Faculty Bibliography

OBJECTIVES/OBJECTIVE:The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. METHODS:In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. RESULTS:In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. CONCLUSIONS:Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

OBJECTIVES/OBJECTIVE:Congenital high airway obstruction syndrome (CHAOS) is characterized by over-distended lungs leading to impaired cardiac return and fetal hydrops. Survivors have been reported following prenatal spontaneous fistulization, fetal procedures to decompress the airway, or ex-utero intrapartum treatment (EXIT). The long-term outcomes of survivors are unclear. METHODS:We performed a retrospective chart review on patients diagnosed with CHAOS in our center between 2005-2025. RESULTS:Of the 28 patients with CHAOS, three (10.7%) underwent a fetal procedure to decompress the airway. Three patients (10.7%) had evidence of spontaneous fistulization. Four patients (14.3%) terminated the pregnancy and four (14.3%) had in-utero fetal demise. Twenty patients (71.4%) were live-born; of these, 14 (70%) died shortly after delivery and two (10%) died in the neonatal period. Seven patients (35%) underwent EXIT-to-tracheostomy at our center, of which four (57.1%) are long-term survivors ranging in age from 4 to 19 years old. Three patients have undergone airway reconstruction between 1.6 and 5.6 years of age; one remains tracheostomy-dependent due to recurrent airway stenosis, one patient has undergone reconstruction and is likely to be decannulated soon, and one patient had successful reconstruction and was decannulated. The fourth patient has not yet undergone airway reconstruction. CONCLUSIONS:CHAOS remains a highly morbid diagnosis, but long-term survivorship and liberation from tracheostomy is possible.

OBJECTIVE:Amnioinfusions in anhydramnios aim to promote fetal lung development, but currently used fluids (Normal Saline [NS], Lactated Ringer's [LR]) fail to mimic the intrauterine environment and increase reactive oxygen species (ROS). We developed a synthetic amniotic fluid (Amnio-well, AW) designed to reduce intrauterine ROS. This study evaluated the pulmonary and gastrointestinal effects of 2 formulations of AW compared with those of NS and LR in a pre-clinical model. METHOD:At gestational age E17.5, pregnant rats underwent amniotic fluid replacement with NS, LR, AW, AW plus epidermal growth factor and transforming growth factor-β (AW++), or sham control. Fetal lungs were harvested at E20.5 for histology, fractional airspace, and blinded pathological evaluation. Surfactant protein (SP-A, SP-B, SP-C) expression and inflammatory gene panels were assessed in lungs and gastrointestinal (GI) tissue. RESULTS:NS and LR lungs demonstrated edema, macrophage infiltration, and reduced airspace (p < 0.001). AW improved SP-B and SP-C relative to control, whereas AW++ suppressed SP-B and SP-C (p < 0.05). Lung gene profiling showed NS/LR induced alterations in histamines, annexins, and immune recruitment, while AW closely resembled control. GI histology was similar across groups, though NS/LR altered TNF, prostaglandin, and adhesion pathways (p < 0.05). CONCLUSION:AW reduced lung inflammation and enhanced surfactant expression compared with NS or LR, with minimal GI effects.

INTRODUCTION/BACKGROUND:Management of relapsed mantle cell lymphoma (MCL) has included Bruton's tyrosine kinase (BTK) inhibitors for more than 10 years, but finding an optimal combination partner that meaningfully improves outcomes while limiting toxicity has been difficult. We conducted a phase 1/2 trial of ibrutinib and the proteasome inhibitor, ixazomib, in patients with relapsed/refractory MCL. PATIENTS AND METHODS/METHODS:Patients and Methods: The primary endpoint for the phase 1 study was to determine the recommended phase 2 dose (RP2D), and for the phase 2 study was the complete response (CR) rate, compared with the previously reported single-agent CR rate of ibrutinib. After the phase 1 portion of the study identified a recommended phase 2 dose of ixazomib 4 mg days 1, 8, and 15, of a 28-day cycle combined with ibrutinib 560 mg daily until progression or unacceptable toxicity. RESULTS:We enrolled 35 BTK-naïve patients to the phase 2 portion of the study. Overall response rate was 77%, and 37% of patients achieved a CR. The 2-year progression-free survival is 44%, and the duration of response is 47%. Treatment-related adverse events were common, resulting in treatment discontinuation for 37% of patients. CONCLUSION/CONCLUSIONS:Given that the progression-free survival (PFS) was not significantly improved compared to historical reports for single-agent BTK inhibitors and the high rate of treatment-related toxicity, this combination does not merit further study in this setting. Additional trials evaluating newer BTK inhibitors and alternative combination partners are warranted.

OBJECTIVE:To compare postnatal MRI outcomes after prenatal myelomeningocele repair using three different dural substitutes. METHOD/METHODS:32 sheep fetuses were included, with 34.3%(11/32) serving as healthy controls and the remaining undergoing prenatal spinal lumbar defect creation to recreate a myelomeningocele in the fetus. 90.5% (19/21) of sheep fetuses with surgically created MMC underwent repair using traditional collagen (Durapair) patch (n = 6), HUC matrix (NEOX RT) patch (n = 6), or a novel PLA/PCL patch (n = 7). All sheep underwent brain and spine MRI within 24 h after delivery. Images were reviewed in Research PACS by a pediatric neuroradiologist and were assessed for ventricle size, degree of hindbrain herniation, spinal cord integrity, and fluid collection at the repair site. RESULTS:There was a significant reduction in hindbrain herniation in all three intervention groups when compared with MMC without prenatal intervention. There was increased incidence of complete spinal cord defect (3/7), pseudomeningocele (5/7) and intraspinal cyst (2/7) at the repair site of the PLA/PCL patch compared with the Durapair and NEOX RT patches. CONCLUSIONS:This study demonstrates equal efficacy in reducing hindbrain herniation in MMC repair by Durapair, NEOX RT, and PLA/PCL patches by MRI. Future studies analyzing the interaction of the patches with the host tissue in animal models and clinical trials will help to better determine the true safety and efficacy of these novel patches for clinical use.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Congenital obstructive hydrocephalus (HCP) causes progressive, irreversible fetal brain damage through ventricular enlargement and increasing fetal cerebral tissue compression. Postnatal treatments of choice include ventriculoperitoneal shunting or endoscopic third ventriculostomy (ETV). Intrauterine treatments, such as ventriculoamniotic shunting, were attempted unsuccessfully 4 decades ago and failed to improve postnatal outcomes, likely due to inadequate fetal patient selection. The aim of this study was to evaluate the efficacy of prenatal ETV for early ventricular decompression and potential prevention of fetal brain damage in hydrocephalic fetal lambs. METHODS:HCP was induced in 24 fetal lambs by injecting BioGlue into the cisterna magna at E85. Three weeks later (E105-110), fetal ETV was successfully performed on 8 fetuses using a small rigid cystoscope. Fetal brain lateral ventricular diameters and cerebral mantle thicknesses were monitored by prenatal and postnatal ultrasounds and fetal MRI. RESULTS:According to the Cincinnati HCP Severity Scale, moderate and severe HCP subgroups responded positively to fetal ETV with reduced cerebral ventricular diameters. Ten days post-ETV, severe HCP fetal lambs improved to moderate levels, whereas those with moderate HCP normalized by birth. A similar improvement pattern was seen for the mechanical compression threshold (ventricular diameters/biparietal diameter). Biparietal diameter values did not significantly differ among nontreated, treated, and normal control groups during pregnancy. MRI revealed a significant increase in brain mantle thickness in the prenatally treated fetuses. CONCLUSION/CONCLUSIONS:Prenatal ETV is feasible in hydrocephalic fetal lambs and effectively reverses ventriculomegaly and brain compression in cases of severe or moderate fetal HCP in this ovine model.

OBJECTIVE:Infants with myelomeningocele (MMC) are at risk of brainstem dysfunction secondary to symptomatic Chiari II malformation with hindbrain herniation (HH), which can manifest as feeding difficulties including aspiration and dysphagia. This study aims to investigate whether prenatal repair of MMC is associated with improved feeding outcomes compared to postnatal repair. STUDY DESIGN/METHODS:Retrospective observational study of 208 infants with MMC, 105 repaired prenatally and 103 repaired postnatally, from January 2011 to July 2022. Primary outcome was feeding tube at discharge and longitudinally through 12 months corrected gestational age (CGA). RESULTS:9.5% of infants repaired prenatally and 13.6% repaired postnatally required feeding tube at discharge (p = 0.3585). By 53 weeks CGA, the prenatal repair group had decreased odds of requiring feeding tube (0.325 [95% CI 0.121, 0.872]). CONCLUSION/CONCLUSIONS:Prenatal MMC repair was associated with decreased need for long-term feeding support, suggesting a potential functional benefit of prenatal repair related to reversal of HH.

BACKGROUND:in participants with relapsed or refractory follicular lymphoma after at least one previous line of chemoimmunotherapy. METHODS:for up to 12 cycles. Epcoritamab was administered weekly in cycles 1-3 and every 4 weeks in cycles 4-12, lenalidomide once daily during cycles 1-12 (days 1-21), and rituximab weekly during cycle 1 and monthly in cycles 2-5. The dual primary endpoints were overall response rate and progression-free survival by independent review committee. The data reported here are from a planned interim analysis carried out after 78% of progression-free survival events had occurred. This study is registered with ClinicalTrials.gov, NCT05409066, and EudraCT, 2021-000169-34, and is ongoing (closed to recruitment). FINDINGS/RESULTS:(grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved. INTERPRETATION/CONCLUSIONS:as a new standard of care for second-line or subsequent treatment of follicular lymphoma. FUNDING/BACKGROUND:AbbVie and Genmab.