Social Determinants of Health and Outcomes After Pediatric Ventricular Assist Device Implantation.

BACKGROUND: Limited research exists on the influence of social determinants of health (SDOH) on outcomes in pediatric patients with advanced heart failure receiving mechanical circulatory support. METHODS: Linkage of the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) and Society of Thoracic Surgeon's Congenital Heart Surgery Database (STS-CHSD) identified pediatric patients who underwent ventricular assist device (VAD) implantation from 2012 to 2022 with available residential zip codes. Utilizing the available zip codes, each patient was assigned a Childhood Opportunity Index (COI) score. Level of childhood opportunity, race, and insurance type were used as proxies for SDOH. Major outcomes included death, transplant, alive with device, and recovery. Secondary outcomes were adverse events. Statistical analyses were performed using the Kaplan-Meier survival, competing risk analyses, and multivariable Cox proportional hazards model. RESULTS: Three hundred seventeen patients were included in the study. Childhood opportunity level and insurance status did not significantly impact morbidity or mortality after VAD implantation. White race was associated with reduced 1-year survival (71% in White vs. 87% in non-White patients, p = 0.05) and increased risk of pump thrombosis (p = 0.02). CONCLUSION: Childhood opportunity level and insurance status were not linked to morbidity and mortality in pediatric patients after VAD implantation. Notably, White race was associated with higher mortality rates. The study underscores the importance of considering SDOH in evaluating advanced therapies for pediatric heart failure and emphasizes the need for accurate socioeconomic data collection in future studies and national registries.

Waitlist Outcomes for Pediatric Heart Transplantation in the Current Era: An Analysis of the Pediatric Heart Transplant Society Database.

BACKGROUND: Waitlist mortality (WM) remains elevated in pediatric heart transplantation. Allocation policy is a potential tool to help improve WM. This study aims to identify patients at highest risk for WM to potentially inform future allocation policy changes. METHODS: The Pediatric Heart Transplant Society database was queried for patients <18 years of age indicated for heart transplantation between January 1, 2010 to December 31, 2021. Waitlist mortality was defined as death while awaiting transplant or removal from the waitlist due to clinical deterioration. Because WM is low after the first year, analysis was limited to the first 12 months on the heart transplant list. Kaplan-Meier analysis and log-rank testing was conducted to compare unadjusted survival between groups. Cox proportional hazard models were created to determine risk factors for WM. Subgroup analysis was performed for status 1A patients based on body surface area (BSA) at time of listing, cardiac diagnosis, and presence of mechanical circulatory support. RESULTS: In total 5974 children met study criteria of which 3928 were status 1A, 1012 were status 1B, 963 were listed status 2, and 65 were listed status 7. Because of the significant burden of WM experienced by 1A patients, further analysis was performed in only patients indicated as 1A. Within that group of patients, those with smaller size and lower eGFR had higher WM, whereas those patients without congenital heart disease or support from a ventricular assist device (VAD) at time of listing had decreased WM. In the smallest size cohort, cardiac diagnoses other than dilated cardiomyopathy were risk factors for WM. Previous cardiac surgery was a risk factor in the 0.3 to 0.7 m2 and >0.7 m2 BSA groups. VAD support was associated with lower WM other than in the single ventricle cohort, where VAD was associated with higher WM. Extracorporeal membrane oxygenation and mechanical ventilation were associated with increased risk of WM in all cohorts. CONCLUSIONS: There is significant variability in WM among status-1A patients. Potential refinements to current allocation system should factor in the increased WM risk we identified in patients supported by extracorporeal membrane oxygenation or mechanical ventilation, single ventricle congenital heart disease on VAD support and small children with congenital heart disease, restrictive cardiomyopathy, or hypertrophic cardiomyopathy.

Predicting Stroke for Pediatric Patients Supported With Ventricular Assist Devices: A Pedimacs Report.

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) provides detailed understanding on pediatric patients supported with ventricular assist devices (VADs). We sought to identify important variables affecting the incidence of stroke in pediatric VADs. METHODS: Between 2012 and 2022, 1463 devices in 1219 patients were reported to Pedimacs from 40 centers in patients aged <19 years at their first VAD implantation. Multiphase parametric hazard modeling was used to identify risk factors for stroke among all device types. RESULTS: Of the 1219 patients, the most common devices were implantable continuous (472 [39%]), followed by paracorporeal pulsatile (342 [28%]), and paracorporeal continuous (327 [27%]). Overall freedom from stroke at 6 months was higher in the recent era (2012-2016; 80.2% [95% CI, 77.1%-82.9%] vs 2017-2023; 87.9% [95% CI, 86.2%-89.4%], P = .009). Implantable continuous VADs had the highest freedom from stroke at 3 months (92.7%; 95% CI, 91.1%-93.9%) and 6 months (91.1%; 95% CI, 89.3%-92.6%), followed by paracorporeal pulsatile (87.0% [95% CI, 84.8%-88.9%] and 82.8% [95% CI, 79.8%-85.5%], respectively), and paracorporeal continuous (76.0% [95% CI, 71.8%-79.5%] and 69.5% [95% CI, 63.4%-74.8%], respectively) VADs. Parametric modeling identified risk factors for stoke early after implant and later. Overall, and particularly for paracorporeal pulsatile devices, early stroke risk has decreased in the most recent era (hazard ratio, 5.01). Among implantable continuous devices, cardiogenic shock was the major risk factor. For patients <10 kg, early hazard was only seen in the previous era. For congenital patients, early hazard was seen in nonimplantable device use and use of extracorporeal membrane oxygenation. CONCLUSIONS: The overall stroke rate has decreased from 20% to 15% at 6 months, with particular improvement among paracorporeal pulsatile devices. Risk factor analyses offer insights for identification of higher stroke risk subsets and further management refinements.

Seventh Annual Society of Thoracic Surgeons Pedimacs Report.

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), supported by The Society of Thoracic Surgeons, provides detailed information on pediatric patients supported with ventricular assist devices (VADs). METHODS: From September 19, 2012, to December 31, 2022, 1463 devices in 1219 patients aged <19 years were reported to the registry from 40 North American hospitals. RESULTS: Cardiomyopathy remains the most common underlying etiology (59%), followed by congenital heart disease (26%) and myocarditis (8%). Implantable continuous devices were most common (39%) type, followed by paracorporeal pulsatile (28%) and paracorporeal continuous (27%) devices. At 6 months after VAD implantation, a favorable outcome (transplant, recovery, or alive on device) was achieved in 85% of patients, which was greatest among those on implantable continuous VADs (92%) and least for paracorporeal continuous VADs (68%), although the patient population supported on these devices is different. CONCLUSIONS: This Seventh Pedimacs Report demonstrates the continued importance of VADs in the treatment of children. With the complexity of cardiac physiologies and sizes of patients, multiple types of devices are used, including paracorporeal continuous, paracorporeal pulsatile, and implantable continuous devices. The preoperative risk factors and differences in patient populations may account for some of the differences in survival observed among these devices. This report, along with other collaborative work, continues to advance the care of this challenging and vulnerable population.

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

Survival in Pediatric Patients With Ventricular Assist Devices: A Special Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report.

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) provides detailed understanding on pediatric patients supported with ventricular assist devices (VADs). We sought to identify important variables affecting mortality in pediatric VADs. METHODS: Patients aged <19 years, from 2012 to 2021, were included. Survival analyses were performed using Kaplan-Meier. Parametric hazard modeling was used to identify risk factors for death. RESULTS: Of the 1109 patients, the most common devices were implantable continuous (IC, 448 [40%]), followed by paracorporeal pulsatile (PP, 306 [28%]), paracorporeal continuous (PC, 293 [26%]), and percutaneous (58 [5%]). Patients with percutaneous device, infants, congenital heart disease, biventricular support, and Interagency Registry for Mechanically Assisted Circulatory Support profile 1 had worse overall survival at 6 months. Positive outcome was 83% at 6 months. Consistent with their cohort composition, device type positive outcomes at 6 months were IC, 92%; PP, 84%; and PC, 69%. Parametric hazard modeling for overall survival showed an early hazard for death with biventricular support, congenital heart disease (CHD), intubation before implantation, PC device, and renal impairment, whereas a constant hazard was associated with ascites. For patients <10 kg, parametric modeling showed an early hazard for CHD, intubation, and renal impairment. Modeling in CHD patients showed an early hazard for biventricular support, renal impairment, and use of PC/PP devices. CONCLUSIONS: This multivariable analysis of the complete Pedimacs database demonstrates that illness at VAD implantation, diagnosis, and strategy of support affect survival and differ by device type. We hope this is the first step in creating a predictive tool to help providers and families have informed expectations.

Factors determining whether diffuse large B-cell lymphoma samples are detected by flow cytometry.

INTRODUCTION: Flow cytometry (FCM) is widely used in the diagnosis of mature B-cell neoplasms (MBN), and FCM data are usually consistent with morphological findings. However, diffuse large B-cell lymphoma (DLBCL), a common MBN, is sometimes not detected by FCM. This study aimed to explore factors that increase the likelihood of failure to detect DLBCL by FCM. METHODS: Cases with a final diagnosis of DLBCL that were analysed by eight-colour FCM were retrospectively collated. Clinical, FCM, histopathological and genetic data were compared between cases detected and cases not detected by FCM. RESULTS: DLBCL cases from 135 different patients were analysed, of which 22 (16%) were not detected by FCM. In samples not detected by flow cytometry, lymphocytes were a lower percentage of total events (p = 0.02), and T cells were a higher percentage of total lymphocytes (p = 0.01). Cases with high MYC protein expression on immunohistochemistry were less likely to be missed by FCM (p = 0.011). Detection of DLBCL was not different between germinal centre B-cell (GCB) and non-GCB subtypes, not significantly affected by the presence of necrosis or fibrosis, and not significantly different between biopsy specimens compared to fine-needle aspirates, or between samples from nodal compared to extranodal tissue. CONCLUSION: The study identifies several factors which affect the likelihood of DLBCL being missed by FCM. Even with eight-colour analysis, FCM fails to detect numerous cases of DLBCL.

Targeting immunosuppressive Ly6C+ classical monocytes reverses anti-PD-1/CTLA-4 immunotherapy resistance.

Introduction: Despite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy. Results: Our results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages. Conclusions: Therapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB.

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

Considerations of valvular heart disease in children with ventricular assist devices.

Ventricular assist devices have become a valuable tool in the treatment of heart failure in children. The use of ventricular assist devices has decreased mortality in children with end-stage heart failure awaiting transplant. It is not uncommon for children with end-stage heart failure associated with cardiomyopathy or congenital heart disease to have significant systemic semilunar and atrioventricular valve regurgitation, which can impact the efficiency and efficacy of hemodynamic support provided by a ventricular assist device. Therefore, implanting clinicians should carefully assess for valve abnormalities that may need repair and impact device selection and cannulation strategy to effectively support this diverse population. The purpose of this review is to provide an overview of this important and relevant topic and to discuss strategies for managing these patients.

Sixth Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: The Society Of Thoracic Surgeons Pedimacs Annual Report.

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), supported by The Society of Thoracic Surgeons, provides detailed information on pediatric patients supported with ventricular assist devices (VADs). METHODS: From September 19, 2012, to December 31, 2021, there were 1355 devices in 1109 patients (<19 years) from 42 North American Hospitals. RESULTS: Cardiomyopathy was the most common underlying cause (59%), followed by congenital heart disease (25%) and myocarditis (9%). Regarding device type, implantable continuous (IC) VADs were most common at 40%, followed by paracorporeal pulsatile (PP; 28%) and paracorporeal continuous (PC; 26%). Baseline demographics differed, with the PC cohort being younger, smaller, more complex (ie, congenital heart disease), and sicker at implantation (P < .0001). At 6 months after VAD implantation, a favorable outcome (transplantation, recovery, or alive on device) was achieved in 84% of patients, which was greatest among those on IC VADs (92%) and least for PC VADs (69%). Adverse events were not uncommon, with nongastrointestinal bleeding (incidence of 14%) and neurologic dysfunction (11% [stroke, 4%]), within 2 weeks after implantation being the most prevalent. Stroke and bleeding had negative impacts on overall survival (P = .002 and P < .001, respectively). CONCLUSIONS: This Sixth Pedimacs Report demonstrates the continued evolution of the pediatric field. The complexity of cardiac physiologies and anatomic constraint mandates the need for multiple types of devices used (PC, PP, IC). Detailed analyses of each device type in this report provide valuable information to further advance the care of this challenging and vulnerable population.

Ventricular Assist Device Outcomes in Infants and Children With Stage 1 Single Ventricle Palliation.

Data on ventricular assist device (VAD) outcomes in infants with stage 1 single ventricle (SV) palliation are limited. We examined the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry for outcomes of pre/poststage 1 SV patients undergoing VAD implantation between March 2018 and October 2020. Data are collected from 32 centers and major adverse events undergo central adjudication. During the study period, 30 stage 1 SV patients underwent VAD implant with median age of 0.9 months (range 0.1-25) and weight 3.7 kg (2.4-17). Preimplant illness severity was high: ventilator support (90%), ECMO (30%), prior cerebral vascular accident (CVA, 23%), and dialysis (13%). Devices used included paracorporeal pulsatile (50%), paracorporeal continuous-flow (37%), and multiple devices (13%). Median support duration was 56 days (range 3-246). A positive clinical outcome (transplanted or weaned) was attained in 63% (63% transplanted, 37% mortality, 0% weaned). VAD adverse events included: major infection (43%), neurologic dysfunction (any = 30%; CVA = 20%), major bleeding (17%), renal dysfunction (13%), and device malfunction (3%). In conclusion, stage 1 SV patients undergoing VAD support have high preimplant illness severity and complexity, as well as significant morbidity and mortality postimplant. A variety of devices and strategies are employed by centers to support this challenging population.

Systemic ventricular assist device support of the Fontan circulation yields promising outcomes: An analysis of The Society of Thoracic Surgeons Pedimacs and Intermacs Databases.

BACKGROUND: Outcomes of ventricular assist device (VAD) support in patients with Fontan circulatory failure (or failing Fontan physiology) are largely unknown. METHODS: We conducted a retrospective analysis of patients with a Fontan circulation who underwent VAD implant in the Society of Thoracic Surgeons Pedimacs and Intermacs Databases from September 19, 2012, to December 31, 2019. RESULTS: We identified 55 Fontan patients who had undergone VAD implant with a median age at implantation of 10.2 years (interquartile range, 6.4-16.9 years) and weight, 26.8 kg (interquartile range, 17.7-53.8 years). More VADs were implanted in 2018-2019 than in 2012-2017 (28 vs 27; P = .01). The later era had higher pre-VAD glomerular filtration rate (101.1 ± 48.5 vs 71.2 ± 34.9; P = .02); there was no difference in Interagency Registry for Mechanically Assisted Circulatory Support profile (P = .69). Kaplan-Meier survival on device was 76% at 6 months with no difference by era. Competing outcomes demonstrated a positive outcome of 81% (alive on VAD, transplanted, or recovered) at 6 months, with 58% of mortality occurring during month 1. Median length of support was 3.8 months (interquartile range, 0.6-6.9 months). Five patients were supported for >1 year with no added mortality; the longest support time was 4 years, 7 months. Adverse event rates included pump thrombosis incidence of 4% (3.3 out of 100 patient-months), stroke 5.5% (1.4 out of 100 patient-months), gastrointestinal bleeding of 7% (2.6 out of 100 patient-months), and nongastrointestinal bleeding of 9% (2.3 out of 100 patient-months). CONCLUSIONS: This is the largest reported analysis of systemic VAD support of Fontan patients. VAD support of the Fontan circulation is becoming more frequent. This analysis demonstrates that VAD use in this growing population can yield promising outcomes.

Fifth Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report.

BACKGROUND: The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) provides detailed information on pediatric patients supported with ventricular assist devices (VADs). METHODS: From September 19, 2012, to December 31, 2020, 1229 devices in 1011 patients were reported to the registry from 47 North American Hospitals in patients aged younger than 19 years. RESULTS: Cardiomyopathy was the most common underlying etiology (58%), followed by congenital heart disease (CHD; 25%) and myocarditis (10%). The most common devices implanted were implantable continuous (IC; 419 [41%]), followed by paracorporeal pulsatile (PP; 269 [27%]), paracorporeal continuous (PC; 263 [26%]), and percutaneous (53 [5%]). Overall, at 6 months after VAD implantation, 83% had a positive outcome (transplant, explant, or alive on device). The freedom from stroke at 3 months was highest in IC VADs (93%), compared with PP VADs (84%) and with PC VADs (75%). There were differences in survival by device type, with patients on IC VADs having the best overall survival and those on PC having the lowest overall survival, though the patient populations being supported by each VAD type differed significantly from each other. CONCLUSIONS: This Fifth Pedimacs Report demonstrates the continued robust growth of VADs in the pediatric community, now with more than 1000 patients reported to the registry. The multiple available device types (PC, PP, IC) serve different populations with different pre-VAD risk profiles, which may account for differences in survival and adverse events between device types.

Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib.

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Acral lentiginous melanoma-Population, treatment, and survival using the NCDB from 2004 to 2015.

Acral lentiginous melanoma (ALM) is a rare histological subtype of cutaneous malignant melanoma that typically presents on the palms and soles. To characterize the demographic and treatment characteristics of ALM, we used the National Cancer Database (NCDB) to describe a large multi-institutional cohort of ALM patients, consisting of 4,796 ALM patients from 2004 to 2015. ALM was more likely to be diagnosed at a later stage overall compared with non-ALM cutaneous melanomas, and more likely to be thicker, ulcerated, lymph node positive, and have lymphovascular invasion and positive margins. When stratified by stage, ALM had worse survival compared with non-ALM patients, most notably in stage III patients with 5-year survival of 47.5% versus 56.7%, respectively (p < .001). In ALM patients, older age, male sex, higher comorbidity burden, increased tumor thickness and ulceration, positive lymph nodes, and positive metastasis were independently associated with lower 5-year survival. Multimodality therapy, defined as surgery in addition to systemic therapy and/or radiation therapy, was associated with higher survival in stage III patients but not in other stages. These results call for further investigation into possible treatment intensification in the ALM population in the future.

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.

Pediatric ventricular assist device registries: update and perspectives in the era of miniaturized continuous-flow pumps.

The success of ventricular assist devices (VADs) in the treatment of end-stage heart failure in the adult population has led to industrial innovation in VAD design, focusing on miniaturization and the reduction of complications. A byproduct of these innovations was that newer generation devices could have clinical applications in the pediatric population. Over the last decade, VAD usage in the pediatric population has increased dramatically, and the newer generation continuous flow (CF) devices have begun to supplant the older, pulsatile flow (PF) devices, formerly the sole option for ventricular assist in the pediatric population. However, despite the increase in VAD implants in the pediatric population, patient numbers remain low, and the need to share data between pediatric VAD centers has become that much more important for the continued growth of VAD programs worldwide. The creation of pediatric VAD registries, such as the Pediatric Registry for Mechanical Circulatory Support (PediMACS), the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) and the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) has enabled the collection of aggregate data from VAD centers worldwide, and provides a valuable resource for clinicians and programs, as more and more pediatric heart failure patients are considered candidates for VAD therapy.