Citations

Cutaneous metastases occur in up to 20% of patients with advanced melanoma and can be difficult to manage with systemic therapy alone. Pembrolizumab is a standard therapy with limited local treatment options for cutaneous manifestations. Imiquimod has shown activity in other skin cancers but is less well studied in melanoma. We conducted a pilot trial to evaluate the feasibility, safety, and preliminary efficacy of combining topical imiquimod with intravenous pembrolizumab in patients with unresectable melanoma with cutaneous metastases. This was a single-center, open-label, non-randomized interventional study (NCT03276832). Eligible patients received pembrolizumab IV every 21 days plus topical imiquimod 5% applied Monday–Friday each cycle. The primary endpoint was objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, and safety. In this study, seven patients were enrolled, five were male and two females; one was Hispanic and six were non-Hispanic White. Median treatment exposure was 8 cycles. ORR was 57.1%, with 3 patients (42.9%) achieving complete response, 1 partial response, and 2 stable disease. The 7-month PFS rate was 57.1%. At study closure, 4 patients remained alive without progression, 2 were alive following progression, and 1 had died of disease. Toxicities were mostly grade 1, with fatigue and anemia most common with minimal grade 2 events. The combination of topical imiquimod and pembrolizumab was feasible, safe, and demonstrated promising antitumor activity in unresectable cutaneous melanoma. A 42.9% CR rate in this small elderly cohort supports further evaluation of local immune modulation with systemic PD-1 blockade for cutaneous melanoma.

OBJECTIVE Ruptured, large pediatric arteriovenous malformations (AVMs) pose a significant management challenge due to high rerupture risk and the morbidity of conventional treatments. Volume-staged stereotactic radiosurgery (VS-SRS) has emerged as an alternative; however, evidence for its use in this specific population is limited. This study aimed to evaluate the long-term efficacy and safety of VS-SRS for ruptured, large AVMs in a dedicated pediatric cohort. METHODS This international, multicenter, retrospective cohort study from 21 centers analyzed outcomes for 42 pediatric patients (age < 18 years) with previously ruptured, large AVMs treated with VS-SRS. The primary outcome was complete AVM obliteration, and secondary outcomes included post-SRS hemorrhage, radiation-induced changes (RICs), and favorable outcome. Favorable outcome in this study was defined as obliteration without post-SRS hemorrhage or permanent RIC. RESULTS At the initial SRS, the median patient age was 14.5 years, and the median AVM volume was 15.0 cm 3 ; most AVMs were high grade (Spetzler-Martin grades IV and V). With a median follow-up of 41.5 months, complete AVM obliteration was achieved in 21 patients (50.0%). The cumulative obliteration rate was 37% at 5 years and 56% at 10 years. Patients with a nidus volume of ≤ 10 cm 3 had significantly higher cumulative obliteration rates than those with a nidus volume > 10 cm 3 (log-rank test, p = 0.021). Similarly, patients treated with a prescription dose > 17 Gy showed significantly higher cumulative obliteration rates compared to those treated with a dose ≤ 17 Gy (log-rank test, p = 0.012). The cumulative 5-year incidences of hemorrhage and RICs following VS-SRS were 19% and 7%, respectively. In multivariable analysis, only larger total AVM volume was an independent predictor of a lower likelihood of favorable outcome (hazard ratio 0.89, 95% CI 0.80–0.99; p = 0.036). CONCLUSIONS In this multicenter pediatric cohort, VS-SRS for ruptured, large AVMs provides a reasonable chance of long-term obliteration, but generally acceptable risks of post-SRS hemorrhage and RICs exist. VS-SRS should be considered as an option for pediatric patients with large, ruptured AVMs.

Background. The adoption of technical variant grafts has expanded the donor pool for pediatric liver transplantation, but it also poses a risk of portal vein thrombosis (PVT). This study evaluated risk and prognostic factors of PVT in children undergoing liver transplantation with technical variant grafts. Methods. A total of 3137 pediatric patients from 19 centers were included: 470 received split/reduced deceased donor grafts and 2667 received living donor grafts. Multivariable logistic regression was used to identify risk factors, whereas time-dependent Cox models were used to assess the impact on survival. Results. PVT occurred in 102 patients (3.3%) and was associated with increased mortality (adjusted hazard ratio, 2.86; 95% confidence interval [CI], 1.13-7.25; P = 0.027) and graft loss (adjusted hazard ratio, 9.97; 95% CI, 4.90-20.3; P < 0.001). Risk factors included younger age, lower weight, higher Pediatric End-Stage Liver Disease score, longer cold ischemia and operation times, higher graft-to-recipient weight ratio, increased red blood cell transfusions, and biliary atresia. After adjusting for center, lower weight (odds ratio, 0.84 per kg; 95% CI, 0.71-1.00; P = 0.047) and biliary atresia (odds ratio, 2.34; 95% CI, 1.10-5.00; P = 0.027) remained predictors. Five-year patient (88.4% versus 93.1%) and graft survival (82.7% versus 96.3%) were significantly inferior in patients with PVT. Conclusions. Low-weight children with biliary atresia constituted a high-risk group, highlighting the necessity for early detection and management.

Abstract The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by ∼20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.

ABSTRACT Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-κB signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.

Abstract Hepatic spheroids are widely used in bioartificial liver (BAL) systems, hepatotoxicology, and pharmacology due to improved functional stability compared with monolayer cultures. However, many existing methods rely on specialized equipment or static platforms that limit scalability and dynamic culture applications. Primary rat hepatocytes were cultured as three‐dimensional spheroids using a rocker‐based suspension system. Spheroid formation was evaluated across a range of rocking speeds (7–18 cycles per minute [cpm]) and inoculation densities. Spheroid morphology was quantified over time using two‐dimensional imaging. Functional performance was assessed by urea and albumin production on days 1, 4, 7, and 10. Spheroid formation efficiency was evaluated using volumetric modeling. Mean spheroid diameter decreased from 199 ± 41 μm at 7 cpm to 80.2 ± 17.6 μm at 18 cpm. The spheroid area was significantly influenced by both culture day ( p < 0.0001) and rocker speed, with significant differences observed across speeds at all time points ( p < 0.001, days 1–7). Mean spheroid area at 10 cpm was 13,750 ± 9051 μm 2 (day 1), 26,730 ± 8658 μm 2 (day 4), and decreased to 22,526 ± 8705 μm 2 (day 7). Urea production differed across speeds (ANOVA, p = 0.043), with peak performance at 12 cpm (median 3.47 μg/μg DNA) compared to 7 cpm (median 0.11 μg/μg DNA). Albumin production was 1086.8 ng/μg DNA on day 1 and 1534.4 ng/μg DNA on day 10. Urea production was 0.62 μg/μg DNA on day 1 and 1.25 μg/μg DNA on day 10. Median hepatocyte incorporation was 86% (range 73%–116%) by day 4. This rocker‐based method provides a simple, low‐cost, and scalable approach for generating hepatic spheroids with tunable size distributions under dynamic conditions. The system supports progressive functional maturation and is compatible with established scale‐up strategies, supporting its potential for translational applications.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B and T cell lineages (B-ALL and T-ALL). Current therapy exploits ALL cells’ low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and the ASNS inhibitor ASX-173. Using a Kras G12D -driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2 –/– T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS hi leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high levels of ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.

ABSTRACT One quarter of patients with diffuse large B‐cell lymphoma (DLBCL) who achieve a complete response following front‐line therapy will eventually experience disease relapse. Existing prognostic models use baseline factors to predict outcomes from the start of initial therapy and are not intended for use following completion of treatment. We developed a conditional event‐free survival (cEFS) tool that predicts a patient's risk of lymphoma recurrence after completing front‐line therapy taking into consideration baseline risk characteristics plus the time the patient has been in remission. Model development used pooled and harmonized data from two observational cohorts and four randomized trials of patients with newly diagnosed DLBCL treated with immunochemotherapy and either achieving a complete response or not experiencing an event within 12 weeks of end of therapy. Cox proportional‐hazards regression modeling with backwards stepwise selection was utilized for model development. External validation was performed using a large independent data registry. In total, data from 2757 patients were used for model development. The risk of experiencing an event at a time point after having survived a period of time could be computed parsimoniously using four basic predictors: age, ECOG performance status grade, Ann Arbor stage, and lactate dehydrogenase level. C‐index in the model development cohort was 0.65 (95% CI, 0.63–0.68), compared to 0.64 (95% CI, 0.62–0.66) in the external validation cohort. We believe that this dynamic risk prediction tool will not only aid clinicians in providing data‐driven recommendations for surveillance, but also assist patients themselves with key decisions, such as family planning.