Faculty Bibliography

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.

BACKGROUND:While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial. OBJECTIVES/OBJECTIVE:Establish a list of genetic movement disorders considered essential as determined by a group of MD experts. METHODS:All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic. RESULTS:Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington's disease, PxMD-PPRT2, Wilson's disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C. CONCLUSION/CONCLUSIONS:This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts.

The protein activating molecule in Beclin1-regulated autophagy1 (AMBRA1), discovered in 2007, is crucial for autophagy and plays roles in nervous system development, cell survival, and proliferation. Here, we investigated AMBRA1's involvement in various cellular processes using a systems-based "omics" approach, focusing on melanoma. Transcriptomic analysis of AMBRA1 overexpression or knock-down was shown to result in significant dysregulation of several transcripts. We identified several novel roles for AMBRA1 in a range of cellular pathways including cancer signaling pathways such as MAPK, angiogenesis, tissue growth factor signaling, axon guidance, and Wnt signaling. Furthermore, using yeast two-hybrid assays, we identified novel binding partners which provide evidence of new roles for AMBRA1 in different cellular processes. Ultimately, we conclude that AMBRA1 loss upregulates metastatic genes/proteins highlighting AMBRA1 as a tumor suppressor gene in melanoma.

Subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm is a highly fatal type of stroke. Cerebral vasospasm (CVS) is a major post-SAH complication leading to delayed ischemic neurological deficits, thereby worsening patient outcomes. Previously, we found that lower plasma levels of the soluble receptor for advanced glycation end products (RAGE) predict symptomatic CVS in patients with SAH. However, the molecular mechanisms underlying CVS remain unclear. Here, using an SAH mouse model with endovascular perforation, we found that neurological deficits, CVS in the circle of Willis, and impaired cortical microarterial perfusion were markedly ameliorated in RAGE-deficient mice. Neutrophils accumulated in the cerebral perivascular space of WT mice after SAH but were markedly reduced in RAGE-deficient mice. Myeloid lineage-targeted deletion of RAGE, including neutrophils, improved CVS after SAH. Inhibition of the high mobility group box 1 (HMGB1)/RAGE axis or neutrophil elastase ameliorated CVS. In a transwell assay, the HMGB1/RAGE axis drives neutrophil migration and NETosis. These findings indicate that neutrophil RAGE signaling contributes to cerebrovascular dysfunction after SAH and suggest that RAGE-mediated neutrophil inflammation may be a therapeutic target in the hyperacute phase to mitigate early brain injury.

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.

In the phase 3 CEPHEUS study, daratumumab plus bortezomib/lenalidomide/dexamethasone (D‑VRd) increased overall MRD-negativity rates versus VRd in transplant-ineligible/transplant-deferred patients with NDMM. We present an expanded MRD analysis of CEPHEUS. Patients who were transplant-ineligible, or deferred transplant as initial therapy, were randomized 1:1 to receive D-VRd or VRd. Overall MRD negativity (NGS) was defined as the proportion of patients achieving ≥CR and MRD-negative status assessed at 10-5 (primary endpoint) and 10-6 thresholds. A total of 395 patients were randomized (D-VRd, n=197; VRd, n=198). With 58.7-months median follow-up, overall MRD-negativity rates were significantly higher with D-VRd versus VRd (10-5, 60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; 10-6, 46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P<0.0001 and P=0.0001, respectively). Sustained MRD negativity (≥12 months) was also significantly higher with D-VRd versus VRd (10-5: 49.2% vs 27.3%; 10-6: 34.0% vs 16.2%; each P<0.0001), with similar benefits at ≥24 and ≥36 months. MRD-negativity rates were higher at all pre-specified timepoints, and cumulatively, with D-VRd versus VRd (10-5 and 10-6). Among patients who achieved MRD negativity, PFS trended in favor of D-VRd versus VRd (10-5, HR, 0.61; 95% CI, 0.35-1.06; P=0.0755; 10-6, 0.66; 95% CI, 0.31-1.41; P=0.2811). Responses with D-VRd are deeper and more durable versus VRd, increasing overall, sustained, and landmark MRD-negativity rates, translating into improved overall PFS for patients treated with D-VRd versus VRd (intent-to-treat), with the potential to improve PFS even among patients who achieve MRD negativity. D-VRd is therefore a new standard-of-care treatment for transplant-ineligible/transplant-deferred NDMM. Registered at www.clinicaltrials.gov: NCT03652064.

BACKGROUND:Despite the availability of multiple screening options, rates of colorectal cancer (CRC) screening remain suboptimal. With recent approval of a blood test for CRC screening, there is an urgent need to understand screening preferences of populations with low screening rates. METHODS:Between October 2023 and June 2024, we conducted a survey on preferences for CRC screening modalities of stool test, blood test and colonoscopy among adults aged 45-75 at ambulatory primary care clinics across multiple community health centers and federally qualified healthcare centers across the city as well as in community settings regardless of prior screening. RESULTS:A total of 1,014 individuals completed the survey. Respondents were 12.8% Black/African American, 51.6% White, 23.4% Hispanic, 15.8% South Asian, and 4.2% Asian. Overall, the highest test preference was for screening colonoscopy (45.5%) followed by blood test (29.9%). Colonoscopy was preferred by individuals under age 70 (47.5%), while stool-based (20.2%) and blood-based (31.9%) tests were the most preferred among above 70 years (p = 0.0429. Whites (54.6%), Blacks (44.6%), and Hispanics (35.9%, p < 0.001) preferred colonoscopy, while Asians (37.2%) and South Asians (24.4%) favored blood tests. Factors associated with preference for a colonoscopy over other screening tests were younger age: respondents aged below 70 years were more likely to prefer colonoscopy, compared to respondents aged above 70 years (OR 1.72, 95% CI [1.20-2.47], p = 0.003); Nonsmoker compared to former/current smokers (OR 2.04, 95% CI [1.10-3.94], p = 0.028); Having undergone a prior colonoscopy (OR 6.83, 95% CI [4.52-10.6], p = < 0.001) or not having a prior stool test (OR 1.56, 95% CI [1.52-2.11], p = < 0.001). Factors associated with preference for a blood test over other screening tests were education level: respondents without any college experience were more likely to prefer blood test compared to respondents with college experience (OR 1.46, 95% CI 1.02-2.07, p = 0.038); Nonsmoker compared to former/current smokers (OR 1.73, 95% CI [1.00-2.99], p = 0.048); Never undergone a prior colonoscopy (OR 1.76, 95% CI [1.23-2.51], p = 0.002). Factors associated with preference for a stool test over other screening tests were: age over 80 years compared to respondents aged below 80 (OR 3.34, 95% CI 1.67-6.55, p < 0.001); respondents with college experience were more likely to prefer blood test compared to respondents without college experience (OR 1.62, 95% CI 1.02-2.66, p = 0.048). CONCLUSION/CONCLUSIONS:Colonoscopy was the preferred test option, followed by blood test. Preferences for screening test varied by age, race, ethnicity, education and prior screening. The study underscores importance of patient preference in deciding which tests to offer based on the patient characteristics. Nonsmokers, those without any college education and those without prior screening preferred blood test for screening.

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.