A Single Institution Experience in the Management of Localized Neuroendocrine Carcinoma of the Bladder.

BACKGROUND: Neuroendocrine carcinoma of the bladder (NEC-bladder) is a rare disease with poor outcomes and variable treatment approaches. MATERIALS AND METHODS: Patients with localized NEC-bladder treated with surgery or radiation between 2001-2021 were retrospectively identified. Rates of pathologic complete response (pCR) and downstaging were evaluated following NAC in surgically-treated patients. Progression-free survival (PFS) and overall survival (OS) were analyzed with univariable (log-rank) and multivariable (MVA; Cox regression) methods. RESULTS: Sixty-five patients were identified having a median age of 73. The tumor histology distribution was small cell (64.6%) or urothelial with NE differentiation (35.4%). Most patients (69.2%) received NAC. Patients received local therapy by surgery (78.5%) or chemoradiation (21.5%). The majority (62.7%) of surgical patients had ≥ pT2 with 37.3% having nodal involvement (pN+). The pCR and downstaging rates were 21.6% and 35.1%, respectively. At a median follow-up of 60 months (m), the median PFS and OS were 16.4m and 25.9m, respectively. NAC improved PFS (p=0.04) and downstaging improved PFS (p=0.012) and OS (p<0.001). Patients receiving NAC with ypN0 vs. ypN+ had median OS of 69.9m vs 15.3m, respectively (p<0.001). MVA identified receipt of NAC and pN as predictors of PFS; pN was predictive of OS. No differences in PFS or OS were seen between histology of primary tumor. The brain metastasis rate was 10.8% with all patients having small cell histology. CONCLUSIONS: Optimized therapy in NEC-bladder includes NAC followed by local consolidation. Ascertainment of ypN0 is associated with long term survival, while pN+ remains associated with poor outcomes.

Extracellular microvesicle microRNAs, along with imaging metrics, improve detection of aggressive prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in men worldwide. Early diagnosis of the disease provides better treatment options for these patients. Magnetic resonance imaging (MRI) provides an overall assessment of prostate disease. Quantitative metrics (radiomics) from the MRI provide a better evaluation of the tumor and have been shown to improve disease detection. Recent studies have demonstrated that plasma extracellular vesicle microRNAs (miRNAs) are functionally linked to cancer progression, metastasis, and aggressiveness. In our study, we analyzed a matched cohort with baseline blood plasma and MRI to access tumor morphology using imaging-based radiomics and cellular characteristics using miRNAs-based transcriptomics. Our findings indicate that the univariate feature-based model with the highest Youden's index achieved average areas under the receiver operating characteristic curve (AUC) of 0.76, 0.82, and 0.84 for miRNA, MR-T2W, and MR-ADC features, respectively, in identifying clinically aggressive (Gleason grade) disease. The multivariable feature-based model demonstrated an average AUC of 0.88 and 0.95 using combinations of miRNA markers with imaging features in MR-ADC and MR-T2W, respectively. Our study demonstrates combining miRNA markers with MRI-based radiomics improves predictability of clinically aggressive prostate cancer.

Surgical Ablative Therapies in Patients With Radiorecurrent Prostate Cancer.

Management of recurrent prostate cancer following radiotherapy and subsequent radical prostatectomy poses considerable challenges due to potential complications for patients. Focal therapies have emerged as a burgeoning approach in prostate cancer treatment. Research indicates that ablative therapies exhibit encouraging oncological efficacy while maintaining acceptable functional outcomes in salvage interventions. Here, we present a contemporary review of focal therapy treatment modalities as well as oncologic and functional outcomes.

Minimally Invasive Management of Inguinal Lymph Nodes in Penile Cancer: Recent Progress and Remaining Challenges.

The diagnosis of occult inguinal lymph node metastasis in clinically node-negative invasive penile squamous cell carcinoma (PSCC) has remained a challenge, with substantial perioperative complications. The recent refinements in the technique of dynamic sentinel lymph node biopsy (DSLNB) demonstrated high diagnostic accuracy with considerably lower morbidity compared to conventional open modified/superficial inguinal lymph node dissection (ILND). Although DSLNB, if available, has been endorsed as the preferred method for nodal staging in patients with invasive PSCC and no palpable inguinal lymphadenopathy in the recent penile cancer guidelines, its utilization has been quite limited so far. Laparoscopic and robotic-assisted ILND have emerged as alternatives for nodal staging in this patient population and are shown to improve the rate of wound infections and postoperative pain. For management of nodal metastasis in patients with clinically palpable inguinal lymph nodes, minimally invasive ILND has shown promising results as well. Nonetheless, given the rarity of PSCC and the absence of prospective studies and clinical trials, nodal staging and treatment of nodal metastasis in clinical practice will likely continue to vary across the medical centers in the following years. In this review, we first summarize the evolution of DSLNB and minimally invasive ILND and discuss the advantages and drawbacks of each management strategy. We further discuss the remaining challenges and future perspectives in the management of inguinal lymph nodes in patients with PSCC.

Improved Survival of Advanced-Stage Anaplastic Thyroid Cancer With Systemic Therapy.

OBJECTIVES: Anaplastic thyroid cancer (ATC) is the most aggressive and fatal thyroid malignancy. Currently, there still exists a paucity of literature studying the relationship between available ATC-targeted therapy, immunotherapy, and survival. We aim to investigate how systemic therapies affect survival outcomes in ATC. METHODS: A single-tertiary-institution chart review of patients diagnosed with advanced-stage ATC, and who underwent surgery as part of their treatment, was performed between 2000 and 2023, with 41 patients included. Demographics, clinical characteristics, and survival data were collected and analyzed via Kaplan-Meier and Cox proportional hazards analyses. RESULTS: 54% of patients were female, and average age was 67.4 years old. The most common mutations identified were BRAF (15 patients), p53 (9 patients), and p63 (2 patients). A total of 18 patients utilized targeted or immunotherapy, with Trametinib and Dabrafenib (9 patients) as the most common agents used. Two-year overall survival was 24%, and 5-year overall survival was 23%, with median survival time of 7.6 months. Kaplan-Meier analysis demonstrated improved survival in patients who received chemotherapy (p = 0.048). Cox proportional hazards analysis demonstrated that patients treated with immunotherapy or targeted therapy had a statistically significant increase in survival compared with patients who did not receive these therapies (p = 0.016). Additionally, females and those with a p63 mutation demonstrated improved survival outcomes (p = 0.010, p = 0.001). CONCLUSIONS: Targeted therapy and immunotherapy use should be strongly considered when treating patients with ATC. Further studies into novel drugs targeting immune checkpoints and combination therapy are needed to better optimize treatment of patients with ATC. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Examining inequities associated with incarceration among breast cancer patients.

INTRODUCTION: Breast cancer treatment patterns and quality of care among patients experiencing incarceration are underexplored. This study examined associations between incarceration and breast cancer disease and treatment characteristics. METHODS: This retrospective analysis was conducted at a tertiary center in the Southeastern United States that serves as the state's safety-net hospital and primary referral site for the state's prisons. All patients ≥18 years diagnosed with breast cancer between 4/14/2014-12/30/2020 were included. Incarceration status was determined through electronic health record review. Linear regression was used to estimate the association of incarceration with time to treatment. Unadjusted overall survival (OS) was estimated using the Kaplan-Meier method with log-rank tests to compare groups. RESULTS: Of the 4329 patients included, 30 (0.7%) were incarcerated at the time of diagnosis or treatment (DI) and 4299 (99.3%) had no incarceration history (NI). Compared to patients who were NI, patients who were DI were younger (p < 0.001), more likely to be unmarried (p < 0.001), and more likely to have family history of breast cancer (p = 0.02). Patients who were DI had an increased time from diagnosis to neoadjuvant chemotherapy (+47.2 days on average, 95% CI 3.9-90.5, p = 0.03) and from diagnosis to surgery (+20 days on average, 95% CI 6.5-33.5, p = 0.02) compared to NI patients. No difference in OS was observed (log-rank p = 0.70). CONCLUSIONS: Patients who are incarcerated experienced significant delays in breast cancer care. While no differences in mortality were appreciated, these findings are concerning, as they indicate poorer care coordination for patients who are incarcerated. Further research is necessary to understand the full scope of these disparities and elucidate factors that contribute to them.

A Primary Telangiectatic Mandibular Osteosarcoma With Germ-Line Malignancy-Associated DNA Damage Repair Gene Polymorphisms: A Case Report.

Primary mandibular telangiectatic osteosarcomas are very rare lesions, with only nine cases reported. Histologically, these lesions show multiple cystic blood-filled cavities traversed by neoplastic bone in septa lined by high-grade malignant cells. Here, we report an 81-year-old woman who presented with a mandibular mass, which was surgically resected and analyzed by histologic examination and whole exome DNA sequencing. A diagnosis of telangiectatic osteosarcoma was given. Comparative sequencing data analysis of paired benign and tumor DNA revealed 1577 variants unique to the tumor DNA, which clustered into several gene families, including those regulating DNA repair and apoptosis. Comparison of benign and tumor DNA revealed many shared gene polymorphisms associated with an increased cancer risk. These included polymorphisms in the ATM, p53, BRCA1, and BRCA2 and many other genes. Interestingly, the patient's family history showed an unusually high cancer incidence, likely related to these cancer risk-associated polymorphisms. To our knowledge, this is the first-time sequencing applied to a mandibular telangiectatic osteosarcoma. Our findings may shed light on the molecular origins of these rare tumors and how they may relate to other tumors in related kindreds.

Effective suppression of tumor growth and hepatic metastasis of neuroblastoma by NKT-stimulatory phenyl glycolipid.

Invariant natural killer T cell (iNKT) cells produce large amounts of cytokines in response to α-Galactosylceramide (α-GalCer) stimulation. An analog containing two phenyl rings on the acyl chain, C34, was previously found to be more Th1-biased than α-GalCer and triggered greater anticancer activities against breast cancer, melanoma and lung cancer in mice. Since liver is enriched in iNKT cells, we investigated anticancer efficacy of C34 on neuroblastoma with hepatic metastasis. C34 induced Th1-biased cytokine secretions in the liver, significantly suppressed neuroblastoma growth/metastasis and prolonged mouse survival. The anti-tumor efficacy might be attributed to greater expansions of hepatic NKT, NK, CD4+ T, and CD8+ T cells as well as reduction of the number of SSCloGr1intCD11b+ subset of myeloid-derived suppressor cells (MDSCs) in the liver of tumor-bearing mice, as compared to DMSO control group. C34 also upregulated expression of CD1d and CD11c, especially in the SSCloGr1intCD11b+ subset of MDSCs, which might be killed by C34-activated NKT cells, attributing to their reduced number. In addition, C34 also induced expansion of CD4+ T, CD8+ T, and NK cells, which might eliminate neuroblastoma cells. These immune-modulating effects of C34 might act in concert in the local milieu of liver to suppress the tumor growth. Further analysis of database of neuroblastoma revealed that patients with high CD11c expression in the monocytic MDSCs in the tumor had longer survival, suggesting the potential clinical application of C34 for treatment of neuroblastoma.

From Detection to Cure - Emerging Roles for Urinary Tumor DNA (utDNA) in Bladder Cancer.

PURPOSE OF REVIEW: This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care. RECENT FINDINGS: Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

Aromatic Amino Acid-Dependent Surface Assembly of Amphiphilic Peptides for One-Step Graphite Exfoliation and Graphene Functionalization.

Amphiphilic peptides show great potential for exfoliating graphite and functionalizing graphene. However, the variety of amino acids complicates our understanding of the underlying mechanisms. In this study, we designed four peptides (C6W1, C6W2, C6W4, and C6W6) with different amounts of aromatic tryptophan amino acids and two additional peptides (C6F4 and C6Y4) by substituting tryptophan with aromatic phenylalanine or tyrosine. This allowed us to investigate the processes and mechanisms of graphite exfoliation and graphene functionalization. Using experimental and computational methods, we discovered that peptides containing tryptophan demonstrated higher exfoliation efficiency and increased tryptophan content further improved this efficiency, resulting in more peptide-functionalized graphene layers. Significantly, the primary driving force for the surface-assisted assembly of peptides on graphite is the π-π stacking interaction between the aromatic ring contributed by aromatic amino acids and the hexagonal rings of the graphite surface. This interaction leads to a layer-by-layer exfoliation mechanism. Our research offers valuable insights into peptide design strategies for one-step graphite exfoliation and graphene functionalization in aqueous environments.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.

Speech and Swallowing Outcomes of Surgically Managed Cervical Chordoma: A Case Series.

OBJECTIVES: Cervical chordoma is a rare, low-grade primary bone tumor occurring in the axial skeleton. Due to challenges in surgical exposure caused by anatomic location, patients may experience dysfunction in speech and swallowing. The objective of this study was to characterize speech and swallowing outcomes for patients undergoing surgical resection of cervical chordoma. Moreover, we detail in-depth two cases with similar initial presentations to compare prognostic factors and management strategies. METHODS: Eleven patients with histologically confirmed cervical chordoma treated between 1993 and 2020 were included in this retrospective case series. Outcomes measured included overall survival, disease-free survival, need for enteral feeds, as well as results of modified barium swallow study (MBSS) and fiberoptic laryngoscopy. RESULTS: The mean age at diagnosis was 55.9 years. The patient population was 81.8% male. Mean survival after diagnosis was 96 months. Four (36.4%) patients required post-operative MBSS and demonstrated aspiration. All four of these patients presented with tumors in the superior cervical spine and received surgeries utilizing anterior approaches. Of the four, 2 required enteral feeds long-term. Four (36.4%) patients endorsed dysphonia. One patient developed post-operative right vocal fold paresis. The remaining three patients experienced stable dysphonia pre- and post-operatively. Additionally, three (27%) patients required tracheostomy placement, two of which remained in place long-term. CONCLUSIONS: Dysphagia is a common side effect of cervical chordoma resection. It is associated with the use of an anterior approach during resection and with tumors located in the superior cervical spine. Patients with postoperative dysphagia should receive early multidisciplinary swallow rehabilitation. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3706-3712, 2024.

A contemporary comparison of laparoscopic versus open partial nephrectomy for renal cell carcinoma.

PURPOSE: To analyze surgical and oncologic outcomes of patients undergoing open partial nephrectomy (OPN) versus laparoscopic partial nephrectomy (LPN) for treatment of renal cell carcinoma (RCC). METHODS: We retrospectively investigated our institutional RCC database for patients who underwent PN for RCC from 1997 to 2018. Decision for technique was at the discretion of the operating urologist, following practice patterns and training history. Outcomes analyzed included pre/peri/post-operative parameters, pathologic outcomes, and disease recurrence rates. RESULTS: 1088 patients underwent PN from 1997 to 2018. After exclusionary criteria, 631 patients who underwent 647 unique PNs for a total of 162 OPN and 485 LPN remained. Baseline, pre-op, and pathologic characteristics were not statistically different. Surgical time was lower in laparoscopic cases [185 vs. 205 min] (p = 0.013). Margin involvement was not statistically different; LPN had lower estimated blood loss (EBL) [150 vs. 250 mL] (p < 0.001) and longer ischemia time [21 vs. 19 min] (p = 0.005). LPN had shorter length of stay [2 vs. 4 days] (p < 0.001), fewer overall complications (p < 0.001), and no significant difference in high-grade complications [2.89 vs. 4.32%] (p = 0.379). Fewer LPN patients developed metastases [1.65 vs. 4.94%] (p = 0.0499). Local recurrence rates were not statistically different [1.24 vs. 3.09%] (p = 0.193). Renal function was equivalent between cohorts post-operatively. CONCLUSION: Long-term oncologic outcomes were not significantly different between LPN versus OPN, with no statistical difference in patient and tumor characteristics. LPN was associated with lower EBL, shorter length of stay, and lower overall complication risk. Renal function was not significantly different between cohorts.

At the Intersection of Intersectionality: Race and Gender Diversity Among Surgical Faculty and Trainees.

OBJECTIVE: To compare the representation of intersectional (ie, racial/ethnic and gender) identities among surgical faculty versus medical students. BACKGROUND: Health disparities are pervasive in medicine, but diverse physicians may help the medical profession achieve health equity. METHODS: Data from the Association of American Medical Colleges for 140 programs (2011/2012-2019/2020) were analyzed for students and full-time surgical faculty. Underrepresented in medicine (URiM) was defined as Black/African American, American Indian/Alaskan Native, Hispanic/Latino/Spanish Origin, or Native Hawaiian/Other Pacific Islander. Non-White included URiM plus Asian, multiracial, and non-citizen permanent residents. Linear regression was used to estimate the association of year and proportions of URiM and non-White female and male faculty with proportions of URiM and non-White students. RESULTS: Medical students were comprised of more White (25.2% vs 14.4%), non-White (18.8% vs 6.6%), and URiM (9.6% vs 2.8%) women and concomitantly fewer men across all groups versus faculty (all P < 0.01). Although the proportion of White and non-White female faculty increased over time (both P ≤ 0.001), there was no significant change among non-White URiM female faculty, nor among non-White male faculty, regardless of whether they were URiM or not. Having more URiM male faculty was associated with having more non-White female students (estimate = +14.5% students/100% increase in faculty, 95% CI: 1.0% to 8.1%, P = 0.04), and this association was especially pronounced for URiM female students (estimate = +46.6% students/100% increase in faculty, 95% CI: 36.9% to 56.3%, P < 0.001). CONCLUSIONS: URiM faculty representation has not improved despite a positive association between having more URiM male faculty and having more diverse students.

PLK1 and its substrate MISP facilitate intrahepatic cholangiocarcinoma progression by promoting lymphatic invasion and impairing E-cadherin adherens junctions.

Intrahepatic cholangiocarcinoma (iCCA) is a subtype of CCA and has a high mortality rate and a relatively poor prognosis. However, studies focusing on increased cell motility and loss of epithelial integrity during iCCA progression remain relatively scarce. We collected seven fresh tumor samples from four patients to perform RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to determine the transcriptome profile and chromatin accessibility of iCCA. The increased expression of cell cycle regulators, including PLK1 and its substrate MISP, was identified. Ninety-one iCCA patients were used to validate the clinical significance of PLK1 and MISP. The upregulation of PLK1 and MISP was determined in iCCA tissues. Increased expression of PLK1 and MISP was significantly correlated with tumor number, N stage, and lymphatic invasion in an iCCA cohort. Knockdown of PLK1 or MISP reduced trans-lymphatic endothelial migration and wound healing and affected focal adhesions in vitro. In cell‒cell junctions, MISP localized to adherens junctions and suppressed E-cadherin dimerization. PLK1 disrupted adherens junctions in a myosin-dependent manner. Furthermore, PLK1 and MISP promoted cell proliferation in vitro and tumorigenesis in vivo. In iCCA, PLK1 and MISP promote aggressiveness by increasing lymphatic invasion, tumor growth, and motility through the repression of E-cadherin adherens junctions.

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor.

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT. METHODS: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. RESULTS: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells. CONCLUSIONS: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT.

Globo H ceramide is an independent prognostic marker for gallbladder cancer.

In recent studies, there has been growing interest in developing cancer therapeutics targeting Globo H ceramide, which is considered as the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. In this study, we aimed to evaluate the expression of Globo H and investigate its prognostic significance in gallbladder cancer (GBC). The tumor specimens and clinical characteristics of GBC patients were collected from the tumor bank and database of Chang Gung Memorial Hospital. Globo H in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry analysis. Through data mining, it was discovered that FUT1 and FUT2, which are key enzymes involved in the biosynthesis of Globo H, were significantly up-regulated in human gallbladder cancer (GBC). Consistent with this finding, Globo H expression was detected in 86% (128 out of 149) of GBC specimens using immunohistochemical (IHC) staining. This was the highest frequency among Globo H expressing cancers. Patients with tumors exhibiting higher Globo H expression (H-score ≥ 80) demonstrated significantly shorter disease-free survival (DFS) and overall survival (OS) (P = 0.0001 and P = 0.0004, respectively). In a multivariable Cox regression analysis, elevated Globo H expression was identified as an independent unfavorable predictor for DFS and OS (hazard ratio: 2.29 and 2.32, respectively, P = 0.008 and 0.001) in primary GBC. Globo H is an independent prognostic marker for GBC.

Priming of macrophage by glycosphingolipids from extracellular vesicles facilitates immune tolerance for embryo-maternal crosstalk.

Glycosphingolipids (GSLs) display diverse functions during embryonic development. Here, we examined the GSL profiles of extracellular vesicles (EVs) secreted from human embryonic stem cells (hESCs) and investigated their functions in priming macrophages to enhance immune tolerance of embryo implantation. When peripheral blood mononuclear cells were incubated with ESC-secreted EVs, globo-series GSLs (GHCer, SSEA3Cer, and SSEA4Cer) were transferred via EVs into monocytes/macrophages. Incubation of monocytes during their differentiation into macrophages with either EVs or synthetic globo-series GSLs induced macrophages to exhibit phenotypic features that imitate immune receptivity, i.e., macrophage polarization, augmented phagocytic activity, suppression of T cell proliferation, and the increased trophoblast invasion. It was also demonstrated that decidual macrophages in first-trimester tissues expressed globo-series GSLs. These findings highlight the role of globo-series GSLs via transfer from EVs in priming macrophages to display decidual macrophage phenotypes, which may facilitate healthy pregnancy.