Paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disease, is associated with high maternal and fetal mortality rates. Only 1 medication approved for PNH, the complement component 5 inhibitor eculizumab, has published evidence of use during pregnancy. What were the circumstances and outcomes of the first use of pegcetacoplan, a complement component 3 inhibitor, by a pregnant woman with PNH? The patient, with a history of 2 miscarriages and a suboptimal response to eculizumab, had hematologic improvement after switching to pegcetacoplan. She continued pegcetacoplan throughout her pregnancy. At gestational week 30, she developed abruptio placentae and breakthrough hemolysis. She delivered a normal-appearing male infant via emergency cesarean section. The breakthrough hemolysis resolved quickly with short-term intensive pegcetacoplan dosing and add-on eculizumab. To date, her laboratory values remain normal, and she has had no thromboembolic events; her son has not demonstrated growth defects. This is the first report of pegcetacoplan treatment for PNH throughout pregnancy. The mother recovered promptly from breakthrough hemolysis that prompted an emergency delivery. Her son, who was born prematurely but healthy, has developed normally.

Background: Urothelial carcinoma (UC) is one of the most common cancers diagnosed worldwide. However, minority populations, such as female, elder, and Black patients, may have disparate outcomes and are commonly neglected in randomized prospective trials. This review aims to study the relationship between age, sex, and race on urothelial cancer prognosis, particularly focusing on contemporary therapy and its effect on overall survival. Methods: Phase III prospective trials since 2016 of immune checkpoint inhibitors, antibody-drug conjugates, or targeted therapies in urothelial carcinoma were identified from PubMed. Trials that did not report on survival by race, sex, or age distribution were excluded, and remaining trials (n = 17) were compared by subgroup. Results: Women were reported to have inferior OS on investigational agents compared to men in 9/17 trials. In a meta-analysis, women had inferior OS to men (OR 0.89 [95% CI: 0.78–0.99]; p = 0.04). Asian/Pacific Islander patients had inferior outcomes to White patients on investigational agents in 3/5 trials. In a meta-analysis, OS was not significant by race (OR 1.18 [0.90–1.46], p = 0.38). Black patients composed <2% of all trial patients, and no subgroup data were reported. Both 65 (n = 7) and 75 (n = 2) were reported as age cut-offs in trial subgroups, and survival data were mixed. Conclusions: Women in UC trials may have inferior survival outcomes to men. Racial diversity was poor and thus limited any conclusions on survival disparities.

Retrospective data suggest poorer survival for female, racial minority, and older advanced urothelial carcinoma (aUC) patients. However, data on survival disparities in the modern era remain limited. This cohort study used Flatiron Health's nationwide de-identified electronic health record (EHR)-derived database. Patients who initiated systemic therapy for aUC between January, 2017 and May, 2024 were included. Baseline characteristics, treatment history, and clinical outcomes were abstracted. PFS and OS were compared by sex (male vs. female), race (White, Black, vs. Asian/Pacific Islander [API]), and age at diagnosis (> 65 years [y] vs. ≤ 65 y), using Kaplan-Meier log-rank analysis and Cox proportional hazards models. Independent sample t-tests and chi-square analyses were used for univariate comparisons. P-values < .05 were considered statistically significant. A total of 5142 patients with aUC were identified. 1419 were (28%) female and 575 (11%) were > 65 y. Of those with recorded race (n = 3492), 1% were API, 5% Black, 14% categorized as "other," and 80% White. There was no difference in PFS (8.7 vs. 9.0 months [m], HR1.03; P = .82) or OS (13.2 vs. 13.5 m; HR1.05, P = .31) between women and men. Women had shorter PFS to men on immune checkpoint inhibitors (ICI) (P = .002) but not with other first-line (1L) therapy. API patients had comparable PFS (9.6 vs. 8.9 m; HR0.91; P = .45) but longer OS (28.5 vs. 14.1 m; HR0.56; P = .008) compared to White patients. Black patients had comparable PFS (7.9 vs. 8.5; HR1.06; P = .81) and OS (11.5 vs. 14.1 m; HR1.32; P = .73) vs White patients. Patients > 65 y had shorter PFS to ≤ 65 y (7.6 vs. 9.0 m; HR1.14, P = .019); however, OS was longer in older patients (16.5 vs. 12.8 m; HR0.80, P < .001). Only on 1L ICI, OS was longer in those > 65 y compared to those ≤ 65 y (HR0.71; P = .021) CONCLUSION: In this large real-world database, female aUC patients had comparable PFS and OS to males. API patients showed superior OS to White patients. Patients > 65 y had inferior PFS but superior OS to patients ≤ 65 y.

Background/Objectives: Enfortumab vedotin plus pembrolizumab (EV+pembro) is the standard first-line treatment for metastatic urothelial carcinoma (mUC), yet no validated on-treatment biomarker identifies patients deriving a durable benefit. We evaluated whether circulating tumor DNA (ctDNA) clearance is associated with response and survival with this regimen alone. Methods: This single-center retrospective study included 25 patients with mUC receiving first-line EV+pembro. A tumor-informed assay (Signatera) measured ctDNA longitudinally. Responses were assessed by RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) were estimated by Cox regression and, to address immortal time bias, with clearance as a time-dependent covariate. Results: Fifteen of 25 patients (60%) achieved ctDNA clearance (ever undetectable). The objective response rate was 76% overall and 100% (15/15) with clearance versus 40% (4/10) without (p = 0.0012). Clearance was associated with longer PFS (HR 0.16, 95% CI 0.05–0.54; p = 0.003) and OS (HR 0.08, 95% CI 0.01–0.68; p = 0.021), with similar Firth penalized HRs (0.17 and 0.11). In the time-dependent analysis, the associations were attenuated (PFS HR 0.35, 95% CI 0.09–1.15, p = 0.085; OS HR 0.14, 95% CI 0.01–0.84, p = 0.029; profile likelihood CIs). A post-nadir ctDNA rise preceded progression or death by a median of 95 days in four patients (death in two). Conclusions: In this first-line EV+pembro cohort, all patients who cleared ctDNA responded, and clearance was associated with longer survival, although this association was attenuated in the time-dependent analysis. These hypothesis-generating findings support the prospective evaluation of ctDNA-guided monitoring.

Muscle-invasive bladder cancer (MIBC) carries high risks of relapse and death despite contemporary care. In this study we aimed to evaluate whether the pretreatment immune microenvironment varied with HER2 status and if the differences influenced the response to neoadjuvant chemotherapy (NAC) and survival. We conducted a retrospective study of 62 treatment-naiive MIBC patients diagnosed on pretreatment transurethral resection of bladder tumor (TURBT) specimens collected between 2008 and 2024. All patients received NAC followed by radical cystectomy. HER2 immunohistochemistry (IHC) was scored 0/1+/2+/3+ using gastroesophageal criteria. PD-L1 was assessed by combined positive score (CPS). CD3, CD20, and CD68 cell densities were quantified by digital image analysis. Overall survival was measured from the date of TURBT. HER2 IHC scores were 2+/3+ in 28 of 62 tumors (45%) and 0/1+ in 34 (55%). All seven IHC 2+ tumors lacked ERBB2 amplification by fluorescence in situ hybridization (FISH). NAC response occurred in 11 of 34 tumors with HER2 IHC 0/1+ (32%) and 9 of 28 tumors with HER2 IHC 2+/3+ (32%) (P = 1.00). PD-L1 expression was not associated with HER2 status. Immune-cell analyses showed trends toward higher CD3+ T-cell density, CD20+ B-cell density, and TM ratio in NAC responders, but no significant differences by HER2 status or combined PD-L1/HER2 subgroup status. After Bonferroni correction for multiple comparisons, none of the immune-cell metrics remained statistically significant. Overall survival did not differ between the HER2 IHC groups (P = 0.71). These findings indicate that HER2 IHC 2+/3+ expression is present in a substantial subset of MIBC but is not associated with NAC response or overall survival in this cohort. Further study is warranted to define the clinical relevance of MIBC with HER2 IHC 2+/3+ and its potential role in HER2-directed therapeutic strategies.

Background: Sarcomatoid renal cell carcinoma (sRCC) is an aggressive RCC subtype with a poor prognosis. Although racial disparities in RCC outcomes are reported, survival patterns across racial and ethnic groups in metastatic sRCC (msRCC) remain unclear. Methods: We conducted a retrospective analysis of 2122 patients with msRCC diagnosed between 2010 and 2020 using the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized by race and ethnicity as non-Hispanic White, non-Hispanic Black, Hispanic, Asian/Pacific Islander, or American Indian/Alaska Native. Three-year cancer-specific survival (CSS) and overall survival (OS) were estimated using Kaplan–Meier methods. Multivariable Cox proportional hazards regression models were used to evaluate racial disparities in survival. Results: Non-Hispanic Black patients experienced the poorest outcomes, with 3-year CSS and OS of 9.3% and 8.6%, compared with 23.3% and 20.9% in non-Hispanic White, 22.1% and 19.0% in Hispanic, 21.2% and 19.4% in Asian/Pacific Islander, and 23.4% and 20.7% in American Indian/Alaska Native patients. Non-Hispanic Black patients were associated with higher estimated hazards of cancer-specific mortality (HR = 1.5, p < 0.0001) and overall mortality (HR = 1.5, p < 0.0001) versus non-Hispanic White. From 2010–2015 to 2016–2020, survival improved across most racial groups with the introduction of immune checkpoint inhibitors. However, non-Hispanic Black patients remained the only group with persistently inferior survival. Subgroup analysis further demonstrated worse survival for non-Hispanic Black patients in both clear cell msRCC and non-clear cell msRCC subgroups. Conclusions: Although survival was higher during the later diagnosis period, non-Hispanic Black patients with msRCC continued to have the poorest observed survival. These differences may be associated with unmeasured social, structural, socioeconomic, healthcare access, treatment, or clinical factors, but their causes cannot be determined from this observational study. Further research is needed to identify the factors underlying these survival differences.