David S. Miller

PURPOSE: Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)-p16-Rb pathway, features shared with hormone receptor-positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS: This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION: Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

OBJECTIVES: Chemotherapy interruptions are a frequent event during treatment of solid tumors and have been associated with adverse survival outcomes. Our objective was to determine the impact of intercycle delay during first-line systemic chemotherapy on survival in patients with metastatic (stage IVB) or recurrent cervical cancer. METHODS: A retrospective cohort study identified patients with metastatic or recurrent cervical cancer treated at our institutions. Demographics, clinicopathologic information, first-line chemotherapy regimens with associated intercycle delays, and outcome measures were abstracted from medical records. Delays were categorized as modifiable (social determinants of health, logistics, treatment break) or nonmodifiable (cytopenias, organ dysfunction, chemotherapy reaction, infection, ECOG status). Data were analyzed using descriptive statistics, Kaplan-Meier survival estimate, and log-rank tests to calculate significance ( P <0.05). RESULTS: Two hundred ten patients were evaluable for this study. 178 (85%) had at least one intercycle delay. One thousand eight hundred seventy-three chemotherapy cycles were completed with 701 (37%) delays. There was an equal proportion of modifiable (352/701) and nonmodifiable (349/701) delays. Patients with one or more intercycle delay had a longer median PFS (13 mo, IQR: 7 to 24) compared with those without delays (8 mo, IQR: 4 to 17), P =0.042. PFS stratified by subgroups revealed patients with modifiable delays as having improved PFS ( P =0.036) and nonmodifiable subgroup trending towards improved PFS ( P =0.058) compared with patients with no delays. There was no PFS difference between the modifiable and nonmodifiable subgroups and no overall survival differences. CONCLUSIONS: Intercycle delays during first-line systemic chemotherapy for metastatic or recurrent cervical cancer do not have an adverse effect on survival.

Objective: Growing evidence indicates anger-related affect (i.e., anger, hostility, and irritability) is a transdiagnostic risk factor for suicide. The goal of this meta-analysis was to systematically review the literature and calculate the effect size of these relationships. Method: = 141,434). Results: = .31) between anger-related affect and suicidal thoughts and behaviors. There were no significant differences between the effect size estimates of the three separate anger constructs. Studies assessing suicide attempts were associated with significantly lower effect sizes than studies assessing death by suicide or suicidal ideation. Studies that assessed suicidal thoughts and behaviors using a clinical interview were associated with lower effect size estimates than those assessing via self-report or chart review. Additionally, studies that assessed current suicidal thoughts and behaviors were associated with higher effect size estimates versus those that assessed lifetime occurrence. Studies that assessed suicide in an outpatient setting were associated with lower effect sizes than those in community, inpatient, or forensic settings. There were no other significant moderators (i.e., sociodemographic or study design variables) of the relationship between overall anger and suicide. Conclusions: Findings highlight the importance of anger as a potential risk factor for suicide. Future research is needed to examine these relationships longitudinally and to look at different facets of anger (e.g. experience vs. expression).

Abstract Background: WEE1, a tyrosine kinase with a role in several stages of the cell cycle, is a promising target in patients with solid tumors with increased levels of Cyclin E1 protein. Azenosertib is a potential best-in-class, highly selective oral WEE1 kinase inhibitor. This first-in-human phase 1 dose escalation/expansion study evaluated safety, tolerability and efficacy of azenosertib monotherapy in heavily pre-treated patients with advanced/metastatic solid tumors including gynecologic malignancies. Methods: This open-label, dose escalation/dose expansion Phase 1 study enrolled patients ≥18 years with advanced/metastatic solid tumors including platinum-resistant ovarian cancer (PROC) and uterine serous carcinoma (USC) who had received ≥1 prior line of therapy. Azenosertib monotherapy was administered continuously or intermittently (5 days on, 2 days off [5:2] or 4 days on, 3 days off [4:3]). The primary objective for dose escalation was to evaluate the safety and tolerability of azenosertib and identify the maximum tolerated dose with continuous and intermittent dosing. The primary objective for dose expansion was to investigate the clinical activity of azenosertib by objective response rate (ORR) per RECIST version 1.1. Duration of response (DOR) and safety were key secondary objectives. Biomarkers of replicative stress, such as Cyclin E1 protein expression, were explored retrospectively by immunohistochemistry. Results: As of December 2, 2024, 193 patients (PROC, n=69; USC, n=35; other solid tumors, n=89) received a total daily dose (300-500mg) of azenosertib, continuously or intermittently (5:2 or 4:3). The median age was 65 years and 98% of patients had ECOG PS ≤1; median number of prior lines of therapy was 5 (PROC), 3 (USC) and 4 (other solid tumors). The most common treatment-related adverse events (TRAEs) were nausea (61%), fatigue (59%), and diarrhea (52%). Most frequent Grade ≥3 TRAEs were fatigue and neutropenia (13% each), and anemia and thrombocytopenia (11% each). These adverse events were clinically manageable. TRAEs led to treatment interruption in 78 patients (40%), discontinuation in 10 patients (5%), and one death (cause unknown at 175mg twice a day 5:2). In patients with PROC who received azenosertib intermittently, ORR was 35% (8/23) in patients with Cyclin E1 positive tumors vs 21% (12/58) overall (median DOR, 5.2 [range 2.8-6.9, Cyclin E1 positive] and 5.1 months [range 3.0-5.9, overall]). In patients with USC who received azenosertib intermittently, ORR was 36% (4/11) in patients with Cyclin E1 positive tumors vs 26% (5/19) overall (median DOR, 5.5 months [range 5.4-NE] for both groups). Conclusion: WEE1 inhibitor azenosertib demonstrated a manageable safety profile at total daily doses (300-500mg), continuously or intermittently (5:2 or 4:3). Promising anti-tumor activity was observed in Cyclin E1 positive PROC and USC tumors, supporting further assessment of azenosertib in these patient populations. The DENALI Part 2 study (NCT05128825) is currently evaluating azenosertib in patients with Cyclin E1 positive PROC. Citation Format: Funda Meric-Bernstam, Gini F. Fleming, Deborah Doroshow, Jennifer Segar, Shiraj Sen, Hirva Mamdani, Alberto A. Mendivil, Jing-Yi Chern, Matthew L. Anderson, Cara A. Mathews, Natraj R. Ammakkanavar, David Miller, Matthew Whitehurst, Ryan Kendle, Alexander Spira, Shanta Chawla, Thejonatha Annareddy, Dongliang Zhuang, Jianhui Ma, Anthony W. Tolcher. Results From the Phase 1 Dose Escalation and Dose Expansion Study of Azenosertib, a WEE1 Inhibitor, in Patients With Advanced Solid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B012.

Objective: To examine the association between malignant peritoneal cytology and survival outcomes in endometrial cancer. Methods: This was an ancillary analysis of prospectively collected surgical-pathological data in the NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol. The study population included 2,383 patients with stage I-III endometrial cancer from 2003-2011. Exposure was peritoneal cytology status: malignant peritoneal cytology (n=215) or negative peritoneal cytology (n=2,168). Main outcome measures were recurrence-free survival and overall survival. Propensity score inverse probability treatment weighting was performed to balance the baseline clinico-pathological characteristics, followed by adjustment for adjuvant therapy. Results: Malignant peritoneal cytology was associated with a 32% increased risk of recurrence (5-year rates, 72% versus 77%, hazard ratio 1.32, 95% confidence interval 1.03-1.69, P=0.028) and 37% increased risk of all-cause mortality (78% versus 83%, hazard ratio 1.37, 95% confidence interval 1.06-1.78, P=0.018) compared to negative peritoneal cytology. When controlling for adjuvant therapy, the association between malignant peritoneal cytology and survival was attenuated for both recurrence-free survival (adjusted-hazard ratio 1.16, 95% confidence interval 0.90-1.50, P=0.24) and overall survival (adjusted-hazard ratio 1.22, 95% confidence interval 0.93-1.60, P=0.16) without statistical significance. Peritoneal cytology status and adjuvant therapy type had a possible interaction on overall survival, and malignant peritoneal cytology was associated with decreased overall survival when radiotherapy was received as adjuvant therapy but not when chemotherapy was utilized (P-interaction=0.059). Conclusion: The results of this prospective assessment suggest that malignant peritoneal cytology is a prognostic factor, may be associated with a modest decrease in survival for endometrial cancer.

&lt;p&gt;Supplementary Figure 1. Progression-free survival and overall survival by randomized treatment (N = 120). Distributions were estimated utilizing the Kaplan-Meier method for progression-free survival (PFS) by investigator assessment. Hazard ratios (HR) are estimated with a proportional hazards model stratified by prior PARP inhibitor (yes vs no) and prior immune checkpoint inhibitor (yes vs no). The confidence intervals (CIs) are adjusted to provide 95% simultaneous coverage for the study’s original 4 treatment comparisons. The P-values are adjusted for multiple comparisons for PFS.&lt;/p&gt;

&lt;p&gt;Supplementary Table 3. Experimental Arm Hazard Ratio Estimates for interim analysis (N = 120)&lt;/p&gt;

&lt;p&gt;Supplementary Table 1. Baseline Patient Characteristics&lt;/p&gt;

&lt;p&gt;Supplementary Table 2: Representativeness of Study Participants&lt;/p&gt;

&lt;p&gt;Appendix&lt;/p&gt;

&lt;p&gt;Supplementary Figure 2. Hazard Ratio estimates in subgroup analysis based on the stratification factors. Hazard ratios (HR) are estimated with a proportional hazards model stratified by prior exposure to PARP inhibitor (PARPi) (yes vs no) and prior immune checkpoint inhibitor (ICi) (yes vs no). Abbreviations: D, durvalumab; C, cediranib; O, olaparib; SOC, chemotherapy.&lt;/p&gt;

&lt;div&gt;AbstractPurpose:&lt;p&gt;We assessed the efficacy of anti–PD-L1 durvalumab in combination with olaparib and cediranib (DOC), compared with the standard-of-care chemotherapy (SOC) in patients with platinum-resistant ovarian cancer (PROC), who had prior bevacizumab.&lt;/p&gt;Patients and Methods:&lt;p&gt;NRG-GY023 was the first randomized four-arm superiority phase II trial enrolling patients with high-grade serous/endometrioid or clear-cell PROC with prior bevacizumab exposure. Patients were randomized 1:2:2:2 to SOC (weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin), DOC, durvalumab + cediranib (DC), or olaparib + cediranib (OC). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, overall response rate, and safety. The design had 80% power to detect an HR of 0.5 using a one-sided, &lt;i&gt;α&lt;/i&gt; = 0.1-level test for each comparison with the SOC with a preplanned interim analysis. Experimental arms with HR estimates (vs. SOC) &gt;0.87 could be discontinued.&lt;/p&gt;Results:&lt;p&gt;A total of 153 patients were enrolled between April 4, 2021, and February 1, 2023. Accrual was permanently closed on February 1, 2023, due to futility. With a data cutoff of September 9, 2024, the median PFS was 3.4, 2.9, 2.5, and 2.8 months, and median overall survival was 7.5, 8.3, 5.7, and 10.2 months for SOC, DOC, DC, and OC, respectively. The overall response rate was 4.3% [95% confidence interval (CI), 0.00–0.19], 15.9% (95% CI, 0.07–0.29), 11.9% (95% CI, 0.05–0.24), and 9.1% (95% CI, 0.03–0.20) for SOC, DOC, DC, and OC, respectively. Compared with SOC, the PFS HR estimates were 1.003 (95% CI, 0.56–1.80), 1.108 (95% CI, 0.63–1.96), and 1.021 (95% CI, 0.57–1.82) for DOC, DC, and OC, respectively. No new safety signals were observed.&lt;/p&gt;Conclusions:&lt;p&gt;In patients with PROC with prior bevacizumab, all experimental arms failed to reach the primary objective of improving PFS compared with SOC.&lt;/p&gt;&lt;/div&gt;

Low-grade serous ovarian cancer (LGSOC) is a rare and distinct cancer broadly driven by alterations in the MAPK pathway, including KRAS mutations in approximately 30% of patients. Although tumor tissue-based biopsy procedures are the standard practice for determining KRAS status in patients with LGSOC, blood-based liquid biopsies could offer less invasive testing if circulating tumor DNA (ctDNA) can reliably detect KRAS mutations in these patients.

TP53wt is found in ∼50% of all MMR proficient (pMMR) A/R EC tumors. TP53wt/pMMR is a unique subgroup with significant unmet need to improve treatment outcomes. SEL maintenance treatment has shown a strong progression-free survival (PFS) signal in TP53wt EC regardless of MMR status, with marked PFS benefit in TP53wt/pMMR. We report unpublished intermediate endpoints from ENGOT-EN5/GOG-3055/SIENDO.

5599 Background: There is a need for novel therapies for aEC that recurs after chemo and IO. LEN has antitumor activity in pts with aEC after platinum-based chemo [Vergote 2020] and is approved in combination with pembrolizumab for aEC following prior systemic therapy. E7386 is a novel oral anticancer agent that inhibits the interaction between β-catenin and CREB-binding protein. Study 102 evaluates E7386 + LEN in pts with solid tumors including aEC. A preliminary analysis of Study 102 (n=16) showed manageable safety and promising antitumor activity in aEC that progressed after platinum-based chemo and anti-PD-(L)1, including responses in pts with prior LEN. We report safety and antitumor activity for the complete dose expansion cohort (n=30) of pts with aEC. Methods: Pts with aEC that progressed after platinum-based chemo and IO received E7386 120 mg BID + LEN 14 mg QD (amended from 20 mg during enrollment). The primary endpoint was safety; secondary endpoints included ORR, duration of response (DOR), clinical benefit rate (CBR), and PFS by investigator per RECIST v1.1. Results: 30 pts were enrolled; 16 (53.3%) previously received LEN. By data cutoff (Oct 22, 2024), 9 (30.0%) pts had treatment ongoing. 29 (96.7%) Pts had treatment-related adverse events (TRAEs), most commonly vomiting (n=21, 70.0%). 12 (40.0%) Pts had grade 3 TRAEs, most commonly nausea/proteinuria/diarrhea/hypertension/anemia (n=2 each, 6.7%). No grade 4-5 AEs were observed. TRAEs led to study drug withdrawal of LEN and E7386 in 1 patient. Overall, 9 pts (3 with prior LEN) had a confirmed response (1 complete and 8 partial) for an ORR of 30.0%. In pts without prior LEN (n=14), the ORR was 42.9%. Additional data are in the Table. Conclusions: E7386 + LEN showed promising antitumor activity with a manageable safety profile in heavily pretreated pts with aEC following platinum-based chemo and IO. The dose-optimization phase of Study 102 for E7386 + LEN in pts with aEC is currently enrolling pts ( NCT04008797 ). Clinical trial information: NCT04008797 . Age, median, yrs (range) 62.0 (36–76) 1 / 2 / 3 prior lines of therapy, n (%) 4 (13.3) / 16 (53.3) / 10 (33.3) Endometrioid / serous / clear cell / other histology, n (%) 16 (53.3) / 3 (10.0) / 2 (6.7) / 9 (30.0) Mismatch repair proficient / deficient / NA a , n (%) b 16 (53.3) / 6 (20.0) / 8 (26.7) TP53 w ild type/ mutation, n (%) c 16 (53.3) / 14 (46.7) Serious TRAEs, n (%) 7 (23.3) ORR / CBR d , % (95% CI) 30.0 (14.7–49.4) / 46.7 (28.3–65.7) SD, n (%) 12 (40.0) DOR, median, mos (95% CI) 8.0 (3.7–9.5) PFS, median, mos (95% CI) 5.3 (3.0–8.9) a Microsatellite instability-low (n=3); unknown (n=4); NA (n=1); b as reported by sites; c circulating tumor DNA analyses were conducted using plasma samples collected at baseline, and were annotated using OncoKB database to identify mutations in TP53 ; d complete response + partial response + stable disease ≥23 wks. NA, not available.

e17522 Background: Chemotherapy interruptions in metastatic cervical cancer are not an infrequent event. Interruptions in treatment of solid tumors have been associated with adverse survival outcomes. Our objective was to determine the impact of treatment interruption during first line systemic chemotherapy on survival in patients with metastatic or recurrent cervical cancer. Methods: An IRB approved retrospective cohort study was designed to identify patients with metastatic (stage IVB) or recurrent cervical cancer treated at our institutions from January 2008 through December 2024. Demographics, clinicopathologic information, first line chemotherapy regimens, associated delays and outcome measures were abstracted from medical records. Exclusion criteria included neuroendocrine histology; refusal or non-initiation of treatment on diagnosis of recurrence, or death; and insufficient clinical data. Delays were categorized as modifiable (social determinants of health, logistics, treatment break) and non-modifiable (cytopenias, organ dysfunction, chemotherapy reaction, infection, ECOG status). Data were analyzed using descriptive statistics, Kaplan-Meier survival estimate, and log-rank tests to calculate significance (p&lt;0.05). Primary endpoints were progression free survival during first line chemotherapy and overall survival. Results: 204 patients with metastatic or recurrent cervical cancer met inclusion criteria. Clinical and demographic attributes of patients are presented in Table 1. A total of 1,833 cycles of first line chemotherapy were completed with 633 interruption events. There were 308 modifiable and 325 non-modifiable interruption events. Median total, modifiable, and non-modifiable interruption events per patient was 2 events. Median number of days a cycle was interrupted was 7 days (1-259). There was no difference in survival between patients with or without interruptions in treatment. However, patients who had modifiable treatment interruptions had a significantly better overall survival compared to those with non-modifiable treatment interruptions (HR 0.60, 95% CI [0.38-0.93], p&lt;0.05). Conclusions: Treatment interruptions during first line systemic chemotherapy for metastatic or recurrent cervical cancer do not affect survival. Demographics and clinical attributes of evaluable patients with stage IVB or recurrent cervical cancer (n=204). Characteristic Median age at diagnosis of IVB or recurrence, years 54.5 (22-81) Race, n (%) White/CaucasianBlack/African AmericanAsianNative American/Alaska Native/Multiracial/Other 149 (73.04)45 (22.06)5 (2.45)5 (2.45) Metastatic (IVB) disease 74 Recurrent disease after surveillance 130 Histology, n (%) Squamous cell carcinomaAdenocarcinomaAdenosquamous carcinomaOther 149 (73.04)40 (19.61)4 (1.96)11 (5.39)

BACKGROUND: Varicocoeles are common in 40% of men presenting with infertility. Semen parameters including sperm motility, low sperm count and sperm morphology are altered by the presence of varicocoeles. Though varicocoelectomy has been associated with improvements in these parameters, studies on long-term outcomes are limited. OBJECTIVES: Analyze pre-operative samples with those collected at multiple post-operative timepoints to assess if sperm parameters continue to improve in the period following varicocoelectomy. MATERIALS AND METHODS: Adult men who underwent varicocoelectomy under a single surgeon from 2017 to 2023 with at ≥1 post-operative semen analysis (SA) were included. Motile sperm count, progressive motility, round cells, semen volume, sperm concentration, sperm morphology, total motility and viability was collected from each patient's SA. Wilcoxon signed-rank tests were used to compare medians of sperm parameters from pre-operative baseline to 6, 12, 18 and 24 months follow up. RESULTS: At 6 months, number of motile sperm increased from 4 to 8 million/mL (p < 0.0001), progressive motility increased from 34% to 42% (p < 0.0001), total motility rose from 37% to 45% (p <0.0001), concentration increased from 6.9 mil/mL to 9 mil/mL (p <0.0001), and morphology increased from 1% to 2% (p = .0026). Viability increased from 60% to 62% (p = .0002). At 6-12 months, number of motile sperm (7 mil/mL, p < 0.0001), progressive motility (38.5%, p = 0.0005), sperm concentration (8 mil/mL, p < 0.0001), and total motility (41.5%, p < 0.0001) remained statistically significant compared to baseline. At 12-18 months, significant increases in progressive motility (35%, p = 0.0272) and total motility (37%, p = 0.0022) persisted. CONCLUSIONS: Our retrospective study demonstrates significant short-term improvements across multiple parameters at 6-months after varicocoelectomy. While we note individual improvement in sperm parameters during longer follow-up period, there was variability based on the time frame. Our findings underscore the impact of varicocoelectomies may have on enhancing short-term male fertility. Future, prospective research is needed to validate these findings.

PURPOSE: We assessed the efficacy of anti-PD-L1 durvalumab in combination with olaparib and cediranib (DOC), compared with the standard-of-care chemotherapy (SOC) in patients with platinum-resistant ovarian cancer (PROC), who had prior bevacizumab. PATIENTS AND METHODS: NRG-GY023 was the first randomized four-arm superiority phase II trial enrolling patients with high-grade serous/endometrioid or clear-cell PROC with prior bevacizumab exposure. Patients were randomized 1:2:2:2 to SOC (weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin), DOC, durvalumab + cediranib (DC), or olaparib + cediranib (OC). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, overall response rate, and safety. The design had 80% power to detect an HR of 0.5 using a one-sided, α = 0.1-level test for each comparison with the SOC with a preplanned interim analysis. Experimental arms with HR estimates (vs. SOC) >0.87 could be discontinued. RESULTS: A total of 153 patients were enrolled between April 4, 2021, and February 1, 2023. Accrual was permanently closed on February 1, 2023, due to futility. With a data cutoff of September 9, 2024, the median PFS was 3.4, 2.9, 2.5, and 2.8 months, and median overall survival was 7.5, 8.3, 5.7, and 10.2 months for SOC, DOC, DC, and OC, respectively. The overall response rate was 4.3% [95% confidence interval (CI), 0.00-0.19], 15.9% (95% CI, 0.07-0.29), 11.9% (95% CI, 0.05-0.24), and 9.1% (95% CI, 0.03-0.20) for SOC, DOC, DC, and OC, respectively. Compared with SOC, the PFS HR estimates were 1.003 (95% CI, 0.56-1.80), 1.108 (95% CI, 0.63-1.96), and 1.021 (95% CI, 0.57-1.82) for DOC, DC, and OC, respectively. No new safety signals were observed. CONCLUSIONS: In patients with PROC with prior bevacizumab, all experimental arms failed to reach the primary objective of improving PFS compared with SOC.

Objective: To evaluate and define the proportion of clinically stage I Uterine Carcinosarcoma (UCS) patients who are upstaged to FIGO stages II-IVB following primary surgery based on final pathology. Methods: We performed a retrospective review of patients diagnosed and treated for UCS at our institution from 2009 to 2023. All patients who underwent primary surgery for UCS and had clinically stage I (uterine-confined) disease were included. Uterine-confined disease was determined based on pre-operative physical exam and imaging. The primary outcome was the proportion of patients who were upstaged after surgery. Results: Ninety-eight patients underwent primary surgery with a median age of 64 years (IQR 59-68). Twenty-six patients (26.6 %) had suspected extra-uterine disease based on pre-operative evaluation and were excluded. Seventy-two patients (73.4 %) had uterine-confined disease based on pre-operative exam/imaging and underwent staging surgery. Of the 72 patients with clinical stage I disease, 39 patients (54.2 %) were ultimately diagnosed with advanced disease (FIGO Stages II-IVB), while 33 patients (45.8 %) had confirmed early-stage disease on final pathology (FIGO Stages IA or IB). Surgical staging revealed the following: 15.4 % (n = 6) were upstaged to Stage II, 5.1 % (n = 2) to Stage IIIA, 5.1 % (n = 2) to Stage IIIB, 35.9 % (n = 14) to Stage IIIC1, 12.8 % (n = 5) Stage IIIC2, and 25 % (n = 10) to Stage IVB. Conclusion: More than 50% of patients with pre-operative "uterine-confined" carcinosarcoma were upstaged on final pathology, mostly commonly to Stage III. Our findings underscore the importance of surgical staging since upstaging carries critical prognostic information and implications for adjuvant treatment planning.

ABSTRACT This article posits an information channel as an explanation for sudden inflations. Households saving via nominal government bonds face a choice whether to acquire costly information about future government surpluses. They trade off the cost of acquiring information about the surpluses that back bond repayment against the benefit of a more informed saving decision. Through the information channel, small changes in the economic environment can trigger large responses in consumer behavior and prices. This setting explains why there can be long stretches of time during which government surpluses have large movements with little inflation response; then at some point, something snaps, and a sudden inflation takes off that is strongly responsive to incoming fiscal news.

Purpose. Determine if molecular classification using mismatch repair (MMR) and p53 protein expression predicts recurrence-free survival (RFS) and overall survival (OS) in endometrial cancer (EC) patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT). Methods. GOG-0258, a phase III randomized trial (NCT00942357), compared CRT to CT. Immunohistochemistry assessed MMR and p53 status. Kaplan-Meier curves and adjusted Cox models analyzed survival outcomes by molecular subtype. Results. ECs classified as deficient MMR (dMMR) (27 %), p53 abnormal (p53abn) (24 %), and p53 wild type (p53wt) (49 %). p53abn were more frequent in patients that were older, Black, and had serous histology (p < 0.001). Median follow up was 113 months. Five-year RFS and OS were worse with p53abn (29 % [Hazard Ratio (HR) = 3.39 (95 % Confidence Interval (CI): 2.34–4.91)] and 39 % [HR = 4.64 (95 % CI: 3.16–6.79)] compared to those with p53wt (referent) (p < 0.001). The five-year RFS and OS for dMMR cancers were (58 % [HR = 1.30 (95 % CI: 0.85–1.97)] and 77 % [HR = 1.53 (95 % CI: 0.99–2.36)] compared to those with p53wt (69 % and 85 %). After adjusting for age, gross residual disease, and treatment, p53wt improved RFS with CRT compared to CT in an exploratory analysis (77 % vs 60 %; HR = 0.54 (95 % CI: 0.32–0.94). The 5-year and 10-year OS rates were similar in CRT compared to CT in all subgroups. Conclusion. Molecular classification appears to be predictive and prognostic, with worse survival in those with p53abn tumors. In an exploratory analysis, p53wt appears to predict improved RFS, favoring CRT over CT. There was no difference in treatment efficacy based on molecular subtype for OS.

This randomized phase III trial aimed to determine whether treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for four cycles (chemoradiotherapy [C-RT]) increased recurrence-free survival (RFS) and overall survival (OS) when compared with carboplatin and paclitaxel for six cycles (chemotherapy [CT]) in locally advanced endometrial cancer (UC). Previously reported results showed that C-RT did not improve RFS compared with CT. Here we report the final OS analysis. Patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage III-IVA UC or stage I/II serous or clear cell UC and positive cytology were enrolled. The primary objective was RFS. Secondary objectives were OS, toxicity, and quality of life. Cumulative probabilities of OS were estimated using the Kaplan-Meier method. Subgroup analyses of treatment effect for FIGO stage, age, race, gross residual disease, histology, lymph-vascular space invasion, and body mass index were performed. In total, 813 patients were randomly assigned (407 C-RT and 406 CT). The median follow-up was 112 months. Median OS was not achieved in either arm. The stratified hazard ratio for death comparing C-RT versus CT was 1.05 (95% CI, 0.82 to 1.34, log-rank two-sided P value = .72). None of the factors analyzed predicted OS benefit from C-RT. Although C-RT reduced the rate of local recurrence compared with CT, it did not increase OS or RFS in stage III/IVA UC.

Abstract Background Rater change is inevitable in often lengthy clinical trials in Alzheimer’s disease. Other groups have previously assessed the impact of rater change on data variability. Their conclusions varied, possibly due to differing methodologies (e.g. ‐ comparing actual vs. absolute change; analyzing data per trial and visit or by combining all trials and visits). Here, we analyze the impact of rater change of MMSE data ‐ using both actual and absolute change ‐ looking only between Screening and Baseline visits. Method MMSE and MMSE change from Screening data were obtained from 11.084 Baseline assessments collected across 13 Alzheimer’s disease clinical trials. Data were broken into 2 groups by the presence of rater change between Screening and Baseline. Two regression models were fitted to the data. In the first model the dependent variable was the MMSE actual change from Screening to Baseline, in the second model the MMSE absolute change was tested. Rater change, clinical trial and their interaction were used as predictors and MMSE Baseline value entering in a cubic form as a covariate. Result In the first model using actual MMSE change, neither rater change, nor the interaction between protocol and rater change was significant. Removing the interaction term, rater change decreased the MMSE change by 0.1 MMSE points (p = 0.06). In the second model, the effect of rater change differed from study to study. Among studies that showed significant rater change effect, the absolute MMSE change increased by 0.46 points on average. Conclusion Our results indicate that rater change may indeed have an impact on MMSE data but the impact is inconsistent. While the actual change was affected only insignificantly, the absolute change as a measure of variability was significantly increased. Substantial differences were observed between individual studies and in only 6 of the 13 studies, rater change significantly increased MMSE absolute change. Given the results, rater change should be considered a risk factor to assessment reliability. Therefore, reasonable efforts should be taken to minimize both its occurrence and its impact on study data.

Abstract Background Clinical trial sponsors rely on research sites to identify and enroll appropriate study participants and to correctly and reliably assess symptom severity and function over the course of the trial. Low‐recruiting sites represent a large financial and operational burden and may negatively impact trial success either by selecting inappropriate participants and/or high prevalence of data quality issues. We previously reported that &gt;60% of sites in schizophrenia clinical trials recruited ≤5 participants. Here we analyze 3 large dementia trials to assess the proportion of low‐recruiting sites and compare their data quality with the remaining sites. Method Data were obtained from 3 large early dementia clinical trials totaling 834 sites. Sites were divided into two groups based on the number of randomized subjects: 1. sites with more than 5 randomized subjects (high‐recruiting sites) and 2. sites with 5 or less randomized subjects (low‐recruiting sites). Data quality issues were defined as administration and scoring errors on relevant scales. These errors were summed per site and then compared by site size using Poisson regression with the site size, study and their interaction as predictors and the number of possible hits as exposure. Result 71 (8.5%) sites did not randomize a subject, 43 (5.2%) sites randomized one subject, and 377 (45.2%) sites randomized ≤5 subjects. Overall, administration and scoring errors were more frequent at low‐recruiting sites (seen at 41.9% visits) compared to 35.3% at the high‐recruiting sites. 2 studies show significantly higher IRRs, 1.59 (1.46, 1.74) and 1.2 (1.15, 1.25) respectively, while the third study has an IRR close to 1 but not statistically significant. Conclusion Our results indicate that low‐recruiting sites (arbitrarily defined as randomizing ≤5 participants) are frequent in large dementia trials. These sites pose considerable cost to sponsors, but more importantly, are more likely to provide questionable data quality. While a single site like this only represents a small risk, in aggregate, they can pose a serious challenge. Clinical trial sponsors should therefore consider strategies to minimize the impact of low‐recruiting sites on study outcomes.

The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

Objectives. To assess the efficacy and toxicity of paclitaxel and carboplatin (PC) compared to bleomycin, etoposide, and cisplatin (BEP) for treatment of newly diagnosed Stage IIA-IV or recurrent chemotherapy-naive ovarian sex cord-stromal tumors (SCST). Methods. This phase II noninferiority trial randomly assigned patients to receive PC (6 cycles P 175 mg/m2 and C AUC = 6 IV every 3 weeks), or BEP (4 cycles B 20 units/m2 IV push day 1, E 75 mg/m2 IV days 1–5, and cisplatin 20 mg/m2 IV days 1–5 every 3 weeks). The primary endpoint was progression- free survival (PFS). This trial is registered with ClinicalTrials.gov, NCT01042522. Results. At the interim analysis, 63 patients (31 PC and 32 B.P. had accrued between Feb 8, 2010 and Apr 30, 2020. Median age was 48 years. 87% had granulosa cell tumors. 37% had measurable disease. The DSMB closed accrual early for futility of PC arm. The futility analysis was supported by an estimated HR = 1.11 [95% CI: 0.57 to 2.13] which exceeded the pre-determined threshold for non-inferiority (1.10). Median PFS was 27.7 months [11.2 to 41.0] for PC and 19.7 months for BEP [95% CI: 10.4–52.7]. PC patients had fewer grade 3 or higher adverse events (PC 77% vs BEP 90%). Conclusions. The study met its pre-specified criterion for stopping early for futility and so failed to demonstrate non-inferiority of PC versus BEP in ovarian SCSTs, in a non-inferiority test with a hazard ratio margin of 1.1. Both PC and BEP may be considered in patients with advanced/recurrent SCST.

OBJECTIVE Patients with cervical cancer who are diagnosed with venous thromboembolism (VTE) have worse outcomes compared to those not affected. There has yet to be a reliable method to predict or prevent VTE in cervical cancer patients. Our objective is to describe the incidence of VTE in patients with recurrent and metastatic (r/mCC) and determine risk factors that may predict VTE in this setting. METHODS We performed an observational cohort study of 386 patients with r/mCC who received at least one line of systemic chemotherapy. We collected demographic, clinical, histologic data and Khorana scores for all patients. Inclusion and exclusion criteria were applied before analysis. Statistical analysis was performed using Pearson chi-square, Student's t-test, and Wilcoxon rank-sum. RESULTS 232 patients were included for evaluation. Mean age was 49 years (range 20-83). The majority (167, 72%) of patients had squamous cell histology. 169 (72.8%) patients received treatment for recurrent disease and 63 (27.2%) for metastatic, stage IVB disease. 180 (78%) patients received prior radiation and 134 (58%) received bevacizumab. VTE was diagnosed in 89 (38%) patients. There were no statistically significant differences amongst clinical and pathologic characteristics between patients who developed VTE and those who did not. There was no significant association between BMI, Khorana score, radiation, bevacizumab, or immunotherapy and the development of VTE. CONCLUSION Approximately 40% of patients with r/mCC experienced a new VTE. There were no independent risk factors that could predict VTE in this population. Due to the overwhelmingly high incidence of VTE, prophylactic anticoagulation could be strongly considered in patients with r/mCC.