Giant condyloma acuminatum (Buschke-Löwenstein tumor; BLT) is a rare HPV-associated disease characterized by progressive proliferation, high recurrence rates (60-70%), and potential for malignant transformation to squamous cell carcinoma. Although histologically benign, aggressive local behavior and involvement of functionally critical anatomical structures present substantial therapeutic challenges. This report describes the successful function-preserving surgical management of extensive treatment-refractory BLT. A 69-year-old woman with a history of malignant lymphoma and diabetes mellitus developed vulvar condyloma that was resistant to sequential imiquimod therapy, cryotherapy, and laser ablation. The lesion progressively enlarged to 15 × 9.5 × 2.5 cm, encompassing the entire vulva and perianal area. Clinical examination and imaging confirmed the absence of urethral and rectal mucosal invasion. Preoperative imiquimod was administered to the urethral meatus, vaginal introitus, and perianal area for 4 weeks to control microscopic disease at functionally critical sites. Surgical resection prioritized function preservation: ≥1 cm margin at the periphery, while mucosal boundaries were approached closely at critical sites. Residual rough mucosal areas underwent bipolar cauterization. Primary closure was achieved without the need for flap reconstruction. Mild postoperative wound dehiscence without infection resolved with conservative management, permitting secondary healing. Five months postoperatively, complete epithelialization was achieved with no recurrence, preserved urinary and bowel function, and the absence of vaginal symptoms. This case demonstrates that combining preoperative imiquimod, function-prioritizing surgical margins, local ablation, and tolerance of secondary healing can achieve oncologic control while maintaining quality of life in extensive BLT. Long-term surveillance remains essential.

Abstract [Introduction]Recent studies have revealed pervasive mutations in cancer-related genes within many normal tissues, including the endometrium. Endometriosis-associated ovarian cancer (EAOC) is hypothesized to arise from endometriotic lesions seeded from the endometrium to the ovary, although direct evidence supporting this origin has been lacking. This study aimed to identify the clonal origin of EAOC in the endometrium by detecting shared somatic mutations between EAOC tumors and endometrial clones. [Methods]We performed high-density sampling of histologically normal endometrial tissues from 6 patients diagnosed with EAOC (5-32 sample/patient, 84 samples in total) and conducted whole-exome sequencing. The resulting somatic mutation profiles were compared with those of the matched EAOC tumors from the same patients. [Results]Endometrial samples harbored a median of 28.5 (range 6-74) somatic mutations. In 78 of 84 histologically normal endometrial samples (93%), one or more of known driver gene mutations involving PIK3CA, PIK3R1, KRAS, PPP2R1A, ARHGAP35 and FBXW7 were identified, with an average of 2.4 mutations/sample (range 0-7). PIK3CA mutations were the most common, detected in 44 of 84 samples (52%), followed by ARHGAP35 mutations (25/84, 30%). Notably, in two cases, we identified an endometrial sample sharing multiple somatic mutations with the EAOC tumors. In Case 1 (74 y/o, ovarian clear cell carcinoma), one of 32 endometrial samples shared 16 mutations with the tumor, including alterations in PTEN, PIK3CA, and KRAS. In Case 2 (31 y/o, bilateral ovarian endometrioid carcinoma), one of 6 endometrial samples shared 11 mutations with the tumor, including in PIK3CA, AKT1, PPP2R1A and CTNNB1. Phylogenetic analysis using whole-genome sequencing estimated that the most recent common ancestor of the cancer diverged from the normal endometrial clone in their early 20s in both cases. In Case 1, the tumor acquired additional copy number alterations not present in the endometrial ancestor, suggesting their potential role in carcinogenesis. By contrast, in Case 2 no clear genetic differences were detected between the ancestral endometrial clone and the ovarian tumor, suggesting that the transition from normal tissue to cancer may be driven by non-genetic events. [Conclusion]We demonstrated that at least some EAOC tumors originate from an ancestral clone in the histologically normal endometrium. This ancestral clone had already acquired multiple driver events contributing to carcinogenesis. Our findings provide new insights into the early events underlying EAOC development. Citation Format: Koichi Watanabe, Nobuyuki Kakiuchi, Kosuke Ieiri, Hirona Maeda, Tomonori Hirano, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Masaki Mandai, Seishi Ogawa, . Identification of the clonal origin of endometriosis-associated ovarian cancer in normal endometrium [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 3529.

We previously reported a phase II Kyoto trial for platinum-resistant ovarian cancer (n = 20) using nivolumab (anti-programmed cell death-1 [PD-1] antibody). We evaluated the associations between clinical outcomes and transcriptomics and T and B cell clonality from tumor and blood cells. We analyzed gene expression microarray with pre- and post-treatment peripheral blood mononuclear cells, α- and β-chain of T cell receptor (TCR) repertoires, and immunoglobulin G (IgG) and M of B cell receptor (BCR) repertoires in 61 samples from 19 patients. Shannon–Weaver diversity scores of the TCR and BCR repertoires were compared between responders and non-responders. RNA sequencing analyzed gene expression and fusion genes in tumor samples (n = 17). BCR repertoire analyses of post-/pre-treatment ratios in four responders (two patients with complete response (CR), one with partial response, and one with stable disease near to CR) revealed significantly decreased BCR-IgG repertoires diversity versus non-responders (Shannon–Weaver index, median 0.84 vs. 1.04, p < 0.05); the diversity of BCR-IgG repertoires recovered over 100 days. More than two passenger fusion genes were detected in six of the seven responders, whereas eight of the ten non-responders lacked fusion genes. The antitumor response significantly correlated with the number of fusion genes (p = 0.0006). Pathway analyses consistently identified immune-related processes, including cytokine-cytokine receptor interactions, neutrophil degranulation, and immunoregulatory interactions in both responders and tumors with high fusion gene counts. Transient oligoclonal expansion of B cells and passenger fusion genes might serve as predictive biomarkers of response to PD-1 blockade in ovarian cancer.

Abstract Uterine serous carcinoma (USC) is an aggressive p53-mutated endometrial carcinoma that exhibits gene mutations in homologous recombination (HR) pathways, similar to high-grade serous ovarian carcinoma (HGSOC). However, the therapeutic effect of PARP inhibitors on USC is limited. This study investigated cyclin-dependent kinase 12 (CDK12), a transcriptional regulator of HR genes, and evaluated the efficacy of a novel CDK12 inhibitor, CTX-439, combined with a PARP inhibitor, olaparib, in patient-derived xenograft (PDX) models of USC. We evaluated the HR deficiency (HRD) scores, genetic alterations, and HR-related gene abnormalities, including CDK12, in USC, other histopathologic types of uterine endometrial carcinoma, and HGSOC using The Cancer Genome Atlas dataset. We also assessed CDK12 function and CTX-439 efficacy in USC utilizing USC cell lines and PDX models. USC exhibited a higher HRD score than other histologic subtypes of uterine endometrial carcinoma but lower than HGSOC. CDK12 amplification occurred more frequently in USC than in HGSOC but was not associated with HRD scores. Tumors with CDK12 amplification demonstrated high CDK12 expression, which correlated with poor prognosis in USC. The CDK12 inhibitor CTX-439 suppressed HR-related gene expression, including BRCA1 and BRCA2; induced apoptosis and DNA damage; and inhibited tumor growth in USC PDX models with high CDK12 expression. Furthermore, CDK12 inhibition enhanced tumor sensitivity to the PARP inhibitor olaparib in USC PDX models. This study indicates that CDK12 is a potential therapeutic target for enhancing the antitumor effects of PARP inhibitors in patients with USC.

While molecular targeted therapy development has expanded the potential for individualized cancer treatment, the optimal therapeutic strategy for patients with complex comorbidities, including renal impairment, remains insufficiently established. We report a case of advanced ovarian cancer in a patient undergoing maintenance hemodialysis who received olaparib, with serial plasma drug concentration measurements performed to characterize its pharmacokinetic profile and provide insights into safe and effective treatment in patients on hemodialysis. A 65-year-old woman with chronic renal failure who was undergoing thrice-weekly maintenance hemodialysis was diagnosed with stage IVB high-grade serous ovarian carcinoma harboring a pathogenic BRCA1 variant identified by tumor testing. Following the first-line chemotherapy, oral olaparib tablets (300 mg/day) was initiated as maintenance therapy. Plasma olaparib concentrations were measured on dialysis and non-dialysis days. Drug concentrations on both days increased to levels comparable to those reported in the package insert (400 mg/day tablet formulation) and in a previously published case of a hemodialyzing patient receiving 400 mg/day in capsule form. No adverse events other than anemia requiring dose interruption, dose reduction, or treatment discontinuation were observed. The initial dose of 300 mg/day was maintained throughout treatment, enabling continued outpatient management until disease progression occurred 2 months later. In this case, olaparib (300 mg/day) was tolerated and achieved plasma concentrations comparable to those observed in non-dialyzing patients receiving olaparib (400 mg/day). Further evidence regarding the association between plasma olaparib concentrations and toxicity in patients on hemodialysis is warranted to optimize treatment strategies.

5599 Background: High-grade serous ovarian carcinoma (HGSC) exhibits heterogeneous tumor microenvironments (TME) that correlate with clinical outcomes. We previously reported four molecular histopathological subtypes of HGSC based on gene expression profiles reflecting TME characteristics: Immune Reactive (IR), Mesenchymal (MT), Solid/Proliferative (SP), and Papillary/Glandular (PG). The IR subtype, characterized by tumor-infiltrating lymphocytes, demonstrates favorable prognosis (PMID:26993207, 30853361). We also identified lower B7-H3 expression in IR compared to non-IR subtypes (PMID:34799346). Here, we developed an AI-based B7-H3 IHC quantification method across TME compartments and investigated its association with molecular subtypes. Methods: Forty-five HGSC patients who underwent primary debulking surgery were enrolled. Molecular histopathological subtyping categorized cases into IR (n=16), MT (n=20), and Other (SP/PG, n=9). B7-H3 immunohistochemistry-stained whole slide images were analyzed using DeepPathFinder, an AI-based pathological image analysis tool that performs automated tissue segmentation and IHC marker quantification. B7-H3 expression was quantified across three tumor-associated compartments: tumor, peritumor (within 1000 μm of the tumor border), and necrosis. An integrated B7-H3 score was calculated as the mean density across these compartments. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression. Results: The integrated B7-H3 score showed a stepwise increase across subtypes: IR (0.148) < MT (0.219) < Other (0.252) (Kruskal-Wallis p=0.091), and was significantly lower in IR compared to non-IR subtypes (0.148 vs 0.229, p=0.034). B7-H3 expression was consistently lower in IR across all compartments: tumor (IR: 0.171, MT: 0.205, Other: 0.257), peritumor (IR: 0.100, MT: 0.154, Other: 0.164), and necrosis (IR: 0.171, MT: 0.298, Other: 0.336; p=0.025). Survival analysis revealed significant prognostic differences among subtypes. Compared to IR, MT showed significantly worse outcomes (PFS: HR=8.35, 95% CI 3.00–23.24, p<0.0001; OS: HR=15.35, 95% CI 3.50–67.31, p=0.0003). The Other subtype also demonstrated inferior OS (HR=6.38, 95% CI 1.17–34.95, p=0.033). Both MT and Other (SP/PG) subtypes, which exhibited higher B7-H3 expression, were associated with worse prognosis. Conclusions: AI-based quantitative B7-H3 evaluation revealed subtype-specific expression patterns in the HGSC tumor microenvironment. B7-H3 expression was lowest in IR and higher in non-IR subtypes across all tumor-associated compartments. These findings suggest that patients with higher B7-H3-expressing subtypes may benefit from B7-H3-targeted therapy.

Supplementary Table S2 shows the molecular and genomic characteristics of uterine serous carcinoma PDX models, including HRD scores, TP53 immunohistochemistry status, gene mutations, and ERBB2 copy number alterations.

Supplementary Figure S4 shows suppression of HR-related gene expression and associated protein changes following CTX-439 treatment in uterine serous carcinoma cell lines, as assessed by RT–qPCR and Western blotting.

Supplementary Figure S1 shows RNA-seq–based analyses of transcriptional changes induced by CTX-439 treatment, including pathway enrichment analyses across multiple USC xenograft models and volcano plots highlighting representative cell cycle–related genes.

Supplementary Figure S2 shows HRD status, CDK12 copy number alterations, and related genomic features in uterine serous carcinoma, including correlations with HRD scores and survival analyses in the TCGA and Kyoto University cohorts.

AIM:To clarify live birth outcomes among women receiving extended or repeated high-dose medroxyprogesterone acetate (MPA) therapy for fertility-sparing management of atypical endometrial hyperplasia or endometrioid carcinoma grade 1. METHODS:We conducted a single-center retrospective case series of 53 patients undergoing MPA therapy between 2005 and 2023. Patients were stratified into three groups: (i) complete response (CR) within 6 months (standard group), (ii) CR after extended treatment beyond 6 months (extended group), and (iii) CR after MPA retreatment for first intrauterine recurrence (retreatment group). Primary outcome was the live birth rate (LBR). Secondary outcomes included the effect of initial reproductive intentions, interval from CR to conception, recurrence rates, and recurrence-free interval (RFI). RESULTS:LBRs were 33% (10/30) in the standard group, 8% (1/12) in the extended group, and 17% (2/12) in the retreatment group. Among eight patients undergoing MPA retreatment for a second or subsequent recurrence, none achieved live birth. Patients with an initial desire for prompt conception had significantly higher LBRs than those without (38% vs. 5%, p < 0.01). Median time from CR to conception leading to live birth was 12 months. Patients achieving live birth had significantly longer RFIs than those without (p < 0.01). CONCLUSIONS:Live birth is most likely when CR is achieved within 6 months of MPA therapy; nonetheless, extended or repeated MPA treatment may still result in live birth. These findings suggest the importance of appropriate patient selection and careful monitoring during extended or repeated therapy and attempting conception promptly in fertility-sparing management of endometrial neoplasia.

Single-organ vasculitis (SOV) of the uterine cervix is extremely rare and presents significant diagnostic challenges when it mimics malignancy. A 22-year-old woman presented with fever, abdominal pain, and abnormal genital bleeding. Imaging revealed a 5 cm cervical mass with multiple lymphadenopathies, suggesting advanced cervical cancer. Cervical cytology revealed atypical glandular cells with frequent mitotic figures, suggesting cervical adenocarcinoma. The convergence of cytological, clinical, and imaging findings led to a compelling diagnosis of malignancy. However, no malignant findings were observed in the histopathological examination. The vascular media showed complete fibrinoid necrosis and the surrounding area demonstrated dirty necrosis with numerous nuclear fragments, consistent with necrotizing vasculitis. Atypical cells were confined to a very small area. Immunohistochemistry results were negative for p16. Remarkably, the mass regressed spontaneously during follow-up without any intervention. Follow-up cytology revealed persistent atypical features despite clinical resolution, creating a diagnostic dilemma requiring careful clinicopathological correlation. Pathological evaluation and careful observation the avoidance of unnecessary invasive treatments. The final diagnosis was single-organ cervical vasculitis. This appears to be the first reported case of a spontaneously resolving cervical SOV with cytological features indistinguishable from those of an adenocarcinoma. The case highlights the critical limitations of cytological diagnosis in differentiating severe inflammatory changes from malignancies. The experience emphasizes that tissue diagnosis is essential before radical intervention, particularly in young patients in whom fertility preservation is paramount, and demonstrates that cytological findings require careful clinical correlation to prevent unnecessary surgeries.

OBJECTIVE:To evaluate reproductive and perinatal outcomes in patients who underwent trachelectomy for early-stage cervical cancer, focusing on predictors of pregnancy achievement and early preterm birth. METHODS:This retrospective cohort study included 37 patients who underwent trachelectomy between January 2010 and February 2025, with perinatal follow-up and delivery management at Kyoto University Hospital. Reproductive outcomes were analyzed in 20 patients who desired pregnancy and received infertility treatment. Perinatal outcomes were assessed in 17 deliveries, comparing 22-33 weeks and ≥ 34 weeks. Clinical variables were compared between groups using the Mann-Whitney U test and Fisher's exact test. RESULTS:Among patients who underwent infertility treatment, 15 (75.0%) achieved at least one clinical pregnancy and 12 (60.0%) achieved live birth. Higher gravida at treatment initiation was significantly associated with pregnancy achievement. Among 17 deliveries, 7 occurred between 22 and 33 weeks and 10 at ≥ 34 weeks. Cervical length before pregnancy and at 22 weeks of gestation did not differ between groups. In contrast, the Nugent score was significantly higher in the 22-33-week group (p = 0.0414), and preterm premature rupture of membranes occurred in all pregnancies in this group versus 40% in the ≥ 34-week group (p = 0.0108). CONCLUSIONS:Vaginal microbiota imbalance was significantly associated with early preterm birth after trachelectomy. These findings suggest that ascending infection due to impaired cervical barrier function may contribute to this risk. Prospective studies incorporating longitudinal microbiota profiling and targeted intervention are warranted.

Supplementary Figure S5 shows that short-term CDK12/13 inhibition by CTX-439 induces DNA damage and enhances cisplatin sensitivity without affecting short-term cell viability in uterine serous carcinoma cell lines.

Supplementary Table S1 shows the primer and probe information used for RT–qPCR analyses and the primary and secondary antibodies used for western blotting in this study.

OBJECTIVE:We aimed to clarify the clinical and prognostic characteristics of cervical adenosquamous carcinoma (ASC) by comparing it with both adenocarcinoma (AC) and squamous cell carcinoma (SCC). METHODS:Using the Japanese nationwide cervical cancer registry, we identified 37,556 patients with SCC, usual-type AC, or ASC who initiated treatment between 2015 and 2020. Propensity score matching (PSM) was conducted to balance baseline characteristics across histologic subtypes, including age, International Federation of Gynecology and Obstetrics (FIGO) stage, and initial treatment modality. Stage-stratified analyses were performed to compare lymph node metastasis (LNM) patterns and prognosis between subtypes. RESULTS:The age distribution of ASC largely overlapped with that of AC and was younger than SCC (median 47, 48, and 53 years, respectively). In contrast, the frequency of LNM in ASC resembled that of SCC; both ASC and SCC generally had higher LNM than AC. Initial treatment strategies were similar between ASC and AC, whereas chemoradiotherapy was more frequently selected for SCC in FIGO IB-IIIC1. After PSM, overall survival was worse for ASC versus SCC (hazard ratio [HR]=1.32; 95% confidence interval [CI]=1.08-1.60) but comparable between ASC and AC (HR=0.93; 95% CI=0.77-1.11). Stage-stratified analyses showed consistently poorer outcomes for ASC versus SCC, particularly in IB1, IIIC1-T1, IIIC1-T2, and IIIC2. In contrast, ASC versus AC revealed bidirectional patterns: ASC tended to fare worse in IB1, IB2, IIIC1-T1, and IIIC2, whereas AC tended to fare worse in IIB and IIIC1-T2. CONCLUSION:ASC displayed an LNM profile more closely resembling that of SCC and showed stage-dependent survival distinct from AC.