Background/Objectives: In order to develop a comprehensive understanding of gastric-type endocervical adenocarcinoma (GEA), an increasingly prevalent HPV-independent cervical cancer, we summarized clinicopathological information and performed prognostic analysis. Methods: A total of 182 patients diagnosed with GEA at our center during the period 2014-2025 were included in this study. Nineteen GEA cases, 6 HPV-independent non-GEA cases, 59 HPV-associated usual endocervical adenocarcinoma cases, and 66 squamous cell carcinoma cases from online database were also included. Results: Vaginal bleeding (39.56%) and watery discharge (35.16%) were the most common symptoms. As many as 21.43% of patients had no specific complaints, and 80% of GEA showed no distinct mass through gynecological examination. A total of 64% of GEA were stage IIB-IV at diagnosis, with a 5-year survival of 41% versus 85% for stage I-IIA (p < 0.05). The rate of lymphovascular space invasion (LVSI), lymph node metastasis, and ovarian metastasis were 49.64%, 42.00%, and 29.29%, respectively. The 5-year survival and recurrence rates after primary therapy were 57% and 23%, respectively. For GEA treatment, surgery might be associated with improved overall survival for the population at stage III-IV. Survival analysis identified deep infiltration depth (≥2/3), a maximum diameter of the tumor (MDOT) of ≥3 cm, and ovary metastasis as potential indicators of worse OS and PFS for whole patients. Additionally, ovary metastasis indicated poor PFS and OS for stage I-II. Genomic information TP53 mutation, PTEN deletion and STK11 mutation might be the most prevalent genomic alterations. Conclusions: These findings indicated GEA as an aggressive cervical cancer, with high rate of lymph node metastasis, high recurrence rate and short 5-year survival. Ovary metastasis reflected advanced disease burden and surgery might be associated with improved survival in advanced stage. For genomic information, GEA showed genetic heterogeneity and a low level of genomic instability.

Abstract Ovarian cancer is the most lethal gynecologic malignancy, characterized by tumor heterogeneity and a high recurrence rate. Patient-derived in vitro tumor models offer a promising strategy for individualized drug screening to overcome limitations of systemic therapy. Among existing modeling methodologies, 3D bioprinting exhibits advantages including high-throughput, high fidelity, and a drug screening timeline of 8 days. Here, we present experimental data of a cohort of novel 3D bioprinted patient-derived ovarian cancer (3DP-OC) models. We established 3DP-OC models by mixing primary ovarian cancer cells with Gelatin Methacryloyl (GelMA) and photoinitiator, and bioprinting in a layer-by-layer manner. In total, 3DP-OC from 79 patients were successfully established, including 61 high-grade serous ovarian cancer patients, 9 ovarian clear cell carcinoma patients, 4 ovarian sarcoma patients, 4 ovarian endometrioid carcinoma patients, and 1 ovarian neuroendocrine cancer patient. 113 3DP-OC models were constructed from different tissue origins (primary lesion and metastatic sites) with high cell viability maintained throughout bioprinting and prolonged in vitro culture. Bulk RNA sequencing and immunohistochemistry confirmed that key molecular markers and Ki-67 levels in 3DP-OC models closely resembled those of their paired tumor tissues, demonstrating that 3DP-OC can serve as a patient avatar for drug sensitivity testing. On days in vitro 5, 3DP-OC models were exposed to gradient concentrations of 15 frequently used chemotherapeutic and targeted drugs in ovarian cancer including paclitaxel, carboplatin, olaparib, etc. Cell viability was quantified to calculate IC50 values of different anti-tumor drugs. Drug sensitivity testing revealed substantial interpatient heterogeneity in therapeutic responses. To further investigate whether this response heterogeneity has clinical relevance, we conducted a prospective observational cohort study that enrolled 41 stage III/IV newly diagnosed ovarian cancer patients. Patients were divided into “3DP-OC identified sensitive group” or “3DP-OC identified resistant group” according to 3DP-OC IC50 values of anti-tumor drugs they received. The median follow-up time for all patients was 580.5 days. The 3DP-OC identified sensitive group exhibited significantly prolonged progression-free survival compared to the 3DP-OC identified resistant group (P < 0.05), with disease progression observed in 16.7% (4/24) and 52.9% (9/17) of patients, respectively. In this study, we established a 3D bioprinted patient-derived cancer model with high success rate of establishment, low intra-batch heterogeneity, and high biological fidelity. 3DP-OC model holds promise for predictive utility in precision oncology as well as the potential to serve as an innovative platform that bridges fundamental cancer research and clinical practice. Citation Format: Jiangang Zhang, Huiyu Yang, Ying Shan, Zihan Zhong, Ziren Kong, Yuning Sun, Huayu Yang, Lingya Pan, Yilei Mao, Ying Jin. Predicting therapy efficacy and revealing tumor heterogeneity using patient-derived 3D bioprinted ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4860.

Background Tertiary lymphoid structures (TLSs) are organized immune aggregates that are associated with favorable outcomes in several solid tumors, but their role in endometrial cancer (EC) remains unexplored. Methods We retrospectively analyzed 93 patients with EC who underwent surgery in a single team at Peking Union Medical College Hospital. TLSs were identified by hematoxylin‒eosin staining and immunohistochemical or immunofluorescence analyses for CD20, CD8, CD4, CXCL13, and CXCR5 expression. Associations with clinicopathological variables and survival were evaluated. Results TLSs were detected in 35 patients (37.6%). They consisted of dense CD20⁺ B cell clusters admixed with CD8⁺ and CD4⁺ T cells and exhibited specific upregulation of the CXCL13/CXCR5 axis. CD20⁺ B cell density was positively correlated with the number of TLSs and with CD8⁺ and CD4⁺ T-cell infiltration. During a median follow-up of 58.1 months, patients with TLSs had significantly improved progression-free survival (PFS, P = 0.032) and overall survival (OS, P = 0.046). Multivariate analysis revealed the presence of TLSs as an independent predictor of reduced recurrence risk (HR 0.125, 95% CI 0.024–0.667; P = 0.015). High coexpression of CD20 and CD8 was associated with the best PFS (P = 0.028), whereas high CD20 expression with low CD4 expression was correlated with the best OS (P = 0.048). Conclusions TLSs are present in patients with EC and confer a significant survival advantage. These findings highlight B-cell-mediated immunity and the CXCL13/CXCR5 axis as promising prognostic biomarkers and potential therapeutic targets in this disease.

Although poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and bevacizumab were approved as first-line maintenance for advanced ovarian cancer (OC), evidence comparing this combination with PARPi monotherapy, especially in BRCA-mutated/homologous recombination-deficient (HRD) patients, is lacking. This study compared combined fuzuloparib (a PARPi) plus apatinib (a vascular endothelial growth factor receptor-2 inhibitor) with either fuzuloparib or placebo as first-line maintenance in patients with advanced OC. Patients who had newly diagnosed, advanced OC and responded to first-line, platinum-based chemotherapy were randomized 2:2:1 to receive combined fuzuloparib (100 mg twice daily) plus apatinib (375 mg daily), fuzuloparib (150 mg twice daily) plus placebo, or double-placebo treatment. The primary end point was blinded independent review committee (BIRC)-assessed progression-free survival (PFS). Six hundred seventy-four patients were randomized to receive fuzuloparib plus apatinib (n = 269), fuzuloparib (n = 269), or placebo (n = 136). At the final analysis (November 1, 2024; 385 BIRC-assessed PFS events; median follow-up, 40 months), the median BIRC-assessed PFS was 26.9 months with the combination versus placebo (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.44-0.75; one-sided p < .0001) and 29.9 months with fuzuloparib monotherapy versus placebo (HR, 0.58; 95% CI, 0.44-0.75; one-sided p < .0001) compared with 11.1 months with placebo. A PFS benefit was observed regardless of germline BRCA1/2 mutation status. In homologous recombination-deficient patients (including those with BRCA1/2 mutations), combined fuzuloparib and apatinib produced a PFS similar to that of fuzuloparib (34.1 vs. 35.8 months, respectively); in homologous recombination-proficient patients, PFS had a trend favoring the combination (16.6 vs. 11.0 months; HR, 0.73; 95% CI, 0.45-1.19). Both treatments were well tolerated. Overall survival was immature. Both fuzuloparib and combination therapy improved PFS compared with placebo as maintenance therapy for patients who had newly diagnosed, advanced OC. Adding apatinib to fuzuloparib did not prolong PFS among homologous recombination-deficient patients. There was a PFS benefit trend among homologous recombination-proficient patients who received combination therapy compared with those who received monotherapy.

PURPOSE:Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological malignancies. Although treatment options for newly diagnosed advanced EOC include primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), the comparative effectiveness of these strategies remains uncertain across different disease stages. MATERIALS AND METHODS:We conducted a retrospective analysis of 297 patients with EOC whose initial treatment strategy was guided by predicted primary resectability using the Suidan model. We assessed their progression-free survival (PFS) and overall survival outcomes stratified by FIGO stage and treatment approach (PDS v NACT-IDS). We also explored molecular markers associated with prognosis and chemotherapy response. RESULTS:Our analysis revealed that patients with stage IIIC EOC had improved survival outcomes with PDS, whereas those with stage IV disease benefited more from NACT-IDS. Furthermore, CDKL3 was identified as a gene associated with poor prognosis and platinum resistance, potentially contributing to the observed differential survival patterns across stages. CONCLUSION:These findings suggest that FIGO stage provides additional value in guiding the selection of patients with EOC who may benefit from neoadjuvant chemotherapy. CDKL3 may serve as a promising biomarker for treatment stratification and a therapeutic target to overcome chemoresistance.

OBJECTIVE:To investigate the prognostic impact of metastatic lymph nodes (MLNs) on advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT). METHODS:This was a retrospective cohort study using data from patients managed by a single gynecological team between June 2012 and June 2023. Among EOC patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV disease, patients who received NACT and who underwent complete cytoreduction during interval debulking surgery were included (the NACT cohort), together with patients who received primary debulking surgery (PDS, including those with both complete and incomplete cytoreduction). Clinically suspicious lymph nodes at diagnosis and/or debulking surgeries were resected. Differences in terms of clinicopathological features, survival profiles, and recurrence patterns were analyzed between groups with different lymph node statuses. RESULTS:The NACT cohort comprised 166 patients (53.6% underwent lymphadenectomy), of whom 58 presented with MLNs (the MLN group) and 108 did not (the NLN group). Among those who underwent lymphadenectomy, a median of 24 pelvic lymph nodes and 13 para-aortic lymph nodes were resected. The MLN group was significantly associated with inferior progression-free survival (PFS) and time to platinum-resistant recurrence (TTPR), even when adjusted by multivariate models. The hazard ratio (95% confidence interval) was 1.90 (1.06-3.41) for the multivariate PFS analysis and 2.50 (1.22-5.13) for the multivariate TTPR analysis. For the PDS cohort (143 patients, 68.5% underwent lymphadenectomy), a median of 25 pelvic lymph nodes and 14 para-aortic lymph nodes were resected. The MLN group (66 patients) manifested non-inferior PFS and TTPR outcomes compared to the NLN group (77 patients). CONCLUSIONS:MLNs may have a negative impact on the prognosis of patients receiving NACT. For such patients, PDS is a preferred choice to delay recurrence and platinum resistance.

OBJECTIVE:The current treatment for early-stage neuroendocrine carcinoma of the cervix (NECC) mainly relies on operation and chemotherapy. We want to evaluate values of postoperative radiation in early-stage NECC. METHODS:Retrospective cohort study. Early-stage NECC patients from 2006 to 2022 in our hospital were included and divided into Postoperative non-radiation group (Group A) and Postoperative radiation group (Group B). We use Kaplan-Meier method to analyze the progression-free survival (PFS), overall survival (OS), recurrence and OS rate. RESULTS:Sixty-six cases were included, 32 (48.5%) in Group A and 34 (51.5%) in Group B. After 35 (range 12-116) months follow-up, 26 (39.4%) had recurrence. Compared with Group A, Group B had lower pelvic recurrence rate (12.5% vs 2.9%, p = 0.142), higher distant recurrence rate (28.1% vs 44.1%, p = 0.177), and similar mortality rate (29.4% vs 31.3%, p = 0.871). Postoperative radiation in patients with cervical stromal invasion ≥1/2 showed an extended trend in PFS (33.9 months vs 47.9 months) and OS (40.7 months vs 70.0 months) but without statistical difference (p = 0.963, p = 0.636). Lymph-vascular space invasion (LVSI) is a high-risk factor for tumour recurrence (HR 9.13, p = 0.005), but radiation after surgery did not improve the PFS (51.5 months vs 48.8 months, p = 0.942) and OS (53.9 months vs 60.6 months, p = 0.715) in patients with LVSI. LIMITATIONS:Retrospective study and relative small sample size. CONCLUSIONS:Postoperative radiation seems to prolong PFS and OS in patients with cervical stromal invasion ≥1/2. LVSI was a high-risk factor for tumour recurrence, but radiation after surgery in patients with LVSI seems have no survival benefits.

Objective: To evaluate the surgery combined chemotherapy and radiation in locally advanced neuroendocrine carcinoma of the cervix (NECC) . Methods: This is a single-center retrospective cohort study. Locally advanced NECC patients admitted to Peking Union Medical College Hospital, Chinese Acadmy of Medical Sciences from January 2011 to April 2022 were enrolled. They were divided into concurrent chemoradiotherapy group, and surgery combined with chemotherapy and radiation group. The Kaplan-Meier method was used to analyze the progression free survival (PFS), overall survival (OS), recurrence rate, and mortality rate. Results: (1) Forty-six cases were included, 22 in concurrent chemoradiotherapy group, 24 in surgery combined chemotherapy and radiation group. With 16 patients (35%, 16/46) received neoadjuvant chemotherapy (NACT), the NACT effective rate was 15/16. (2) The median follow-up time was 27.5 months (range: 10-106 months), with 26 (57%, 26/46) experienced recurrences. There were 4 (9%, 4/46) pelvic recurrences and 25 (54%, 25/46) distant recurrences, and 3 (7%, 3/46) both pelvic and distant recurrences. Compared with concurrent chemoradiotherapy group, surgery combined chemotherapy and radiation group had lower pelvic recurrence rate [14% (3/22) vs 4% (1/24); χ2=1.296, P=0.255] but without statistic difference. Both groups had similar distant recurrence rate [55% (12/22) vs 54% (13/24); χ2=0.001, P=0.979] and overall recurrence rate [59% (13/22) vs 54% (13/24); χ2=0.113, P=0.736]. (3) During the follow-up period, 22 cases (48%, 22/46) died, with 11 cases (50%, 11/22) in concurrent chemoradiotherapy group and 11 cases (46%, 11/24) in surgery combined chemotherapy and radiation group, without significant difference (χ2=0.080, P=0.777). The postoperative 3-year and 5-year OS rates were 62.3% and 36.9%. Compared with concurrent chemoradiotherapy group, the patients in surgery combined chemotherapy and radiation group showed an extended trend in PFS (17.0 vs 32.0 months) and OS (37.0 vs 50.0 months) but without statistic differences (P=0.287, P=0.125). Both groups had similar 3-year OS rate (54.2% vs 69.9%; P=0.138) and 5-year OS rate (36.1% vs 38.8%; P=0.217). Conclusions: Our study supports the multi-modality treatment strategy (including surgery, chemotherapy and radiation) as an important component in the treatment of locally advanced NECC. The combination of surgery, chemotherapy and radiation seems to have advantages in the treatment of locally advanced NECC, but needs to be confirmed by further multicenter studies.

e15088 Background: Patient-derived tumor model offers an individualized approach to overcome interpatient heterogeneity in cancer therapy. 3D bioprinting (3DB) enables construction of in vitro model with high-throughput, high-fidelity, and high efficacy. We hereby report a pipeline of establishing pan-cancer patient-derived 3DB (PT-3DB) models with personalized drug sensitivity results in 148 patients from multiple medical centers. Methods: Tumor tissues of 148 patients were collected with informed consent at 4 medical centers in Beijing, Hangzhou and Ningbo from 2022-12 to 2023-12. Tumors were digested into cell suspension and mixed with GelMA, and PT-3DB was fabricated by extrusion-based bioprinter. A panel of chemotherapies and targeted therapies was selected based on first-line treatment of corresponding cancer type. PT-3DB was treated with drugs in dose gradient at DIV 5. Cell viability was measured by ATP quantification at DIV 8 and dose-response curve and IC50 of each drug was calculated. Results: We have established PT-3DB in 148 patients with success rate of > 95% and turnaround time of only 8 days. 137 were surgically resected samples and 11 were biopsy samples. Cancer types included ovarian cancer (OC, n = 52), colorectal cancer (CRC, n = 51), hepatobiliary cancer (HBC, n = 17), breast cancer (BC, n = 10), high-grade glioma (HGG, n = 10), cervical cancer (CC, n = 4), pancreatic cancer (PC, n = 2), and gastric cancer (GC, n = 2). A total of 27 drugs were screened, of which 15 were chemotherapies and 12 were targeted therapies. The median number of drugs tested for each patient was 5 (4-6) (Q25-Q75). Significant interpatient heterogeneous drug response was observed within each cancer type and between tumors with the same treatment regime. Representative data were presented in the attached table. Conclusions: We have successfully constructed pan-cancer PT-3DB platform for personalized drug screening in 148 cases, with outstanding stability across multiple centers. The timeline of 8 days preceded pathological diagnosis, which is the earliest start of systematic treatment, underscoring its high translational potential. PT-3DB has demonstrated interpatient heterogeneous response to systematic treatment, providing a strong foundation for precision medicine. Our ongoing research aims to correlate PT-3DB drug responses with clinical outcomes. [Table: see text]

To the Editor: Endometrial cancer (EC) is the sixth most common cancer diagnosed in women, and its prevalence is reportedly increasing worldwide. Endometrial clear cell carcinoma (ECCC) accounts for 2–5% of all EC, and is a rare but ominous subtype of high-risk EC that has a poorer prognosis and exhibits greater chemoresistance. Owing to the rarity of ECCC, few clinical trials have included patients with this disease exclusively, and limited data are available regarding its pathogenesis and clinical progression compared with other more common subtypes of EC. Venous thromboembolism (VTE) has been known to be associated with underlying visceral malignancy since the 19th century, and has been observed at greater incidence rates in patients with cancer. Meanwhile, deep vein thrombosis (DVT) is a significant complication during gynecologic cancer surgery given that the embolus can cause life-threatening conditions, such as pulmonary embolism (PE) and acute cerebral infarction. The potential impact of VTE on survival remains largely unknown with respect to people with ECCC. Therefore, we conducted this retrospective study to investigate the characteristics of patients with ECCC and determine whether VTE has an impact on survival outcomes. Patients with ECCC who underwent primary surgical staging at Peking Union Medical College Hospital (PUMCH) were retrieved, and the study was approved by the Institutional Ethics Review Committee of PUMCH (No. K23C0468), with waived consent as retrospective study. The inclusion criteria were patients with a pathological confirmation of ECCC who underwent primary staging surgery. Electronic medical records of all patients were collected and reviewed. Patients who received post-recurrence treatment without centralized pathology review were excluded. Perioperative VTE was defined as the development of VTE within 30 days pre- or post-surgery. All pathology slides were centralized and assessed by the Pathology Department of PUMCH using the World Health Organization criteria, and miscellaneous carcinoma was defined as one or more pathological entities accompanying the clear cell carcinoma (CCC). The progression-free survival (PFS) was calculated as the interval in months between the date of the primary surgery and that of the detection of any progression or recurrence, including via biopsy pathology or imaging with or without elevated serum CA-125. Overall survival (OS) was calculated as the interval in months between the date of primary surgery and the date of death. Patients lost to follow-up were right-censored. Mann–Whitney, Pearson, and Fisher's exact χ2 (two-tailed) tests were performed for intergroup comparisons. Kaplan–Meier survival curves were analyzed according to VTE status and stage, and the log-rank test was applied to quantify survival differences. Univariate and multivariate Cox regression analyses were conducted on the variates including VTE status, age, comorbidities, stage, surgical completeness, adjuvant therapies, lymphovascular space invasion (LVSI), deep myometrial invasion (DMI), parametrial involvement (PI), and histology; the hazard ratios (HRs) were calculated with 95% confidence intervals (CIs). All statistical analyses were performed using SPSS version 20 (IBM Corp, Armonk, NY, USA); the threshold of statistical significance was set at P <0.05. The records of 137 patients who underwent primary surgery between November 2009 and April 2022 following a histological diagnosis of ECCC were retrieved. The median age at diagnosis and primary surgery was 61 years (range, 31–82 years). Majority had stage I (56.2%, 77/137) or stage III (25.5%, 35/137) ECCC. Among patients with advanced stages, suboptimal cytoreductive surgery was performed in 4 who had a residual mass >1 cm. During the surveillance, the majority of patients received monotherapy or combined adjuvant therapies after primary surgery: 65 patients received mono-adjuvant therapy (either chemotherapy [41.6%, 57/137] or radiotherapy [5.8%, 8/137]); 51 patients (37.2%) were managed by combination chemoradiotherapy; No adjuvant therapy was administered for 15.3% (21/137) of the patients. Patients were screened for VTE under the physician's guidance with or without indications, including elevated d-dimer level, swelling or pain in the lower extremities, or hypoxemia. A total of 22 patients (16.1%) were diagnosed with perioperative VTE during primary treatment. In patients screened positively with VTE, 9 patients were positive for DVT preoperatively; 2 of them were simultaneously diagnosed with PE; 13 patients (including 8 with DVT) had newly diagnosed VTE after surgery; 1 had an isolated PE; and 4 had concomitant DVT and PE [Supplementary Table 1, https://links.lww.com/CM9/B827]. The basic characteristics and prognoses of patients in these two groups were compared [Supplementary Table 2, https://links.lww.com/CM9/B827]. A significantly higher percentage of LVSI was observed in patients with VTE (P = 0.033); however, no significant differences were detected in other parameters. There were no fatalities caused directly by VTE-related complications in our study. Not counting one patient who was lost to follow-up during the first month, the median follow-up time was 49.9 months and ranged from 6.8 months to 146.5 months. The median PFS for the entire cohort was 42.3 months (95% CI, 44.9–58.7). Patients with perioperative VTE had a shorter median PFS than those without (13.3 months vs. 47.3 months, P = 0.001) [Figure 1A]. The median OS in the overall population was 49.2 months (95% CI, 50.6–63.6), and consistent with PFS, the median OS of patients with VTE was significantly shorter than that in patients without (19.8 months vs. 57.0 months, P = 0.008) [Figure 1B]. When stratified according to disease stage, significant differences in survival were only observed in the early stages. The median PFS of patients with stage I/II disease was 63.2 months (95% CI, 59.9–76.9) in the non-VTE population vs. 17.1 months (95% CI, 13.0–48.0) in those with perioperative VTE (P = 0.047) [Figure 1C]. Furthermore, the median OS was 65.3 months (95% CI, 62.3–78.7) vs. 23.1 months (95% CI, 17.9–50.5), respectively, in this subgroup (P = 0.001) [Figure 1D]. As shown in Figure 1, a more marked difference in OS was observed when the analysis was limited to patients with stage I/II ECCC (Figure 1Bvs.Figure 1D).Figure 1: Kaplan–Meier survival curves comparing patients with ECCC who experienced perioperative VTE to those who did not. (A) PFS in patients with all disease stages, (B) OS in patients with all disease stages, (C) PFS among patients with stage I/II ECCC, (D) OS among patients with stage I/II ECCC, ECCC: Endometrial clear cell carcinoma; OS: Overall survival; PFS: Progression-free survival; VTE: Venous thromboembolism.On univariate analysis, patients with perioperative VTE had a 3.3-fold increase in the risk of tumor progression (HR, 3.3; 95% CI, 1.6–7.0; P = 0.002) and a 3.3-fold increase in the risk of death (HR, 3.3; 95% CI, 1.3–8.5; P = 0.012) overall. After controlling for known survival-related factors, we used multivariate Cox regression analysis and found that VTE status, age at diagnosis, comorbidities, tumor stage, and gross residual disease were independently associated with tumor progression and death, whereas adjuvant therapy, LVSI, DMI, or tumor histology did not significantly influence survival. Compared with the non-VTE group (all stages), increases of 7.1-fold (95% CI, 2.1–23.7; P = 0.001) and 4.0-fold (95% CI, 1.7–9.3; P = 0.002) were found in the risk of death and disease progression in the perioperative VTE group, respectively. Additionally, a more marked increase in the risk of death was observed when the analysis was limited to patients with early-stage disease (HR, 24.9; 95% CI, 1.6–382.0) (Supplementary Table 3, https://links.lww.com/CM9/B827 for all stages and Supplementary Table 4, https://links.lww.com/CM9/B827 for stage I/II). In the present study, 16.1% of the patients received perioperative VTE during primary treatment. LVSI and other well-known survival risk factors were included in our regression analyses, and perioperative VTE, age ≥60 years, advanced-stage disease, and suboptimal cytoreductive surgery were independently associated with worse survival outcomes in the overall cohort. Perioperative VTE during primary treatment was linked to shorter PFS and OS without being a direct cause of death. When stratified according to tumor stage, VTE diagnosis at primary surgery remained an independent risk factor for survival in patients with stage I/II disease. A remarkably lower incidence rate of VTE was reported in a retrospective study of 422 patients with EC of all types (6.16% overall and 0.7% within 60 days post-surgery),[1] suggesting that the ECCC tumor biology may specifically play a role in thrombogenesis. In the present study. Perioperative VTE and other factors without LVSI were independently associated with worse survival outcomes in the cohort overall. Patients without VTE experienced longer PFS and OS than those with the condition, whether overall or in the early-stage population alone. A similar phenomenon was observed in patients with OCCC, wherein Diaz et al[2] observed a difference in survival rates among patients with early-stages disease. A potential explanation could be that the increased tumor burden and compromised health status of individuals with advanced-stage CCC may supersede the negative impact of VTE on survival. The relationship between VTE and survival outcomes in patients with EC was first described by Matsuo et al[3], who concluded that VTE could be regarded as a surrogate for EC aggressiveness; however, only 25 of 516 patients with clear cell histology (4.9%) were included in their analyses. Several cancer-specific mechanisms that may contribute to thrombogenesis have been proposed, including leucocytosis, thrombocytosis, increased levels of tissue factor (TF)-positive microvesicles and hypofibrinolysis.[4] The expression of TF (a transmembrane receptor with potent pro-coagulant function) by activating the extrinsic coagulation cascade pathway has been detected in certain cancerous tissues.[5] There is only limited evidence regarding the potential mechanism of cancer-related thrombosis in the field of endometrial carcinoma; hence, further studies are required to understand the etiology of thrombogenesis in this population. It was previously proposed that VTE itself might contribute to tumor invasion and metastasis, as elevated levels of preoperative serum TF have been positively correlated with death from ovarian cancer. Nevertheless, the tumor-type specific mechanism underlying the association between VTE and poor survival in ECCC remains to be elucidated. We found no significant association between adjuvant therapy and survival in our study, which was in contrast to data from Cetinkaya et al's study.[6] Adjuvant therapies for ECCC were highly individualized in our research, which could potentially lead to compromised anti-tumor efficiency. Studies involving larger cohorts ought to elucidate the value of adjuvant therapies in patients with ECCC. Given the limited information on ECCC, a rare disease, ours is one of the few studies to investigate the influence of perioperative VTE status on survival using a relatively large cohort from a single institution. Patients with no VTE were found to have significantly longer PFS and OS, and VTE at the time of primary surgery was found to be an independent predictor of disease progression and death. These results further emphasize the importance of preoperative screening and postoperative surveillance for DVT in patients with cancer, as well as better awareness of its potentially negative impact on survival, especially in patients with CCC. Given that our study was limited by its retrospective nature and by the fact that the analysis was correlative, we were unable to extract certain details regarding molecular subtypes or anticoagulant management, which would have strengthened the data derived from our multivariate models. Prospective studies and in vitro assays may further validate our findings and improve our understanding of the relevant mechanisms. In summary, we found that 16.1% of patients with ECCC developed VTE perioperatively regardless of tumor stage. Perioperative VTE at primary surgery was independently associated with a significantly higher risk of cancer recurrence and death, although the greater risk of death was not directly caused by the VTE itself. Funding This study was supported by the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-083), the Capital's Funds for Health Improvement and Research (No. 2022-1-4011), and the National Natural Science Foundation of China (NSFC) (No. 82271886). Conflicts of interest None.

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.

Abstract Objective To describe the characteristics of children and adolescents with borderline ovarian tumors (BOTs) and evaluate the efficacy and safety of fertility-sparing surgery (FSS) in these patients. Methods Patients with BOTs younger than 20 years who underwent FSS were included in this study. Results A total of 34 patients were included, with a median patient age of 17 (range, 3–19) years; 97.1% (33/34) of cases occurred after menarche. Of the patients, 82.4% had mucinous borderline tumors (MBOTs), 14.7% had serous borderline tumors (SBOTs), and 2.9% had seromucinous borderline tumor (SMBOT). The median tumor size was 20.4 (range, 8–40)cm. All patients were at International Federation of Gynecology and Obstetrics stage I and all underwent FSS: cystectomy (unilateral ovarian cystectomy, UC, 14/34, 41.2% and bilateral ovarian cystectomy, BC, 1/34, 2.9%), unilateral salpingo-oophorectomy (USO; 18/34; 52.9%), or USO + contralateral ovarian cystectomy (1/34; 2.9%). The median follow-up time was 65 (range, 10–148) months. Recurrence was experienced by 10 of the 34 patients (29.4%). One patient with SBOT experienced progression to low-grade serous carcinoma after the third relapse. Two patients had a total of four pregnancies, resulting in three live births. The recurrence rate of UC was significantly higher in MBOTs than in USO (p = 0.005). The 5-year disease-free survival rate was 67.1%, and the 5-year overall survival rate was 100%. Conclusions Fertility-sparing surgery is feasible and safe for children and adolescents with BOTs. For patients with MBOTs, USO is recommended to lower the risk of recurrence.

Objective To summarize the characteristics and outcomes of patients undergoing in vitro fertilization (IVF) after fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer (AH/EC), and to analyze the factors influencing reproductive outcomes and disease recurrence. Methods This study retrospectively reviewed the medical records of 125 women who underwent assisted reproductive technology (ART) after fertility-sparing treatment of AH/EC in Peking Union Medical College Hospital from March 2013 to March 2023. Data of clinical features, reproductive outcomes, and recurrence were collected. The primary outcomes were clinical pregnancy and live birth. The secondary outcome was disease recurrence. Results A total of 125 patients were involved in the study. The average age to start IVF cycle was 33.66±3.56 years.109 patients underwent at least one embryo transfer. The clinical pregnancy rate and live birth rate per ET were 35.80% and 17.70%, respectively. The cumulative pregnancy rate was 74.31%. The total recurrence rate during IVF was 8%. The younger onset age of AH/EC and controlled ovarian stimulation (COS) with levonorgestrel-releasing intrauterine system (LNG-IUS) were the two factors that were negatively correlated with live birth. COS with LNG-IUS and a history of recurrence before IVF were significantly correlated with the risk of recurrence. Conclusion IVF was noted as an effective method to achieve pregnancy in a relatively short period of time, and reproductive outcomes for AH/EC patients were satisfied. Repeated AH/EC treatment was feasible, while recurrence might affect subsequent fertility outcomes. COS with LNG-IUS did not exhibit to have negative effects on obtaining embryos. However, the effects of LNG-IUS on recurrence and endometrial receptivity are still remain unknown, and deserve further assessment.

Objective: To evaluate the effect of postoperative radiotherapy and high-risk pathological factors on the prognosis of early-stage neuroendocrine carcinoma of cervix (NECC). Methods: A single-center retrospective cohort study of early-stage NECC in Peking Union Medical College Hospital from January 2011 to April 2022 were enrolled. The patients were treated with radical hysterectomy±adjuvant treatment. They were divided into postoperative non-radiation group and postoperative radiation group. The possible postoperative recurrence risk factors identified by univariate analysis were assessed using multivariate logistic regression. The Kaplan-Meier method was used to analyze the progression free survival (PFS), overall survival (OS), recurrence rate, and mortality rate. Results: (1) Sixty-two cases were included in the study, including 33 cases in postoperative non-radiation group and 29 cases in postoperative radiation group. (2) The median follow-up time was 37 months (ranged 12-116 months), with 23 cases (37%) experienced recurrences. There were 7 cases (11%) pelvic recurrences and 20 cases (32%) distant recurrences, in which including 4 cases (6%) both pelvic and distant recurrences. Compared with postoperative non-radiation group, the postoperative radiation group had a lower pelvic recurrence rate (18% vs 3%; P=0.074) but without statistic difference, a slightly elevated distant recurrence rate (24% vs 41%; P=0.150) and overall recurrence rate (33% vs 41%; P=0.513) without statistically significances. Univariate analysis showed that lymph-vascular space invasion and the depth of cervical stromal invasion≥1/2 were risk factors for postoperative recurrence (all P<0.05). Multivariate analysis showed lymph-vascular space invasion was an independent predictor for postoperative recurrence (OR=23.03, 95%CI: 3.55-149.39, P=0.001). (3) During the follow-up period, 18 cases (29%, 18/62) died with tumor, with 10 cases (30%, 10/33) in postoperative non-radiation group and 8 cases (28%, 8/29) in postoperative radiation group, without significant difference (P=0.814). The postoperative 3-year and 5-year survival rate was 79.2%, 60.8%. The depth of cervical stromal invasion≥1/2 was more common in postoperative radiation group (27% vs 64%; P=0.011), and postoperative radiation in such patients showed an extended trend in PFS (32.3 vs 53.9 months) and OS (39.4 vs 73.4 months) but without statistic differences (P=0.704, P=0.371). Compared with postoperative non-radiation group, the postoperative radiation did not improve PFS (54.5 vs 37.3 months; P=0.860) and OS (56.2 vs 62.4 months; P=0.550) in patients with lymph-vascular space invasion. Conclusions: Postoperative radiation in early-stage NECC patients has a trend to reduce pelvic recurrence but not appear to decrease distant recurrence and overall recurrence, and has not improved mortality. For patients with the depth of cervical stromal invasion≥1/2, postoperative radiation has a trend of prolonging OS and PFS but without statistic difference. Lymph-vascular space invasion is an independent predictor for postoperative recurrence, but postoperative radiation in such patients does not seem to have any survival benefits.

BackgroundPrimary small cell neuroendocrine carcinomas of the cervix and endometrium are rare gynecological malignancies with limited treatment options. This study aimed to improve the understanding of the carcinogenesis process and identify potential therapeutic targets for these two tumor types by constructing the mutational landscape at the whole exome level.MethodsPrimary tumor tissues and their matched blood samples were obtained from 10 patients with small cell cervical neuroendocrine carcinoma (NECC) and five patients with small cell endometrial neuroendocrine carcinoma (NECE). Whole exome sequencing was performed to construct the somatic mutation profiles. Mutational signature and recurrent mutated gene analysis were used to identify tumor subtypes and common carcinogenesis processes.ResultsBased on the burden of different mutational signatures, the NECCs in this work can be divided into two subtypes, including the mismatch repair deficiency like (dMMR-like) type (4/10) and the high spontaneous deamination type (6/10). Components of the PI3K/AKT signaling and RAS signaling were exclusively mutated in these two subtypes, respectively. The integration of human papillomavirus made a limited contribution to tumorigenesis in NECC (20%). The dysfunction of the mismatch repair system and microsatellite instability are the major features of NECE. PI3K/AKT, JAK/STAT signaling, and chromatin remodeling activity were the common mutated pathways in NECE. PIK3CA, WNK2, and KMT2B underwent mutations in both the dMMR-like subtype of NECC (50% – 75%) and in NECE (60% – 80%) specimens, while exhibiting infrequent mutational occurrences in publicly available data pertaining to neuroendocrine carcinomas of the lung or bladder (< 10%).ConclusionWe identified the two subtypes of NECC with distinct mutated pathways and potential therapy targets. The dMMR-like type NECC and NECE may share a similar carcinogenesis process that include dysfunction of PI3K/AKT signaling, cell cycle, antiapoptotic processes, and chromatin remodeling activity.

Objective: To compare the survival outcomes between surveillance and adjuvant chemotherapy in patients with stage Ⅰ ovarian immature teratoma (IMT) underwent fertility-sparing surgery. Methods: Clinical and pathological records of patients with stage Ⅰ ovarian IMT between Jan. 2011 to Feb. 2023 were collected from Peking Union Medical College Hospital, except stage Ⅰa grade 1. The consultation of risks and benefits regarding adjuvant chemotherapy was conducted by gynecologic oncologists. A shared decision about surveillance or chemotherapy was made by physician and patients or their guardians. Patients who finally decided to undergo surveillance were included in the surveillance group (n=40), the others were included in the adjuvant chemotherapy group (n=63). Clinical characteristics, treatment and survival outcomes were analyzed and compared between two groups. Results: A total of 103 patients were included. The median age of initial diagnosis was 20 years old (range: 3-39 years old), and the median follow-up time was 31 months (range: 1-254 months). The age, International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grade, surgical method, and preoperative and postoperative alpha-fetoprotein levels in the surveillance group and the adjuvant chemotherapy group were similar (all P>0.05). The surgical approach and maximum tumor diameter between two groups were significantly different (all P<0.05). Forty patients of the surveillance group were identified, only one patient with stage Ⅰa grade 2 IMT who underwent cystectomy had malignant recurrence on the same ovary. Another 63 patients received adjuvant chemotherapy after surgery, five patients had malignant recurrence, and two of them died of disease progression after relapsed. There were no significant differences in disease-free survival (DFS;20 vs 36 months) and overall survival (OS; 23 vs 39 months) between the surveillance group and the adjuvant chemotherapy group (follow-up time censored at 72 months; DFS: P=0.325, OS: P=0.278). Conclusions: There are no differences in survival outcomes between patients with stage Ⅰ ovarian IMT underwent adjuvant chemotherapy or not. Active surveillance might be safe and preferable in stage Ⅰ IMT patients underwent complete resection of tumor.

A series of high-level evidence-based medical evidence has clarified that Poly ADP ribose polymerase (PARP) inhibitors as maintenance therapy have significantly prolonged progression-free survival (PFS) in patients with newly diagnosed and platinum-sensitive recurrent ovarian cancer who have achieved complete response (CR) or partial response (PR) after platinum-based chemotherapy. With the wide application of PARPi, the possibility of PARPi rechallenge in maintenance settings for patients who have received prior PARPi therapy has become an increasing concern in clinical practice. This study will investigate the efficacy and safety of niraparib combined with anlotinib maintenance treatment in patients with platinum-sensitive recurrent (PSR) non-mucinous EOC who have previously received maintenance therapy with one PARPi. The main inclusion criteria of this study include patients aged ≥18 years, with histologically diagnosed platinum-sensitive recurrent high-grade serous or endometrioid epithelial ovarian cancer (EOC) (including primary peritoneal and/or fallopian tube cancer); known BRCA mutation status; received one prior PARPi therapy, which includes any agent (including niraparib) used in maintenance setting and the duration of maintenance treatment of ≥6 months; received ≤3 lines of chemotherapy, the time between the penultimate and the last line of platinum-containing chemotherapy was >6 months; the most recent course of platinum-containing chemotherapy should have at least 4 cycles, in the opinion of the investigator, in response (CR or PR) or may have no evidence of disease (if optimal cytoreductive surgery was conducted prior to chemotherapy); patients must have either CA-125 in the normal range or CA-125 decrease by >90% during last line chemotherapy, and that is stable for at least 7 days; bevacizumab use as part of an earlier line of therapy is permitted; and has ECOG performance status of 0 to 2. Patients will receive niraparib 200 mg or 300 mg once daily and anlotinib 10 mg orally once daily on days 1–14 of each 21-day cycle.

Progression-free survival (PFS) was significantly extended with niraparib maintenance treatment versus placebo in patients (pts) with newly diagnosed advanced ovarian cancer (aOC) in the phase III PRIME study (NCT03709316), but 40.4% of pts. required dose modifications due to treatment-emergent adverse events (TEAEs) and the impact of these modifications is still unknown. This study aimed to compare the efficacy of niraparib with TEAE-caused dose reductions or no dose reductions in the first-line maintenance setting. This was a post hoc analysis of niraparib-treated pts. from PRIME, which randomized adult pts. with newly diagnosed aOC 2:1 to receive niraparib or placebo after a response to first-line platinum-based chemotherapy. The starting daily dose was 200 mg for pts. with a body weight of <77 kg and/or a platelet count of <150,000/μL at baseline and 300 mg for all others. With no dose interruption or reduction in the first two cycles, the daily dose for pts. starting at 200 mg could be increased to 300 mg at the investigators' discretion. The daily dose could be reduced stepwise by 100 mg to manage treatment-related adverse events, and if tolerability improved following reductions, it could be escalated stepwise by 100 mg without exceeding the initial level. The primary endpoint was PFS (BICR). Subgroups comprised niraparib-treated pts. who experienced TEAE-caused dose reductions or had no dose reductions. Dose reductions included reductions following interruptions as specified in the protocol and direct reductions. Of 255 niraparib-treated pts., 103 (40.4%) experienced dose reductions, including direct reductions in 6, due to TEAEs (Fig. 1A), most commonly, platelet count decreased (24.3%), anemia (10.2%), and neutrophil count decreased (9.8%). The median time from randomization to first dose interruption or direct reduction, whichever came earlier, due to TEAEs was 29 days (range: 8–397), and the median time from first dose interruption to the resumption of treatment was 15.5 days (range: 1–28). The distribution of daily dose levels at each cycle is presented in Fig. 1B. Key baseline characteristics were overall balanced between subgroups with TEAE-caused reductions and no reductions. In pts. with TEAE-caused reductions and no reductions, the median total exposure time was 21.9 (range: 1.1–37.8) and 17.5 (range: 0.1–38.5) months (mo), and median relative dose intensity (average actual daily dose/planned starting daily dose) was 58% (range: 26%–106%) and 100% (range: 98%–147%), respectively. Median PFS (95% CI) with TEAE-caused reductions versus no reductions was 27.6 (16.6-not estimable [NE]) versus 24.8 (16.6–NE) mo (HR: 0.89, 95% CI: 0.61–1.30), with not reached versus 24.8 mo in pts. carrying germline BRCA mutations (HR: 0.60, 95% CI: 0.29–1.25) and 16.6 versus 24.8 mo in pts. carrying no germline BRCA mutations (HR: 1.02, 95% CI: 0.66–1.60). The efficacy of niraparib maintenance treatment with an individualized starting dose in pts. with newly diagnosed aOC was not impacted by dose modifications due to TEAEs, regardless of germline BRCA mutation status.

Importance:The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective:To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants:This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions:Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/μL [to convert to ×109/μL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements:The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results:A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance:This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration:ClinicalTrials.gov Identifier: NCT03709316.