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Outcomes of kidney-alone transplantation (KAT) in former simultaneous liver-kidney (SLK) transplant candidates after liver waitlist delisting are not well defined. Using Scientific Registry of Transplant Recipients (SRTR) data, we identified adult recipients who underwent KAT between 2005 and 2025 after prior SLK listing (RLD-KAT), which was matched 1:5 to primary KAT recipients without liver disease by age, transplant year, and diabetes status. Patient and graft survival were evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards models. We identified 163 RLD-KAT recipients matched to 815 controls. Unadjusted Kaplan-Meier analyses demonstrated lower patient survival in RLD-KAT (p = 0.020), whereas death-censored and overall graft survival were similar (p > 0.05). In multivariable models, death-censored graft survival (HR 0.89; 95% CI 0.51–1.53), overall graft survival (HR 1.00; 95% CI 0.73–1.36), and patient survival (HR 1.07; 95% CI 0.76–1.5) did not differ significantly. Six RLD-KAT recipients (3.7%) subsequently underwent liver transplantation. Kidney-alone transplantation in prior SLK candidates was associated with acceptable patient and graft outcomes and a low incidence of subsequent liver transplantation.

The intestinal epithelium is exposed to diverse combinations of microbiota-derived compounds; however, the mechanisms by which the host integrates these signals remain poorly defined. Studying two highly abundant microbial metabolites, we identified the purine metabolite hypoxanthine as an effector metabolite that directly drives signaling and the short-chain fatty acid butyrate as a regulatory metabolite that conditions host responsiveness. Specifically, hypoxanthine activates the adenosine A1 receptor–TRPC4 axis in enterochromaffin (EC) cells, triggering calcium influx and serotonin release resulting in accelerated gastrointestinal transit locally and increased platelet activation systemically. In contrast, butyrate epigenetically upregulates specific G protein–coupled receptors and ion channels to enhance response to hypoxanthine and the neurotransmitters norepinephrine and dopamine. These findings define a cooperative signaling framework and highlight the role of EC cells as a distinct epithelial signaling hub that senses and integrates microbial metabolite signals to drive physiological responses. Our findings provide a mechanistic foundation for therapeutic strategies that leverage combinatorial microbial signaling.

Background. The use of immune checkpoint inhibitors (ICIs) in kidney transplant recipients (KTR) for cancer treatment is limited by concerns of allograft rejection and uncertain oncologic efficacy. Methods. We conducted a single-center retrospective study of KTR with unresectable or metastatic malignancies treated between 2018 and 2025. The primary study cohort included 33 patients treated with ICI, whose outcomes were compared with 20 matched KTR treated with non-ICI systemic chemotherapy (SC). Results. KTR treated with ICI achieved an objective response rate of 36.4% (12/33) versus 30.0% (6/20) with SC, and a clinical benefit rate of 54.5% (18/33) versus 35.0% (7/20); neither difference was statistically significant (objective response rate P = 0.77; clinical benefit rate P = 0.27). Disease progression occurred in 81.8% of ICI-treated patients and 95.0% of SC-treated patients ( P = 0.23), and death because of cancer progression occurred in 63.6% and 75.0%, respectively ( P = 0.58). Median progression-free survival was 7.3 mo (95% confidence interval [CI], 4.3-10.8 mo) in the ICI group versus 4.1 mo (95% CI, 2.8-6.3 mo) in the SC group (log-rank P = 0.156). Median overall survival was 15.1 mo (95% CI, 7.6-37.3 mo) with ICI versus 8.7 mo (95% CI, 4.9-14.8 mo) with SC (log-rank P = 0.079). Posttreatment allograft rejection occurred in 12.1% of ICI-treated patients and 0.0% of SC-treated patients ( P = 0.29), with irreversible graft loss in 3.0%. Grade ≥2 immune-related adverse events occurred in 12.1% of ICI-treated patients, and no treatment-related deaths were observed. Conclusions. ICI therapy was associated with a trend toward longer overall survival when compared with SC and with a low rate of rejection and allograft loss.

Purpose: To describe a case of locally invasive conjunctival squamous cell carcinoma (SCC) refractory to plaque radiotherapy. Case Description: A 69-year-old man presented with a recurrent conjunctival tumor after 6 previous cycles of topical 5-fluorouracil chemotherapy and excisional biopsy showing invasive SCC with positive margins. There was a mild anterior chamber reaction. By the time of repeat excisional biopsy, the conjunctiva had ulcerated with underlying scleralysis associated with histopathologic evidence of scleral involvement by SCC. After subsequent tectonic scleral patch grafting, plaque radiotherapy was applied after which the disease appeared to be controlled for 9 months. The eye then developed progressive conjunctival ulceration and scleralysis with progressive ectropion. Exenteration was performed, revealing locally invasive SCC into palpebral conjunctiva, ciliary body, and choroid. Conclusions: Conjunctival SCC can be locally invasive with destruction of the globe, despite plaque radiotherapy. Clinicians should be suspicious of invasive diseases in cases of ocular surface squamous neoplasia that are poorly responsive to topical chemotherapy. Associated anterior chamber cell and progressive scleralysis should also raise concern for invasive malignancy.

Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve decision-making. Materials and Methods: Fifty-four donors undergoing NRP and their recipients were included. FMN was measured at the start, 1 h, and end of NRP. Lactate was measured at the start, 30, 60, and 90 min of NRP. Primary outcomes were early allograft function using the early allograft dysfunction (EAD) criteria and the model for early allograft function (MEAF). Secondary outcomes included the association with donor warm ischemia time (DWIT), stratified by 30 min. Spearman’s rho assessed correlations. Results: Forty (74%) livers were transplanted, with 5 (12.5%) recipients developing EAD and the mean MEAF score was 3.13 (1.49). FMN at all time points was significantly greater in the EAD group compared to the non-EAD group and was significantly correlated with the MEAF score (Peak FMN: rho = 0.507, p = 0.001). FMN during perfusion did not differ between DWIT < and ≥30 min. Lactate levels were similar across all groups and did not discriminate for adverse allograft outcomes. However, lactate levels during perfusion were higher in the DWIT ≥ 30 min group. Conclusions: These findings suggest that during NRP, elevated FMN, but not lactate, is associated with early allograft function.

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

Abstract. Introduction: Preterm birth drives adverse perinatal maternal and infant health outcomes through heterogeneous symptoms, severity, and etiologies. Delivery prior to reaching 37 weeks of gestation may result from medically indicated intervention for pregnancy complications or spontaneously in the absence of prior symptoms. Placental tissue collected following preterm birth exhibits differential DNA methylation compared to full-term placentas and may indicate pregnancy health during gestation. Placental DNA currently has limited utility for assessing health of ongoing pregnancy, as sampling placental tissue during gestation increases the risk of infection and miscarriage. Risks associated with placental sampling during pregnancy limit the use of DNA methylation in clinical preterm birth prediction. Assessing preterm birth risk during gestation requires non-invasive methods for characterizing placental DNA methylation. Results: We quantified genome-wide DNA methylation patterns of hypermethylated cell-free DNA in pregnant (n = 99) and non-pregnant (n = 93) plasma using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). In each sample, we assessed DNA methylation status in 300-bp genomic windows, examining both sequencing read counts and calculated absolute molar DNA amount. Known hypermethylated placental regions, including RASSF1, STAT5A, and ERG promoters showed significantly increased odds of detection in pregnant samples, suggesting enrichment of cell-free placental DNA. Of the 536,444 300-bp windows examined, 173,071 (32%) showed significant enrichment in pregnant plasma. Linear modeling identified 107,505 differentially methylated regions (DMRs) associated with pregnancies later diagnosed with intrauterine growth restriction (IUGR) (n = 22). Alu elements showed increased representation in these DMRs than expected, while other repetitive elements exhibited underrepresentation. Discussion: These results demonstrate cfMeDIP-seq's ability to enrich for cell-free placental DNA and characterize cell-free DNA methylation signatures of pregnancies complicated by IUGR. Enrichment of cell-free placental DNA enables non-invasive profiling of placental DNA methylation from maternal plasma. Detectable epigenetic signatures in maternal plasma may identify pregnancies at elevated risk for preterm birth before clinical symptoms appear. Our findings further highlight the potential of cell-free placental DNA for monitoring pregnancy health.

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414