Citations

Abstract Advancements in understanding H3 K27-altered diffuse midline glioma (DMG) biology have not yet translated into effective therapies for these tumors likely due to delivery challenges across the blood-brain barrier (BBB) and variable tumor genetics. This study systematically probes convective-enhanced delivery (CED) as a means to administer small molecule drugs directly to DMG tumors, circumventing constraints imposed by the BBB. Our findings emphasize the necessity of strategic drug selection and pharmacokinetic analysis in refining CED approaches, advocating for precision medicine techniques specialized for DMG. We demonstrate that while most small molecule drugs are rapidly cleared from the brain following CED, their retention and effectiveness are substantially improved by co-administration of systemic efflux transporter (ET) inhibitors such as everolimus. The synergistic potential of combining everolimus with topotecan or ponatinib offers a novel therapeutic pathway, advocating for further investigation into this DMG management strategy.

ABSTRACT Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host’s immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428–e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8 ], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, “rhinocerebral mucormycosis.” A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.

Abstract This study reports the first pig-to-human lung xenotransplantation using a six gene-edited pig lung. A left lung from a gene-edited Chinese Bama Xiang pig was transplanted into a 39-year-old brain-dead human recipient. The xenograft maintained viability and functionality for 216 hours without signs of hyperacute rejection. Postoperatively, severe edema resembling primary graft dysfunction (PGD) was observed, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9 under the current immunosuppressive regimen. This pioneering study suggests that genetically modified pig lungs could potentially be used for future clinical applications in xenotransplantation.

BackgroundMultiparametric MRI may cause overdiagnosis of clinically significant prostate cancer (csPCa) with the Prostate Imaging Reporting and Data System version 2.1 (PI‐RADS v2.1).ObjectivesTo investigate the diagnostic performance of stiffness as a standalone and complementary marker to PI‐RADS v2.1 for diagnosing csPCa.Study TypeProspective.SubjectsOne hundred forty‐seven participants with pathologically confirmed prostate lesions (≥1 cm), including 71 with csPCa.Field Strength/SequenceT1‐weighted fast spin‐echo, T2‐weighted fast spin‐echo, single‐shot echo‐planar diffusion‐weighted imaging, fast 3D gradient‐echo T1‐weighted dynamic contrast‐enhanced imaging, and 3D single‐shot spin‐echo based echo‐planar MR elastography at 3.0 T.AssessmentThe PI‐RADS v2.1 score was assessed by three radiologists independently. Lesion shear stiffness (SS) values at 60 Hz and 90 Hz were measured. A modified PI‐RADS integrating stiffness with PI‐RADS v2.1 was developed. Diagnostic performance for csPCa was compared between stiffness, PI‐RADS v2.1 and the modified PI‐RADS.Statistical TestSpearman's correlation, Fleiss κ and intraclass correlation, Pearson correlation, one‐way analysis of variance, area under the receiver operating characteristic curve (AUC), and the Delong test. Significance level was P < 0.05.ResultsIn the peripheral zone, csPCa (N = 35) had significantly higher SS than non‐csPCa at 60 Hz (3.22 ± 0.66 kPa vs. 2.56 ± 0.56 kPa) and at 90 Hz (5.64 ± 1.30 kPa vs. 4.48 ± 0.84 kPa). PI‐RADS v2.1 showed 100% sensitivity, 58% specificity, and 0.79 AUC for detecting csPCa. SS achieved 97% sensitivity, 52% specificity, and 0.80 AUC at 60 Hz, while SS had 63% sensitivity, 87% specificity, and 0.78 AUC at 90 Hz. The modified PI‐RADS, combing SS at 60 Hz with PI‐RADS v2.1, resulted in a significantly increased AUC (0.86) compared to that of PI‐RADS v2.1, with a sensitivity of 97% and specificity of 75%.Data ConclusionStiffness can help identifying csPCa in the peripheral zone. Combining stiffness with the PI‐RADS v2.1 improved the diagnostic accuracy and specificity for csPCa.Evidence Level1Technical EfficacyStage 2

Abstract Background and Aims Individuals with inflammatory bowel disease (IBD) experience a high symptom burden, including abdominal pain, fatigue, anxiety, depression, and sleep disturbances; yet, little is known regarding the relationship between sex and gender on symptoms. We sought to report symptom severity for cisgender men, cisgender women, and transgender and gender-diverse (TGD) individuals. In addition, we used network analysis to identify core symptoms and explore if symptoms and their relationships differ between cisgender men and cisgender women. Methods This was a cross-sectional study. We recruited adults with IBD online through ResearchMatch. Individuals responded to Patient-Reported Outcomes Measurement Information symptom questionnaires, as well as demographic and clinical questionnaires. Network analysis was used to identify the core symptoms driving the symptom structure. Results One-hundred and fifty-seven (63.3%) participants identified as cisgender women, 84 (33.9%) as cisgender men, and 7 (2.8%) as TGD. Cisgender men (M = 61.8) and TGD (M = 61.3) groups reported higher abdominal pain levels compared with cisgender women (M = 57.8; P = .02). Transgender and gender-diverse individuals reported higher depression levels (M = 64.8) compared with cisgender men (M = 56.7) and cisgender women (M = 54.4; P = .01). Using a network analysis approach, anxiety and fatigue emerged as core symptoms for the entire sample (clinically active and inactive disease), and among only those with active clinical disease. Fatigue was a top core symptom for cisgender women; anxiety emerged as a top core symptom for cisgender men. Conclusions This study highlights that fatigue and anxiety are core symptoms among individuals with IBD and demonstrates a potential sex and/or gender difference in core symptoms. Replication of this study is needed with further consideration of inclusion of TGD patients.

PURPOSE The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND. METHODS The Oncoplastic Breast Consortium-05/ICARO cohort study (ClinicalTrials.gov identifier: NCT06464341 ) retrospectively analyzed data from patients with stage I to III breast cancer with ITCs in SLNs after NAC from 62 centers in 18 countries. The primary end point was the 3-year rate of any axillary recurrence. The rate of any invasive recurrence was the secondary end point. RESULTS In total, 583 patients were included, of whom 182 (31%) had completion ALND and 401 (69%) did not. The median age was 48 years. Most patients (74%) were clinically node-positive at diagnosis and 41% had hormone receptor–positive/human epidermal growth factor receptor 2–negative tumors. The mean number of SLNs with ITCs was 1.2. Patients treated with ALND were more likely to present with cN2/3 disease (17% v 7%, P < .001), have ITCs detected on frozen section (62% v 8%, P < .001), have lymphovascular invasion (38% v 24%, P < .001), and receive adjuvant chest wall (89% v 78%, P = .024) and nodal radiation (82% v 75%, P = .038). Additional positive nodes were found at ALND in 30% of patients, but only 5% had macrometastases. The 3-year rates of any axillary and any invasive recurrence were 2% (95% CI, 0.95 to 3.6) and 11% (95% CI, 8 to 14), respectively, with no statistical difference by type of axillary surgery. CONCLUSION The nodal burden in patients with ypN0(i+) was low, and axillary recurrence after ALND omission was rare in patients selected for this approach. These results do not support routine ALND in all patients with ypN0(i+).