed. Of these, 116 patients who underwent radical hysterectomy (RH) were selected after applying the exclusion criteria. All MIRH patients underwent VC. Clinicopathological characteristics and survival outcomes between the ORH and MIRH groups were compared using appropriate statistical testing.Ninety one patients were treated with ORH and 25 with MIRH during the study period. Among the MIRH patients, 18 underwent laparoscopy-assisted radical vaginal hysterectomy and 7 underwent laparoscopic RH. Preoperative conization was performed more frequently in MIRH patients than in ORH patients (44% vs 22%, respectively, P = .028). The incidence of lymph node invasion was higher in the ORH group than in MIRH group (37.4% vs 12.0% respectively; P = .016). Following RH, ORH patients underwent adjuvant treatment more frequently than MIRH patients (71.4% vs 56.0%, respectively, P = .002). There were no significant differences between ORH and MIRH patients for either progression-free survival (PFS) (91.3% vs 78.7%, respectively; P = .220) or 5-year overall survival (OS) (96.6% vs 94.7%, respectively, P = .929). In univariate analysis, lympho-vascular space invasion was the only clinicopathological feature associated with decreased PFS. No other clinicopathological factors was significantly associated with PFS or OS in univariate and multivariate analyses.Despite a higher incidence of unfavorable prognostic factors in ORH patients, their survival outcomes were not different to those of MIRH patients with VC.

Multiple Primary Malignancies in Patients with Gynecologic Cancer.

OBJECTIVE: To investigate the prevalence and oncologic outcomes of patients with multiple primary malignant tumors (MPMT) with gynecologic cancer. METHODS: This retrospective study included 1929 patients diagnosed with gynecologic cancer at a tertiary medical center between August 2005 and April 2021. The clinical data included cancer location, age at primary malignancy diagnosis, interval between primary and secondary cancer, stage of cancer, family history of cancer, genetic testing, dates of last follow-up, recurrence, and death. RESULTS: The prevalence of MPMT with gynecologic cancer in patients was 8.6% and the mean diagnostic period between primary and secondary cancer was 60 months. Furthermore, 20 of the 165 patients with MPMT had multiple primary gynecologic cancers (MPGC), whereas 145 had gynecologic cancer coexisting with non-gynecologic cancer (GNC). Endometrial-ovarian cancer (60%) was the most common coexisting cancer in the MPGC group, whereas the most common non-gynecologic cancer in the GNC group was breast cancer (34.5%). There were 48 patients with synchronous cancer and 117 patients with metachronous cancer. The incidence of synchronous cancer was higher in the MPGC group than in the GNC group (p = 0.037). Significantly more patients had early-stage ovarian cancer in the MPGC group than in the GNC group (p = 0.031). The overall recurrence and mortality rates were 15.8% and 8.5%, respectively, in patients with MPMT. CONCLUSION: Synchronous cancer incidence was significantly higher in the MPGC than in the GNC group. Early-stage ovarian cancer was more highly diagnosed in patients with MPGC than in those with GNC. A systematic examination after primary cancer diagnosis could facilitate the early diagnosis of secondary primary malignancy, thereby improving patient prognosis.

Loop electrosurgical excision procedure combined with cold coagulation for cervical intraepithelial neoplasia and adenocarcinoma in-situ: a feasible treatment with a low risk of residual/recurrent disease.

OBJECTIVE: This study was performed to evaluate the significance of positive resection margins (RMs) with the loop electrosurgical excision procedure combined with cold coagulation (LEEP with CC) as a definitive treatment for patients with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in-situ. METHODS: We retrospectively reviewed 467 patients who underwent LEEP with CC. A right-angled triangular loop in a single pass followed by a CC (120 °C) to the cone bed for 10 to 20 s was used. Pathology reports and clinical data were obtained and evaluated. RESULTS: Histopathology evaluation of LEEP tissue samples revealed the presence of CIN 1 in 69, CIN 2/3 in 366, AIS in 5 and invasive carcinoma in 16 (microinvasive squamous cell carcinoma (SCC) and invasive SCC, 13 and 3) patients. Margins were positive in 66 (14.5%) cases: 0 in CIN 1, 54 in CIN 2/3 (12.4%), 1 in AIS (20.0%) and 11 in microinvasive/invasive SCC (68.8%). Although 54 CIN2/3 patients with positive RMs did not undergo additional treatment, 1 of these (1.9%) was confirmed to have residual CIN3 at the first follow-up. Two of 8 (25.0%) microinvasive SCC patients with positive RMs were confirmed to have residual diseases (1 microinvasive SCC and 1 invasive SCC) after hysterectomy. Four out of 360 (1 positive RM, 3 negative RM) CIN cases recurred during the study period. CONCLUSIONS: These results suggest that CIN patients with positive RMs after LEEP with CC may be followed up without additional treatment.

Changes of vaginal microbiota during cervical carcinogenesis in women with human papillomavirus infection.

OBJECTIVE: To evaluate the changes of vaginal microbiota during cervical carcinogenesis in women with high-risk human papillomavirus infection. MATERIALS AND METHODS: Vaginal microbiota was analyzed using next-generation sequencing in women with normal, cervical intraepithelial neoplasia (CIN), or cervical cancer. RESULTS: A marked decrease of Lactobacillus crispatus was found in the CIN/cancer groups compared with that in the normal group. The diversity of microorganisms increased in patients with CIN or cervical cancer with HPV infection. Atopobium vaginae (OR 4.33, 95% CI 1.15-16.32), Dialister invisus (OR 4.89, 95% CI 1.20-19.94), Finegoldia magna (OR 6.00, 95% CI 1.08-33.27), Gardnerella vaginalis (OR 7.43, 95% CI 1.78-31.04), Prevotella buccalis (OR 11.00, 95% CI 2.00-60.57), and Prevotella timonensis (OR 6.00, 95% CI 1.46-24.69) were significantly associated with the risk of CIN 2/3 or cervical cancer. CONCLUSION: Women with the CIN and cervical cancer showed a high diversity in vaginal microbiota. Depletion of Lactobacillus crispatus and increased abundance of anaerobic bacteria were detected in women with cervical disease.

Isotretinoin exposure in pregnant women in Korea.

OBJECTIVE: Isotretinoin is a notorious teratogen otherwise used for the treatment of acne vulgaris. Some countries, including those in North America and the European Union, implemented the pregnancy prevention program (PPP); however, no PPP has yet been established in South Korea. So the aim of this study was to evaluate the rate of pregnant women exposed to isotretinoin among the callers of the Korean Mother Safe Counseling Center. METHODS: This is a prospective cohort study. We evaluated the demographic characteristics, obstetric history, and isotretinoin exposure of pregnant women based on the mother safe registry from April 2010 to July 2016. RESULTS: Among 22,374 callers, 650 (2.9%) pregnant women were exposed to isotretinoin. The mean age was 29.0±4.4 years in the isotretinoin-exposed group and 32.0±4.2 years in the unexposed group (P<0.001). Moreover, the incidence of pregnancies within 30 days after isotretinoin discontinuation or during isotretinoin intake was 78.9% (513/650). The median duration of isotretinoin exposure was 18 (1-4,231) days. Furthermore, from 2011 to 2015, the incidence of isotretinoin exposure was 2.9±1.2 pregnancies per 10,000 births in South Korea. CONCLUSION: Approximately 80% of pregnant women are exposed to isotretinoin within the recommended 30 days of contraception or during pregnancy. Therefore, the PPP has to be established in South Korea.