Urine and serum metabolomic analysis of endometrial cancer diagnosis and classification based on ultra-performance liquid chromatography mass spectrometry.

OBJECTIVE: This study aimed to reveal the urinary and serum metabolic pattern of endometrial cancer (EC) and establish diagnostic models to identify EC from controls, high-risk from low-risk EC, and type II from type I EC. METHOD: This study included 146 EC patients (comprising 79 low-risk and 67 high-risk patients, including 124 type I and 22 type II) and 59 controls. The serum and urine samples were analyzed using ultraperformance liquid chromatography mass spectrometry. Analysis was used to elucidate the distinct metabolites and altered metabolic pathways. Receiver operating characteristic (ROC) analyses were employed to discover and validate the potential biomarker models. RESULTS: Serum and urine metabolomes displayed significant differences between EC and controls, with metabolites related to amino acid and nicotinamide metabolisms. The serum and urine panels distinguished these two groups with Area Under the Curve (AUC) of 0.821 and 0.902, respectively. The panel consisting of serum and urine metabolites demonstrated the best predictive ability (AUC = 0.953 and 0.976 in discovering and validation group). In comparing high-risk and low risk EC, differential metabolites were enriched in purine and glutamine metabolism. The AUC values for serum and urine panels were 0.818, and 0.843, respectively. The combined panel exhibited better predictive accuracy (0.881 in discovering group and 0.936 in external validation). In the comparison between type I and type II group, altered folic acid metabolism was identified. The serum, urine and combined panels discriminated these two groups with the AUC of 0.829, 0.913 and 0.922, respectively. CONCLUSION: The combined urine and serum metabolome effectively revealed the metabolic patterns in EC patients, offering valuable diagnostic models for EC diagnosis and classification.

Fertility-sparing re-treatment for endometrial cancer and atypical endometrial hyperplasia patients with progestin-resistance: a retrospective analysis of 61 cases.

OBJECTIVE: This study aimed to evaluate the oncological and reproductive outcomes of fertility-preserving re-treatment in progestin-resistant endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) women who desire to maintain their fertility. METHODS: Our study included 61 progestin-resistant EC/AEH patients. These patients underwent treatment with gonadotropin-releasing hormone agonist (GnRHa) solely or a combination of GnRHa with levonorgestrel-releasing intrauterine system (LNG-IUD) or aromatase inhibitor (AI). Histological evaluations were performed every 3-4 months. Upon achieving complete remission (CR), we recommended maintenance treatments including LNG-IUD, cyclical oral contraceptives, or low-dose cyclic progestin until they began attempting conception. Regular follow-up was conducted for all patients. The chi-square method was utilized to compare oncological and fertility outcomes, while the Cox proportional hazards regression analysis helped identify risk factors for CR, recurrence, and pregnancy. RESULTS: Overall, 55 (90.2%) patients achieved CR, including 90.9% of AEH patients and 89.7% of EC patients. The median re-treatment time was 6 months (ranging from 3 to 12 months). The CR rate for GnRHa alone, GnRHa + LNG-IUD and GnRHa + AI were 80.0%, 91.7% and 93.3%, respectively. After a median follow-up period of 36 months (ranging from 3 to 96 months), 19 women (34.5%) experienced recurrence, 40.0% in AEH and 31.4% in EC patients, with the median recurrence time of 23 months (ranging from 6 to 77 months). Among the patients who achieved CR, 39 expressed a desire to conceive, 20 (51.3%) became pregnant, 11 (28.2%) had successfully deliveries, 1 (5.1%) was still pregnant, while 8 (20.5%) suffered miscarriages. CONCLUSION: GnRHa-based fertility-sparing treatment exhibited promising oncological and reproductive outcomes for progestin-resistant patients. Future larger multi-institutional studies are necessary to confirm these findings.

Survival outcomes and establishment of a novel risk stratification system in patients with ovarian yolk sac tumors.

OBJECTIVE: To evaluate the survival outcomes and establish a risk stratification system in patients with ovarian yolk sac tumors (OYST). METHODS: The recurrence-free survival (RFS), disease-specific survival (DSS), and prognostic factors were retrospectively evaluated in 151 OYST patients treated in our hospital between 2006 and 2022. A risk stratification system based on the identified prognostic factors was established. RESULTS: The median follow-up time was 5.1 years, with a 5-year RFS and DSS rate of 75.5% and 91.2%, respectively. FIGO stage III-IV and the interval between treatment and normalization of AFP were two prognostic predictors. Significant differences in RFS and DSS (both P < 0.001) were identified between patients who had normalized AFP ≤ 3 and ≥ 4 cycles of chemotherapy, or among patients who had normalized AFP after ≤2, 3-4, and ≥ 5 cycles of chemotherapy. FIGO stage I - II and stage III-IV were scored as 0 and 2, respectively. AFP normalization ≤2, 3, 4, and ≥ 5 cycles of chemotherapy were scored as 0, 1, 2, and 4, respectively. A total score of 0-1, 2-3, and ≥ 4 were stratified patients into low-risk (96 patients), intermediate-risk (35 patients), and high-risk groups (20 patients), respectively. Patients in three risk stratifications manifested significant differences in both RFS and DSS (P < 0.0001). CONCLUSION: This risk stratification system based on tumor stage and the interval between treatment and normalization of AFP may help to guide clinical management by dividing OYST patients into three risk groups.

Advanced ovarian yolk sac tumor: upfront surgery or neoadjuvant chemotherapy followed by interval debulking?

OBJECTIVE: To compare surgery and survival outcomes between neoadjuvant chemotherapy and primary debulking surgery in patients with advanced ovarian yolk sac tumor. METHODS: In this retrospective cohort analysis, patients with stage III to IV ovarian yolk sac tumor or mixed germ cell tumors containing yolk sac tumor elements, and who underwent surgery at Peking Union Medical College Hospital between January 2011 and December 2021, were identified. Patient characteristics, treatment, and survival data were analyzed between the two groups. RESULTS: A total of 40 patients were enrolled: 19 patients received neoadjuvant chemotherapy followed by interval surgery, and 21 patients were treated with primary debulking surgery. After neoadjuvant chemotherapy, the surgical conditions of patients were improved. All patients achieved cytoreduction to R0 or R1 at interval surgery. No statistical difference was found in 3-year disease-free survival and overall survival between the neoadjuvant chemotherapy group and the primary debulking surgery group (log rank p=0.4 and 0.94). Patients had less blood loss (328.4 vs 1285.7 mL, p=0.029), lower transfusion volume (1044.4 vs 3066.7 mL, p=0.011), and fewer peri-operative complications (15.8% vs 47.6%, p=0.032) at the interval debulking surgery after neoadjuvant chemotherapy compared with patients who underwent primary debulking surgery. CONCLUSION: For patients with advanced-stage ovarian yolk sac tumor, neoadjuvant chemotherapy followed by interval surgery is an alternative option, especially for those who cannot tolerate the primary debulking surgery because of high tumor burden and vulnerable status.

Urine metabolomics for assessing fertility-sparing treatment efficacy in endometrial cancer: a non-invasive approach using ultra-performance liquid chromatography mass spectrometry.

OBJECTIVE: This study aimed to reveal the urine metabolic change of endometrial cancer (EC) patients during fertility-sparing treatment and establish non-invasive predictive models to identify patients with complete remission (CR). METHOD: This study enrolled 20 EC patients prior to treatment (PT) and 22 patients with CR, aged 25-40 years. Eligibility criteria consisted of stage IA high-grade EC, lesions confined to endometrium, normal hepatic and renal function, normal urine test, no contraindication for fertility-sparing treatment and no prior therapy. Urine samples were analyzed using ultraperformance liquid chromatography mass spectrometry (UPLC-MS), a technique chosen for its high sensitivity and resolution, allows for rapid, accurate identification and quantification of metabolites, providing a comprehensive metabolic profile and facilitating the discovery of potential biomarkers. Analytical techniques were employed to determine distinct metabolites and altered metabolic pathways. The statistical analyses were performed using univariate and multivariate analyses, logistic regression and receiver operating characteristic (ROC) curves to discover and validate the potential biomarker models. RESULTS: A total of 108 different urine metabolomes were identified between CR and PT groups. These metabolites were enriched in ascorbate and aldarate metabolism, one carbon pool by folate, and some amino acid metabolisms pathways. A panel consisting of Baicalin, 5beta-1,3,7 (11)-Eudesmatrien-8-one, Indolylacryloylglycine, Edulitine, and Physapubenolide were selected as biomarkers, which demonstrated the best predictive ability with the AUC values of 0.982/0.851 in training/10-fold-cross-validation group, achieving a sensitivity of 0.975 and specificity of 0.967, respectively. CONCLUSION: The urine metabolic analysis revealed the metabolic changes in EC patients during the fertility-sparing treatment. The predictive biomarkers present great potential diagnostic value in fertility-sparing treatments for EC patients, offering a less invasive means of monitoring treatment efficacy. Further research should explore the mechanistic underpinnings of these metabolic changes and validate the biomarker panel in larger, diverse populations due to the small sample size and single-institution nature of our study.

Survival outcomes and the prognostic significance of clinicopathological features in patients with endometrial clear cell carcinoma: a 35-year single-center retrospective study.

BACKGROUND: To evaluate the oncological outcomes and the impact of clinicopathological factors on endometrial clear cell carcinoma (ECCC) outcomes. METHODS: Medical records of patients with primary ECCC treated at our center between 1985 and December 2020 were reviewed. Overall survival (OS) and progression-free survival (PFS) were the endpoints. The Kaplan-Meier method and Cox regression analysis were used. RESULTS: In total, 156 patients were included, of whom 59% and 41% had early- and advanced-stage ECCC, respectively. The median age of onset was 61 years, and 80.8% of the patients were postmenopausal. Ninety-two (59%) and 64 (41%) patients had pure ECCC and mixed endometrial carcinoma with clear cell carcinoma (CCC) components, respectively. Mixed pathological components, elevated cancer antigen 125 levels, positive lymphovascular space invasion, deep myometrial invasion, and malignant peritoneal washing cytology (PWC) were more frequently observed in the advanced stage. Thirty-nine patients (25%) experienced relapse and 32 patients (20.5%) died. The 5-year PFS and OS rates for the entire cohort were 72.6% and 79%, respectively. Multivariate analysis showed that advanced-stage disease and positive PWC significantly decreased PFS, while advanced-stage disease and older age (> 61 years) significantly decreased OS. CONCLUSIONS: ECCC is a rare and aggressive type II endometrial carcinoma that is common in older women and patients with advanced-stage disease. Positive PWC was associated with decreased PFS, although its presence did not influence the stage. Positive PWC, and advanced stage and older age were independent negative prognostic factors.

Abdominal pregnancy: a case report and review of 17 cases.

PURPOSE: To analyze the clinical characteristics of abdominal pregnancy, and to explore the diagnosis and prognosis of different treatment methods. METHODS: The cases of patients with abdominal pregnancy admitted to Peking Union Medical College Hospital between January 1, 1989 and January 1, 2021, were analyzed retrospectively. RESULTS: The median age of 17 patients was 34 years (22-42 years); the median gestational duration was 57 days (from 41 days to 32 weeks). Among all 17 patients, 15 (88.24%) presented with abdominal pain. The implantation sites of the gestational sac included the bladder peritoneal reflection, anterior wall of the rectum, omentum, serous membrane of the uterus, and inside or on the surface of uterosacral ligament. In all, only 29.41% cases (5/17) were diagnosed before surgery. All 17 patients were treated via surgery. Further, 58.82% (10/17) patients recovered without complications, 29.41% (5/17) developed fever, 5.88% (1/17) underwent reoperation because of intra-abdominal bleeding, and 5.88% (1/17) developed double lower limb venous thrombosis. All 17 patients survived. CONCLUSION: The preoperative diagnosis rate of abdominal pregnancy is low. Planting sites in the pelvic peritoneum and pelvic organs are more common than the others. Laparoscopic surgery in the first trimester of pregnancy can achieve better therapeutic effects. However, the blood supply of the placenta should be fully evaluated before surgery. When it is expected that attempts to remove the placenta will cause fatal bleeding, the placenta can be left in place, but long-term close follow-up should be paid attention to.

Immunologic Signatures across Molecular Subtypes and Potential Biomarkers for Sub-Stratification in Endometrial Cancer.

Current molecular classification approaches for endometrial cancer (EC) often employ multiple testing platforms. Some subtypes still lack univocal prognostic significance, highlighting the need for risk sub-stratification. The tumor immune microenvironment (TIME) is associated with tumor progression and prognosis. We sought to investigate the feasibility of classifying EC via DNA sequencing and interrogate immunologic signatures and prognostic markers across and within subtypes, respectively. Formalin-fixed paraffin-embedding (FFPE) samples from 50 EC patients underwent targeted DNA and RNA sequencing, and multiplex immunofluorescence assay for TIME. DNA sequencing classified 10%, 20%, 52%, and 18% of patients into the subtype of POLE-mutant, microsatellite instability-high (MSI-H), TP53-wt, and TP53-mutant. POLE-mutant tumors expressed the highest T-effector and IFN-γ signature and the lowest innate anti-PD-1 resistance signature among subtypes. TP53-wt revealed a converse enrichment trend for these immunologic signatures. Survival analyses using the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) dataset identified associations of CCR5 (hazard ratio (HR) = 0.71, p = 0.035), TNFRSF14 (HR = 0.58, p = 0.028), and IL-10 (HR = 2.5, p = 0.012) with overall survival within MSI-H, TP53-mutant, and TP53-wt subtype, respectively. A TIME comparison between the sub-stratified subgroups of our cohort revealed upregulated tumor infiltration of immune cells in the low-risk subgroups. Our study demonstrates that targeted DNA sequencing is an effective one-stop strategy to classify EC. Immunomodulatory genes may serve as prognostic markers within subtypes.

Oncological and reproductive outcomes after fertility-sparing surgery in patients with seromucinous borderline ovarian tumor: Results of a large retrospective study.

OBJECTIVE: To evaluate the oncological and reproductive outcomes in patients with seromucinous borderline ovarian tumors (SMBOT) treated with fertility-sparing surgery (FSS). METHODS: We retrospectively reviewed the medical records of patients with SMBOT who underwent surgery between 2000 and 2019. A centralized histological review was performed and recurrence rates were compared between different surgical procedures. RESULTS: A total of 105 patients fulfilled the inclusion criteria, of whom 65 underwent FSS and 40 were treated with radical surgery (RS). Fourteen patients had recurrent disease after a median follow-up time of 59.6 months (range: 22.1-256.8 months). All but one relapsed with SMBOT. There was no significant difference in disease-free survival (DFS) between the two groups (P = 0.141). Multivariate analysis showed that only bilateral involvement was associated with increased recurrence (P = 0.008). In the subgroup of patients treated with conservative surgery, there was no significant difference in DFS with regard to surgical procedures (ovarian cystectomy vs salpingo-oophorectomy, P = 0.487). Of the 12 patients in the FSS group who developed recurrence, 11 underwent a second round of FSS and all remained alive with no evidence of disease at the end of follow-up. Of 20 patients desiring pregnancy, 16 patients were successful and resulted in 17 term deliveries. CONCLUSIONS: FSS is feasible for young patients who wish to preserve their fertility. Patients initially treated with ovarian cystectomy may be managed by close surveillance if post-operative imaging are negative. Repeat FSS remains a valuable alternative for young patients with recurrent SMBOT after thorough communication.

Oncological and reproductive outcomes for gonadotropin-releasing hormone agonist combined with aromatase inhibitors or levonorgestrel-releasing intra-uterine system in women with endometrial cancer or atypical endometrial hyperplasia.

OBJECTIVE: To evaluate the efficacy and safety of gonadotropin-releasing hormone agonist (GnRHa) combined with a levonorgestrel-releasing intrauterine device (LNG-IUD) or aromatase inhibitor (letrozole) in women with endometrial carcinoma or atypical endometrial hyperplasia who wished to preserve fertility. METHODS: Patients at the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital between January 2013 and December 2020 were retrospectively reviewed. A total of 179 patients who were unsuitable to undergo treatment with high-dose oral progestin, including those with progestin allergies, body mass index ≥30 kg/m2, liver and/or renal dysfunction, hypercoagulable state, and thrombosis were included. Patient data were retrieved from medical records and a prospectively maintained database that represented the standard protocol was followed for all patients. Clinical characteristics, treatment outcomes, adverse events, and reproductive outcomes were collected and analyzed. Logistic regression models were constructed to determine the associations between complete remission, recurrence, and fertility. RESULTS: Overall, 169 patients (94.4%) achieved complete remission; 58 (96.7%) had atypical endometrial hyperplasia and 111 (93.3%) had endometrial carcinoma. The complete remission rates for the GnRHa plus LNG-IUD and GnRHa plus letrozole groups were 93.5% and 95.8%, respectively. The median time to complete remission was 6 (range 3-18) months: 4 (range 3-10) months for atypical endometrial hyperplasia and 8 (range 3-18) months for endometrial carcinoma. After a median follow-up of 27.5 (range 3-92) months, 41 (24.3%) women developed recurrence, with a median recurrence time of 17 (range 6-77) months. Of the patients with complete remission, 134 patients desired to conceive and 42 (32.3%) became pregnant, 24 (17.9%) were successfully delivered, 5 (3.7%) were still pregnant, while 13 miscarried. CONCLUSION: GnRHa combined treatment provides favorable oncological and reproductive outcomes. Larger multi-institutional studies are required to confirm these preliminary findings.

Surgical staging of apparent early-stage ovarian mucinous carcinoma.

OBJECTIVES: The aim of the study was to explore the rate of upstaging after complete surgical staging among patients with apparent FIGO stage I ovarian mucinous carcinoma. METHODS: Ovarian mucinous carcinoma patients with surgical treatment at the Peking Union Medical College Hospital between October 2020 and January 1994 were retrospectively reviewed. RESULTS: In total, 163 patients were included in this study. Surgical restaging was performed in 89 patients after initial incomplete surgical staging, and one-step complete surgical staging was performed in 74 patients. Among these initially incompletely staged patients, residual tumors were found in 16 patients (16/89, 17.9%). Among the 19 patients with apparent FIGO stage IA, no patient was found to have residual tumors after incomplete staging surgery, according to the final pathology result of restaging surgery. Ovarian cystectomy (OR=4.932, 95% CI= 1.347-18.058, P=0.016) was an independent risk factor for residual tumors after incomplete staging surgery. Among all 163 patients, upstaging occurred in 15 patients (15/163, 9.2%). Among 44 apparent FIGO stage IA patients, no patient was upstaged to FIGO II-IVB. Moreover, both a history of ovarian mucinous tumor (OR=4.745, 95% CI= 1.132-19.886, P=0.033) and bilateral ovary involvement (OR=9.739, 95% CI= 2.016-47.056, P=0.005) were independent risk factors for upstaging to FIGO stage II-IVB. CONCLUSIONS: For patients with apparent FIGO stage IA disease, the possibility of residual tumors and upstaging is relatively low. For patients with cystectomy, bilateral mucinous carcinomas, or a history of ovarian mucinous tumors, complete staging surgery maintains greater significance.

Low-grade endometrial stromal sarcoma with intracaval or intracardiac extension: a retrospective study of eight cases.

PURPOSE: This study aimed to improve the knowledge of low-grade endometrial stromal sarcoma (LG-ESS) with intracaval or intracardiac extension and tried to identify the potential risk factors and optimal treatment method influencing prognosis. METHODS: We performed a retrospective review of eight LG-ESS patients with intracaval or intracardiac extension who underwent treatment at Peking Union Medical College Hospital between 2012 and 2020. RESULTS: The median age at diagnosis was 44 years, ranging from 28 to 56 years. Abnormal uterine bleeding was the most common intimal symptom (3/8), followed by low back discomfort (2/8), edema of the lower limbs (2/8), abdominal pain (1/8), and dyspnea (1/8). All patients underwent resection of the intravascular and extravascular portions of the tumor. Two patients were in stage IIIC, and six were in stage IVB. After surgery, four patients received adjuvant radiotherapy, of whom three also received letrozole. One patient was treated with letrozole alone, and one patient received medroxyprogesterone. The average follow-up time was 34.5 months, ranging from 6 to 98 months. No patients died or relapsed during the follow-up period. CONCLUSIONS: LG-ESS with intracaval or intracardiac extension is an uncommon type of tumor which is easily misdiagnosed and can only be diagnosed by histological evaluation after surgery. Complete tumoral excision followed by adjuvant therapy may benefit patient survival time. Long-term follow-up is essential due to the high rate of late recurrence.

[Clinical Characterization of Patients with Ovarian Mass Combined with Dysplasia of Secondary Sexual Characteristics].

Objective To investigate the clinical characteristics of preadolescent and adolescent female patients with ovarian mass combined with dysplasia of secondary sexual characteristics. Methods This study retrospectively analyzed 18 cases of ovarian mass combined with dysplasia of secondary sexual characteristics aged 0-19 years admitted to Peking Union Medical College Hospital from January 2012 to November 2019.By analyzing the clinical manifestations,surgical methods,postoperative pathology,therapies and prognosis of the cases,we summarized the diagnosis and treatment ideas. Results Among the 18 cases,7(7/18,38.9%)developed secondary sex signs before puberty,including 5 cases showing precocity(including 2 cases of juvenile granulosa cell tumor,1 case of gonadoblastoma,1 case of ovarian follicular cyst,and 1 case of 46,XY simple gonadal dysplasia combined with dysgerminoma)and 2 cases presenting masculine manifestations(1 case of steroid cell tumor and 1 case of sclerosing stromal tumor).The rest 11(11/18,61.1%)cases showed abnormal development of secondary sexual characteristics during puberty,including 8 cases with masculine manifestations or abnormal menstruation after menarche(7 cases with sex cord stromal cell tumor and 1 case with cystic granulosa cell tumor),2 cases with primary amenorrhea(1 case with androgen insensitivity syndrome combined with testicular sertoli cell tumor and 1 case with endometriosis cyst combined with reproductive tract malformation),and 1 case diagnosed as 46,XX gonadal dysplasia with serous cystadenoma and no secondary sexual development during puberty. Conclusions Sex hormone levels should be actively tested in the case of prepubertal secondary sexual characteristics appearing early,pubertal secondary sexual characteristics being abnormal(underdevelopment),and/or menstrual abnormalities.Imaging examination should be performed to exclude ovarian organic lesions,and chromosome karyotype analysis should be performed if necessary.The diagnosis of ovarian mass in preadolescent and adolescent females with related symptoms should first be alerted to cord stromal cell tumor.It is recommended to rule out the possibility of combined reproductive tract malformation in the adolescent patients with primary amenorrhea.Chromosome examination should be conducted to rule out the possibility of gonadal dysplasia in the adolescent patients with primary amenorrhea and/or no development of secondary sexual characteristics.

Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer.

BACKGROUND & AIMS: Our previous genomic whole-exome sequencing (WES) data identified the key ErbB pathway mutations that play an essential role in regulating the malignancy of gallbladder cancer (GBC). Herein, we tested the hypothesis that individual cellular components of the tumor microenvironment (TME) in GBC function differentially to participate in ErbB pathway mutation-dependent tumor progression. METHODS: We engaged single-cell RNA-sequencing to reveal transcriptomic heterogeneity and intercellular crosstalk from 13 human GBCs and adjacent normal tissues. In addition, we performed WES analysis to reveal the genomic variations related to tumor malignancy. A variety of bulk RNA-sequencing, immunohistochemical staining, immunofluorescence staining and functional experiments were employed to study the difference between tissues with or without ErbB pathway mutations. RESULTS: We identified 16 cell types from a total of 114,927 cells, in which epithelial cells, M2 macrophages, and regulatory T cells were predominant in tumors with ErbB pathway mutations. Furthermore, epithelial cell subtype 1, 2 and 3 were mainly found in adenocarcinoma and subtype 4 was present in adenosquamous carcinoma. The tumors with ErbB pathway mutations harbored larger populations of epithelial cell subtype 1 and 2, and expressed higher levels of secreted midkine (MDK) than tumors without ErbB pathway mutations. Increased MDK resulted in an interaction with its receptor LRP1, which is expressed by tumor-infiltrating macrophages, and promoted immunosuppressive macrophage differentiation. Moreover, the crosstalk between macrophage-secreted CXCL10 and its receptor CXCR3 on regulatory T cells was induced in GBC with ErbB pathway mutations. Elevated MDK was correlated with poor overall survival in patients with GBC. CONCLUSIONS: This study has provided valuable insights into transcriptomic heterogeneity and the global cellular network in the TME, which coordinately functions to promote the progression of GBC with ErbB pathway mutations; thus, unveiling novel cellular and molecular targets for cancer therapy. LAY SUMMARY: We employed single-cell RNA-sequencing and functional assays to uncover the transcriptomic heterogeneity and intercellular crosstalk present in gallbladder cancer. We found that ErbB pathway mutations reduced anti-cancer immunity and led to cancer development. ErbB pathway mutations resulted in immunosuppressive macrophage differentiation and regulatory T cell activation, explaining the reduced anti-cancer immunity and worse overall survival observed in patients with these mutations.

Oncological and Reproductive Outcomes of Cystectomy Compared with Unilateral Salpingo-Oophorectomy as Fertility-Sparing Surgery in Patients with Apparent Early Stage Pure Immature Ovarian Teratomas.

PURPOSE: To compare the oncological and reproductive outcomes of patients with apparent early stage pure ovarian immature teratomas (IMTs) treated with unilateral salpingo-oophorectomy (USO) or cystectomy. PATIENTS AND METHODS: We retrospectively reviewed the medical records of patients with apparent early stage pure ovarian IMTs who received fertility-sparing surgery (FSS) between 1984 and 2019. FSS was defined as preservation of the uterus and at least one adnexa. Recurrence rates were compared between patients receiving USO and cystectomy. Reproductive outcomes and menstrual histories were assessed by telephone interview. RESULTS: A total of 124 patients were included, of whom 83 underwent USO and 41 underwent cystectomy. After a median follow-up of 70.6 months (range: 6.2-410.6 months), eight patients suffered recurrences (5 in the USO group and 3 in the cystectomy group). The median times to recurrence were 5.0 and 5.1 months in the USO and cystectomy groups, respectively (P = 0.764). All patients with recurrence were successfully salvaged by surgery, except for one death. Univariate analysis showed no difference in disease-free survival and overall survival between the groups (P = 0.781, 0.155). Of the 111 patients contacted by telephone, 97 resumed menstruation following the surgery. Of the 31 patients desiring pregnancy, 26 achieved 28 pregnancies. USO (83.3%), like cystectomy (85.7%), resulted in excellent pregnancy rates. CONCLUSIONS: A USO is the standard treatment for women with early stage pure IMTs who want to preserve fertility. However, a cystectomy with adjuvant chemotherapy may be a suitable fertility-sparing therapy when a cystectomy is the only surgical option.

Alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC): a retrospective study of 27 cases.

OBJECTIVE: The aim of the study was to investigate the relative risk factors associated with the prognosis and effective treatments of alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC). METHOD: We presented three cases of AFP-producing EOC and performed a brief review to summarize the clinicopathological features and prognostic factors of 24 cases that have been previously reported. We evaluated the correlations among prognostic and clinical parameters, such as stage, pathology and chemotherapy regimens. In addition, a retrospective review of these 27 cases was conducted, and survival curves were estimated using the Kaplan-Meier method. RESULTS: The patients were aged between 23 and 77 years. The median overall survival was 10 months, and ten (37.04%) patients died within 18 months. We compared the overall mean survival times of all patients in different stages, and the results suggest that the postoperative pathological staging is hardly correlated with prognosis (P = 0.76). There was a correlation between pathology and prognosis (P = 0.0018). The mean survival time was longer for patients who had undergone chemotherapy than for those without chemotherapy (14.88 vs 0.65 months) (P < 0.0001). Moreover, although patients had a good response to the regimens for PEB and TC (P = 0.004), there was no significant difference between PEB and TC (P = 0.386). CONCLUSIONS: AFP-producing EOC is uncommon and regarded as an extremely malignant type of tumor. Patients with chemotherapy may have a longer survival time; additionally, PEB and TC may be an optimal selection for this kind of tumor. Further large-scale studies are needed to confirm our findings.

Clinical Characteristics and Mutation Analyses of Ovarian Sertoli-Leydig Cell Tumors.

BACKGROUND: There are limited studies on Sertoli-Leydig cell tumors (SLCTs) and no data in the population of Chinese patients with SLCTs from the genetic level. In addition, previous studies on SLCTs have focused exclusively on mutations in the DICER1 gene and no data exists on the genetic landscape of SLCTs. METHODS: Patients with moderately or poorly differentiated SLCTs who underwent surgical resection between January 2012 and October 2018 in our institution were recruited. Whole exome sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue and peripheral blood or normal tissue samples. RESULTS: Seventeen patients were recruited with 19 tumor samples. The rate of tumor-associated germline mutations was 6 of 17 (35.3%), and that of DICER1 germline mutations was 4 of 17 (23.5%). Regarding clinical relapse, patients with germline tumor-associated mutations had significantly poorer prognosis than those without (p = .007), and those with germline DICER1 mutations were relatively more likely to exhibit clinical relapse, although not to a significant degree (p = .069). Regarding somatic mutations, firstly, the subclone evolution analysis demonstrated that the two tumors on the contralateral ovary were primary tumors, respectively. Secondly, somatic mutations were most commonly found in CDC27 (10/19, 52.6%), DICER1 (4/19, 21.1%), and MUC22 (4/19, 21.1%). And the analysis of cancer cell fractions showed that DICER1 mutations were correlated with tumorigenesis of SLCTs. The rates of germline and somatic DICER1 mutations were higher in patients who were younger than 18 years than those in older patients (p = .022 and p = .001, respectively). CONCLUSION: Our study indicates that genetic testing may have important clinical significance for patients with SLCTs, particularly for younger patients. IMPLICATIONS FOR PRACTICE: Bilateral ovarian Sertoli-Leydig cell tumors were verified to be primary tumors from the genetic perspective. The rates of germline and somatic DICER1 mutations were 4 of 17 (23.5%) and 4 of 19 (21.1%), respectively. The rates of germline and somatic DICER1 mutations were higher in patients who were younger than 18 years than those in older patients (p = .022 and p = .001, respectively).

Diagnosis and management of growing teratoma syndrome after ovarian immature teratoma: A single center experience.

OBJECTIVES: To evaluate the diagnostic, surgical, and oncological outcomes of patients with growing teratoma syndrome (GTS). METHODS: Patients diagnosed with ovarian immature teratoma (IMT) between 1980 and 2018 at Peking Union Medical College Hospital (PUMCH) were evaluated for the development of GTS. Their clinical characteristics, surgical and pathological data, and oncological outcomes were collected. RESULTS: Between 1980 and 2018, 175 cases of IMT were referred to PUMCH. Thirty-five patients subsequently developed GTS with a crude rate of approximately 20%. The median interval between the initial diagnosis of IMT and the first occurrence of GTS was 18.5 months (range, 6-78 months). Residual disease (P < 0.001) and gliomatosis peritonei (GP) at initial surgery (P = 0.023) were independent risk factors for GTS development. Fertility-sparing surgery for GTS was performed in 27 patients and four patients achieved five singleton pregnancies. The median follow-up time was 73 months (range, 11-401 months). Eleven patients developed at least one recurrence. Residual disease after GTS surgery was associated with GTS recurrence (P = 0.001). By the end of follow-up, 27 patients were alive without disease and the other eight patients were alive with disease. CONCLUSION: The presence of residual disease and GP at initial surgery are risk factors for GTS. Complete surgical resection is the cornerstone for treatment of GTS. The presence of residual disease after surgery for GTS is a risk factor for GTS recurrence. Fertility-sparing surgery should be performed because spontaneous pregnancy is possible. The overall prognosis of GTS is excellent.

Role of staging surgery and adjuvant chemotherapy in adult patients with apparent stage I pure immature ovarian teratoma after fertility-sparing surgery.

OBJECTIVE: The standard treatment for young patients with stage I malignant ovarian germ cell tumors, except stage I dysgerminoma and stage IA G1 immature teratoma, is unilateral salpingo-oophorectomy with complete staging surgery followed by platinum-based chemotherapy. However, the role of complete staging surgery and adjuvant chemotherapy remains controversial. The aim of this study was to investigate the role of complete staging surgery and adjuvant chemotherapy in patients with early-stage pure immature teratoma after fertility-sparing surgery. METHODS: Patients with stage I pure immature teratoma who underwent fertility-sparing surgery between January 1986 and June 2018 were reviewed retrospectively. Fertility-sparing surgery was defined as preservation of the uterus and at least one adnexa. The inclusion criteria were age >18 years, stage I disease (confined to one ovary), and diagnosis of pure immature teratoma. Patients with distant metastasis or mixed ovarian germ cell tumor were excluded. Complete staging surgery was defined as peritoneal cytology examination, peritoneal biopsy, omentectomy, or omental biopsy with or without lymph node dissection. Patients designated with stage I disease without complete staging surgery were categorized as stage X. Disease-free survival was defined as the interval from the date of surgery to the date of recurrence or censoring. Disease-free survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 75 patients were included in the analysis, with a median age of 26 years (range 18-40): 26 (34.7%) patients had received complete staging surgery; 51 (68%) patients received postoperative adjuvant chemotherapy while 24 (32%) underwent surgery alone; and 4 patients (5.3%) had recurrent disease during a median follow-up time of 80.2 months (range 13.7-261). The recurrence rates in the chemotherapy group and surveillance groups were 3.9% and 8.3%, respectively (p=0.46). All patients were successfully salvaged, except for one death. Tumor relapse occurred in patients with all grades of immature teratoma (G1: 1/35; G2: 2/25; G3: 1/15). Univariate analysis revealed that complete staging surgery, adjuvant chemotherapy, and tumor grade were not associated with 5 year disease-free survival (p=0.69, p=0.46, p=0.7, respectively). The 5 year disease-free survival rate was 94.6% and the overall survival rate was 98.7%. CONCLUSION: Adult patients with stage I pure immature teratoma had 98.7% overall survival and recurrence rates were low after fertility-sparing surgery.

Outcomes and prognostic factors of patients with recurrent and persistent malignant ovarian germ cell tumors.

OBJECTIVE: Due to the rarity of recurrent and persistent malignant ovarian germ cell tumors (MOGCTs), there is no standardized protocol for salvage therapy. This study aimed to investigate the outcomes and prognostic factors of patients with recurrent and persistent MOGCTs. METHODS: Clinical data for 59 patients with recurrent and persistent MOGCTs admitted to Peking Union Medical College Hospital from January 1, 2000, to April 30, 2018, were retrospectively analyzed. RESULTS: Twenty-one cases (35.6%) were recurrent, and 38 (64.4%) were persistent. Patient age ranged from 1 to 39 years, and disease stage was as follows: 33 stage I, 4 stage II, 21 stage III, and 1 stage IV. There were 19 immature teratomas, 26 yolk sac tumors, 1 dysgerminoma, and 13 mixed germ cell tumors. Regarding the primary surgery, fertility was preserved in 49 patients and not preserved in 10 patients. Among the patients who underwent fertility-preserving primary surgery, 40 had fertility preserved in the second operation, and 9 did not. In the mean follow-up of 52.6 months (range 2-279 months) after recurrence, 19 patients (32.2%) experienced a second relapse, and 16 (27.1%) died. The 5-year survival and progression-free survival rates after relapse were 70.0% and 67.0%, respectively. The optimal salvage surgery and chemotherapy regimen after relapse were independent prognostic factors (P < 0.05). CONCLUSIONS: The prognosis of recurrent and persistent MOGCTs was good after salvage therapy. The optimal salvage surgery and adjuvant standardized chemotherapy significantly impact patient prognosis. For young nulliparous patients, secondary fertility-sparing salvage therapy can be considered.