Citations

Abstract Purpose/Objective(s) To report outcomes for disseminated Medulloblastoma (stage M1-M3) who received radiation (RT) on the Pediatric Proton/Photon Consortium Registry (PPCR). Materials/Methods 71 patients were included with either M1 (6), M2 (21), or M3 (44) Medulloblastoma on PPCR. Survival (OS, Overall; EFS, Event Free) analyses were performed using the Kaplan Meier method and log rank p-values from RT start. Median follow up was calculated using the reverse Kaplan Meier method. Results Median age at RT was 7.5 years (range 2.4-21.89) and the median follow up was 4.3 years. Histology was classic (52), diffuse anaplasia (12), focal anaplasia (5), desmoplastic nodular (1), or other (1). Treatment included surgery, chemotherapy with or without stem cell support, and RT. 54 patients had gross total resection (GTR) or near total resection (NTR); 14 had subtotal resection (STR). Pre-RT chemotherapy was given in 69 (97.1%) patients; 23 had myeloablative chemotherapy with stem cell support. The 5 and 10-year OS of the entire cohort were 73% and 65%, and 5 and 10-year EFS were 65% and 59%. Patients with progression prior to RT (10 patients) had inferior OS (5-year OS 44%) compared to patients without progression pre-RT (5-year OS 78%, p = 0.045). There was a trend for better OS (p = 0.07) and improved EFS (p = 0.043) for M2 stage. GTR/NTR did not impact OS (p = 0.75) or EFS (p = 0.97) compared to STR. Craniospinal (CSI) radiation (70 patients, 99%) doses were: £ 23.4Gy (11.4%), 23.5Gy-36Gy (11.4%), or ³ 36Gy (74.3%). Patients receiving CSI ³ 36Gy had superior OS (p = 0.043), with 5 and 10-year OS of 82% and 71% compared to 5 and 10-year OS of 52% and 52% for lower dose CSI. Conclusion Full dose CSI (36Gy) for M1-M3 medulloblastoma was associated with excellent long-term survival this series, whereas lower dose CSI and progression prior to RT had inferior outcomes.

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 both 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 cellular interactions and therapeutic vulnerabilities within the tumour microenvironment of MYC-driven medulloblastoma (MB) have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy‐related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy‐related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood‐derived immune cell subsets and 103 circulating immunological proteins. Meta‐analysis revealed a genome‐wide significant association between the ULK4 rs6599175C allele and increased MGUS risk ( p = 3.35 × 10 −8 ). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B‐cell differentiation. Additionally, the CDKN2A rs2811710 variant showed a suggestive association with MGUS risk ( p = 2.17 × 10 −4 ), affecting transcription factor binding involved in B‐cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome‐wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B‐cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

Extramedullary presentations of multiple myeloma (MM) involving the central nervous system (CNS) carry a dismal prognosis. Although historically rare, management of extramedullary disease—including CNS manifestations—has become increasingly clinically relevant as advances in systemic therapies have prolonged control of medullary disease. CNS manifestations may occur across a variety of clinical settings and at different time points throughout the disease course. Common symptoms include visual changes, headaches, loss of sensation, confusion, and seizures. MRI identifies leptomeningeal enhancement and/or parenchymal lesions in approximately 90% of cases, and lumbar puncture with cerebrospinal fluid testing for clonal plasma cell populations is confirmatory. Encouragingly, the incorporation of novel therapeutic agents has improved historically poor outcomes in CNS MM. Novel immunotherapeutic approaches using CAR T-cell therapy and bispecific T-cell–engaging antibodies have recently demonstrated significant efficacy in consolidating responses. Multimodality treatment strategies incorporating intrathecal chemotherapy, systemic novel agents, radiation therapy, and immunotherapy hold promise for achieving more durable responses in this devastating manifestation of MM.

Abstract As a group of diverse co-authors working in the fields of clinical radiology and oncology, we have first-hand experience of the systems that impact medical careers. Women remain underrepresented in most spaces and often face a complex set of obstacles exacerbated by additional protected characteristics such as race, disability and sexual orientation. The impact of flexible working and care giving responsibilities on career development as well as leadership opportunities further widens the gap between under- and overrepresented groups. In this commentary we describe the intersectional challenges faced by women in our specialties and the challenge of navigating these spaces to achieve career success. We explore the various forms of discrimination and its impact on representation in medicine. Potential strategies and solutions aimed at promoting a more equitable specialty are also highlighted.

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.

Abstract Background Ceftriaxone-resistant Escherichia coli infections are increasingly common, partially because of the emergence of E. coli sequence type 131 (ST131), including its subclade C2/H30Rx, which produce extended-spectrum β-lactamases. Methods A prospective cohort including 14 US sites, which enrolled monomicrobial ceftriaxone-resistant and susceptible E. coli bloodstream infection (BSI) cases in a 1:1 ratio, was used to compare ST131 versus non-ST131 E. coli BSI, with specific attention to E. coli ST131 C2/H30Rx. Desirability of outcome ranking was determined at 30 days after infection onset. Results This analysis included 282 patients with E. coli BSI; 43% (121/282) were E. coli ST131 and 23% (66/282) belonged to the C2/H30Rx subclade. Resistance to ceftriaxone was present in 79% (96/121) ST131, 86% (57/66) E. coli ST131 C2/H30Rx, and 27% (43/161) E. coli non-ST131. Compared to patients with non-ST131 E. coli BSI, patients with ST131 BSI were older (median 70 years, [Q1 62, Q3 76] years vs 65 years, [51, 74]; P = .005) and more often admitted from long-term care facilities (21/121 [17%] vs 7/161 [4%], P < .001). Overall and empiric carbapenem use was more frequent in the treatment of patients with ST131 BSI compared with non-ST131 BSI (overall 89/121 [74%] vs 50/161 [31%]; empiric: 58/121 [48%] vs 31/161 [19%], P < .001). Desirability of outcome ranking outcomes were similar between groups. Conclusions Most ceftriaxone-resistant E. coli from US patients with E. coli BSI belong to ST131, particularly E. coli ST131 C2/H30Rx, serving as an important driver of carbapenem use.

Abstract Background Cardiomegaly is a clinically significant incidental finding on chest computed tomography (CT) associated with heart failure, arrhythmias, and sudden cardiac death. Qualitative radiologist assessment is variable, and automated AI tools may enable objective opportunistic cardiac volumetry. Purpose To evaluate whether AI-enabled total cardiac volume (TCVAI) derived from non-ECG-gated, non-contrast chest CT can identify cardiomegaly as defined by echocardiography. Materials and Methods This retrospective study included 307 consecutive patients (median age, 67 years; 56% male) who underwent non-contrast chest CT at a single center on 7 scanner types (4 vendors) and clinically indicated echocardiography within 31 days. A commercially available AI tool (AI-Rad Companion, Siemens Healthineers) automatically quantified TCVAI, indexed to body surface area (TCVAI/BSA). Echocardiography reports were reviewed for chamber dilation and left ventricular hypertrophy (LVH), collectively defined as cardiomegaly. Associations between TCVAI/BSA and echocardiographic findings were assessed using correlation, ordinal regression, and receiver operating characteristic (ROC). Interscan repeatability was evaluated in 248 patients with 544 repeat CT examinations. Prespecified sex-specific thresholds were tested in a temporally independent validation cohort of 50 patients. Results Median TCVAI was higher in patients with cardiomegaly than those without (1061.9 vs 798.4 mL; P < .001). TCVAI/BSA was associated with chamber dilation and LVH severity on univariate analysis and remained associated in multivariable ordinal models, except for right ventricular dilation. Discriminatory performance was fair to good, with area under the curve (AUC) 0.81 (95% CI, 0.75-0.87) in men and 0.77 (95% CI, 0.69-0.85) in women. Interscan repeatability was excellent (intraclass correlation coefficient [ICC]: 0.93). In independent validation, performance ranged from sensitivity 89.3%/specificity 27.3% at a high-sensitivity threshold to sensitivity 28.6%/specificity 100% at a high-specificity threshold. Conclusion AI-derived cardiac volume from routine chest CT shows fair to good performance for identifying echocardiography-defined cardiomegaly with high measurement repeatability, supporting a potential role for automated cardiac volumetry as an objective, opportunistic biomarker.

Abstract INTRODUCTION Guidelines recommend non-surgical biopsy for indeterminate pulmonary lesions > 8 mm. Shape-sensing robotic-assisted bronchoscopy (ssRAB) is growing in use to biopsy small pulmonary nodules; however current literature is limited to single center studies with limited follow-up. This study, PRECIsE, assessed safety and performance of the first ssRAB iteration across multiple sites and nascent users. METHODS Prospective, multicenter, observational study evaluating ssRAB without cone-beam CT guidance in patients with nodules 10–30 mm located in or beyond the sub-segmental airways. Patients were followed for 2 years; the primary endpoint was sensitivity for malignancy with diagnostic yield, and safety as secondary endpoints. Multilevel logistic regression models were used to control for factors associated with sensitivity and diagnostic yield. RESULTS A total of 305 procedures were performed across 6 centers. Median nodule size was 17.0 mm (IQR: 14.0–23.0) with bronchus sign present in 37% of cases. Sensitivity for malignancy through 2 years was 81.3% (95% CI: 75.7, 86.1). Multi-level modelling demonstrated female sex, smaller nodule size, lower lobe location, semi-solid density, and higher body-mass-index were associated with lower sensitivity. Diagnostic yield was 74.1% (95% CI: 68.8, 78.9) according to the ATS/ACCP criteria and 77.5% [95% CI: 72.4, 81.8] according to the intermediate criteria. Multi-level modeling demonstrated a non-significant site/center level effect on ATS/ACCP diagnostic yield (P = .36). Pneumothorax requiring intervention was 1.6% (5/305); bleeding was 1.0% (3/305) with two (2) Nashville grade 2 and one (1) Nashville grade 3 events. CONCLUSIONS The first iteration of ssRAB demonstrated encouraging performance and a strong safety profile among nascent users for the biopsy of small peripheral nodules.