Citations

Summary Outcomes for high‐risk paediatric classic Hodgkin lymphoma (cHL) improved with the addition of brentuximab vedotin (Bv) to doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (AVEPC) chemotherapy. We evaluated the prognostic implications of distant extra‐nodal sites contributing to stage IV disease. On AHOD1331 (NCT02166463), patients aged 2–21 years with high‐risk cHL (stage IIB with bulk/IIIB/IVA/IVB) were randomized to 5 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE‐PC) versus Bv‐AVEPC. Patients with stage IV disease, determined by protocol‐defined and centrally reviewed Positron Emission Tomography ‐ Computed Tomography (PET‐CT), were identified. Baseline characteristics and progression‐free survival (PFS) were compared by pattern of stage IV involvement (lung, bone, bone marrow, multiple sites and others). A total of 340 patients (median age 15 years) with stage IV disease were included. Of these patients, 173 (51%) received ABVE‐PC and 167 (49%) Bv‐AVEPC. PFS was highest with lung‐only involvement (4‐year PFS 88.6%) and lowest with bone marrow‐only involvement (4‐year PFS 71.9%). Compared to ABVE‐PC, Bv‐AVEPC improved PFS among all stage IV patients (hazard ratio [HR] 0.53, 90% confidence interval (CI) 0.33–0.85) and in the lung‐only and bone‐only subgroups. However, no PFS benefit was observed in those with bone marrow‐only involvement. Among paediatric patients with stage IV cHL, Bv‐AVEPC improved PFS across most patterns of stage IV disease, except in those with bone marrow involvement. These results will guide efforts to improve outcomes among children with stage IV cHL.

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

This Viewpoint describes a plateau in the discovery of clinically meaningful autoantibodies in autoimmune encephalitis (AE) and suggests efforts that are likely to offer greater benefits to patients living with AE.

Abstract One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell interactions between tumour and immune cells may provide insight into critical intercellular communications and manipulations occurring within the tumour immune microenvironment (TME). We hypothesised that the key cell-cell interactions in MYC-driven primary and recurrent MB may reveal dominant immune-suppressive mechanisms and uncover targetable therapeutic vulnerabilities. Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for 10X MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models of primary and recurrent-MB, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. Key therapeutic vulnerabilities within the TME of MYC-driven MB have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

Abstract Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.

Abstract Mild traumatic brain injury (mTBI) commonly induces transient acute (APTH) or persistent (PPTH) post-traumatic headache (PTH) that often resembles migraine. As orexin B sensitizes male but not female murine, nonhuman primate, and human dorsal root ganglion neurons and supradural orexin B/orexin receptor 2 (OX2R) signaling elicits migraine-like pain in naïve male, but not female, mice we explored possible sexually dimorphic contributions of orexin B/OX2R to PTH. In mice of both sexes, mTBI-induced transient cephalic allodynia, a surrogate measure of APTH. After APTH resolution, allodynia was reinstated by exposure to normally innocuous stress or by inhalational delivery of a subthreshold concentration of umbellulone, a TRPA1 agonist, suggesting the expression of PPTH. In contrast to these nonselective stimuli, subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal delivery of a CRISPR/Cas9 plasmid to edit trigeminal OX2R expression prevented APTH and development of PPTH selectively in male mTBI mice. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), beginning immediately after mTBI, prevented APTH as well as PPTH. Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. EEG/EMG-defined sleep architecture or immobility-defined sleep was not disrupted in this mTBI model suggesting that suvorexant benefits are unlikely related to sleep modulation. Our findings reveal a male-specific mechanism of PTH maintained by orexin B/OX2R signaling and suggest that approved DORAs may be beneficial in treating APTH and preventing transition to PPTH in men. Importantly, DORAs may also be effective in men with established PPTH.

ABSTRACT Background While guidelines state that patients with NCCN favorable intermediate risk (FIR) prostate cancer (PCa) may consider active surveillance (AS), there is a relative lack of longer term follow up data informing AS inclusion criteria of patients with Grade Group (GG) 2 prostate cancer in the MRI era. Here we evaluate patient outcomes from a MRI‐screened AS‐eligible cohort of FIR GG2 PCa receiving radical prostatectomy (RP). Methods Patients with prostate MRI, NCCN FIR GG2 PCa (PSA < 10 ng/mL, ≤ cT2a, < 50% core positivity), and no prior treatments who underwent RP from 2015 to 2023 were included from a prospectively maintained prostatectomy registry. Primary outcomes were adverse pathologic features (APF) at RP (GG3‐5, ≥ pT3a, or pN1) and biochemical recurrence (BCR). Logistic regression and Cox regression identified factors associated with APF at RP and time to BCR, respectively. Results Of 522 patients, 110 (21%) had APF at RP and 45 (9%) developed BCR with median follow up 2.4 years (IQR 1.3–2.8). On multivariable logistic regression, % Gleason pattern 4 (%GP4, %GP4 > 25% OR 2.14, 95% CI 1.28–3.58, p = 0.004) was independently associated with APF. On multivariable Cox regression for time to BCR, PSAD (HR 1.06, 95% CI 1.04–1.09, p < 0.001) and positive surgical margins (HR 1.06, 95% CI 1.09–3.78, p = 0.03) were independently associated with BCR. PIRADS, % core positivity, and specimen involvement were associated with neither APF nor BCR. Conclusions % Gleason pattern 4 > 25% and PSAD are the primary factors associated with adverse outcomes and should be considered for patients with FIR GG2 PCa considering active surveillance. PIRADS and measures of biopsy cancer volume were not associated with APF or BCR. These results may inform patient selection for active surveillance among patients with FIR GG2 PCa.

Objective The United Nations defines sustainability as meeting needs of the present without compromising future generations. While often equated to “saving the planet”, sustainability is a diverse topic. Healthcare generates &gt;5% of CO 2 emissions worldwide, yet sustainability efforts in urology are limited. The North Central Section of the American Urological Association (NCSAUA) recently convened a Sustainability Task Force to address this topic. This study queried members on sustainability in urologic practice. Methods Following literature review on sustainability in surgery/urology, a 19-item anonymous REDCap survey was developed and distributed via email to NCSAUA members (N = 1607). The survey assessed current best practice, institutional/personal sustainability, and demographics. Responses were compiled and summarized using descriptive statistics. Results Survey response rate was 4.9% (79/1607). Respondents were most commonly from metropolitan areas (82%), male (71%), and in practice for 5–14 years (29%). Sustainability topics were prioritized as: (1) financial, (2) future workforce, (3) environmental. Over half (56%) reported no institutional sustainability programs or were unaware of them. Instrument (67%), computer (68%), and paper (65%) recycling were supported by a majority of respondents. However, only 28% and 29% of respondents reported current institutional use of instrument and computer recycling, respectively. Telemedicine was infrequent, with most urologists (58%) conducting 0-5% of visits virtually. Conclusions Current institutional and urologic practice emphasis on sustainability is low. Respondents ranked highest sustainability priorities as financial and future workforce. Efforts to address environmental sustainability were also supported, namely reduction of disposables and waste. The findings support the development of targeted programs to advance sustainability priorities widely.