Citations

Although structured reporting of adverse events related to medical therapies is a critical aspect of clinical trials, the current practice fails to capture postoperative complications accurately or systematically, which precludes our ability to fully assess the impact of the risks of surgical interventions on oncologic outcomes. The incorporation of standardized, procedure‐specific definitions and severity classifications for postoperative complications into adverse event reporting in trials conducted through the National Clinical Trials Network is proposed.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Abstract Age‐associated muscle weakness and atrophy of limb muscles, termed sarcopenia, is a major factor in the morbidity of the elderly. It is becoming increasingly recognized that a substantial contribution to the sarcopenic phenotype arises from motor neuron (MN) death in old age and subsequent muscle denervation. In human and rodent models, mitochondrial dysfunction is a leading culprit in both muscle and MN deterioration with age. In other motor pools within the Fischer 344 (F344) aging rat model, we showed that sarcopenia is selective to type IIx/b muscle fibers. We also showed a loss of larger MNs and denervation of the IIx/b fibers, which together comprise more fatigable fast (type FF) motor units. This selective vulnerability of larger MNs and type IIx/b muscle fibers to sarcopenia is further reflected by reductions in oxidative capacity of IIx/b fibers, as assayed by determining the maximum velocity of the succinate dehydrogenase reaction (SDHmax). Here, we hypothesize similar changes will occur in F344 tibialis anterior (TA) muscle from young (6‐months) and old (24‐months) groups. We also predict lumbar MN death in young and old F344 rats. We found selective atrophy of type IIx/b fibers in the TA from old rats. In old age, SDHmax was reduced but only in IIx/b TA fibers. These muscle observations were concomitant with the death of larger lumbar MNs in old age. This study indicates the remarkable selectivity of type FF TA motor units to age‐associated perturbations and sarcopenia.

ABSTRACT Background Babesia microti , a parasite transmitted by the Ixodes scapularis tick, can cause infections ranging in presentation from asymptomatic to fulminant, life-threatening disease. Ocrelizumab, an anti-CD20 B-lymphocyte monoclonal antibody used to treat multiple sclerosis, increases the risk of severe or relapsing infections with tick-borne pathogens. In rare cases, babesiosis may trigger hemophagocytic lymphohistiocytosis (HLH). Case Summary We report a case of babesiosis manifesting in a subacute fashion with secondary HLH in a 51-year-old female on B cell-depleting therapy. She presented in December with generalized weakness and fever and was found to have pancytopenia, transaminitis, and hyperinflammatory markers consistent with HLH. A microbial cell-free DNA next-generation sequencing test detected Babesia microti , with subsequent confirmation by blood PCR and smear demonstrating <0.01% parasitemia. The patient improved following treatment with atovaquone and azithromycin, along with corticosteroids for HLH. Conclusion This case highlights the heterogeneity of babesiosis and its potential to present with minimal parasitemia, yet severe systemic inflammation in immunocompromised hosts. Additionally, this case underscores the importance of maintaining a broad differential in patients on B cell-depleting agents who present with new pancytopenia and systemic inflammatory symptoms. Early utilization of microbial cell-free DNA next-generation sequencing tests may aid in timely diagnosis and treatment.

An accurate differential diagnosis for diffuse lung disease can be confidently established by using a systematic approach to identify the predominant radiographic pattern, determine the distribution of disease, and assess for architectural or volume change.

ABSTRACT The role of DNA topoisomerase II beta (TOP2B) in cardiomyocyte differentiation is poorly understood. To address this, human induced pluripotent stem cells (hiPSC) were differentiated into cardiomyocytes (CM) that were wild type (WT) or contained a genomic deletion of Topoisomerase 2B (BKO). Both WT and BKO hiPSC could be induced to differentiate into sheets of beating cardiomyocytes. BKO hiPSC take slightly longer to differentiate into sheets of beating CM than WT iPSC. RNA was prepared from both undifferentiated and differentiated WT and BKO hiPSC. RNA-seq was used to examine gene expression changes when the WT and BKO hiPSC were differentiated into CM. Gene expression changes following differentiation of BKO cells were largely similar to those in WT cells. In addition, the differentiated WT CM were treated with dexrazoxane (ICRF-187), a TOP2 catalytic inhibitor that targets both TOP2A and TOP2B, or topobexin, a new TOP2B selective catalytic inhibitor. Topobexin inhibition partially phenocopied a TOP2B deletion and thereby providing an alternative to TOP2B gene knockout in many cell lines. In future, hiPSC derived CM with and without TOP2B and inhibition by topobexin ex vivo CM could be used to study anthracycline-induced cardiotoxicity and to screen for cardioprotectants.

<p class="MsoNormal"> <span lang="EN-US">The Semantic Web has the ultimate goal of making a machine understand Internet data. To enable the encoding of semantics with the data, well-known technologies are used such as RDF (Resource Description Framework) and OWL (Web Ontology Language). These technologies formally represent the meaning involved in information. For example, ontology can describe concepts, relationships between things, and categories of things. These embedded semantics offer significant advantages such as reasoning over data and dealing with heterogeneous data sources.<o:p></o:p></span> </p>

PURPOSE Adherence to operative standards and thorough documentation of surgical technique are critical, particularly in multidisciplinary clinical trials. We sought to evaluate variability in the performance and documentation of oncologically relevant aspects of technical surgery among patients enrolled in Alliance A021501, a phase 2 National Clinical Trials Network randomized clinical trial of neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma. METHODS We reviewed the primary operative and pathology reports of all enrolled patients who underwent complete pancreatic resection. Operative techniques and pathologic end points with potential to influence recurrence and survival were evaluated. RESULTS Fifty-one of 126 study participants (40.5%) underwent complete pancreatectomy. The extent of lymphadenectomy was documented in 36 (70.6%) operative reports, and 5 (9.8%) reports outlined the specific lymph node stations removed. Periadventitial dissection of the superior mesenteric artery was described in 25 of 50 (50.0%) operative reports. Immediate histopathologic analysis of the hepatic duct and pancreatic parenchyma margins was documented in 29 of 50 (58.0%) and 32 of 49 (65.3%) reports, respectively, and presence or absence of residual disease following resection was documented in 9 of 51 (17.6%) reports. Specimen orientation was documented in 19 of 51 (37.3%) pathology reports, and 30 of 49 (61.2%) pathology reports stated the distance between the tumor and final SMA margin. CONCLUSION Even in this rigorously controlled, multicenter, randomized pancreatic cancer clinical trial, performance of key elements of technical surgery was inconsistent, and documentation was incomplete. Standardization of technique and documentation in clinical trials and within clinical practice should be addressed to improve quality assurance and trial interpretability.

Whole-body cross-sectional imaging has largely replaced skeletal survey as the standard for evaluating hematologic malignancies and bone marrow disorders, but the practical choice between whole-body low-dose CT (WBCT) and whole-body MRI (WBMRI) remains incompletely resolved. This clinical review provides a practical, scenario-based comparison of WBCT and WBMRI across diagnosis, staging, treatment response, and surveillance. We emphasize real-world practical considerations, including scanner access, expertise, patient tolerance, radiation considerations, and cost. In multiple myeloma, with available comparative evidence, we include a focused research synthesis of 3 studies (152 patients) demonstrating high pooled CT-MRI concordance of 0.895 (95% CI: 0.834-0.935) with no detectable heterogeneity ( I 2 =0%), supporting either modality as a reasonable first-line depending on the clinical question. Across all included disease categories, the broader pooled concordance estimate was 0.797 (95% CI: 0.667-0.885) with substantial heterogeneity reflecting variability in clinical context, reference standard, and protocol. WBMRI dominates in non-neoplastic marrow disorders where marrow characterization is essential. In lymphoma, FDG-PET/CT remains the standard for adult disease, with WBMRI most indicated in pediatrics and adolescents. Emerging CT techniques, including dual-energy CT with virtual noncalcium images and photon-counting detector CT, are extending CT into the marrow imaging space and narrowing the historical gap with MRI. Modality selection should be guided by the specific clinical scenario, available resources, and patient factors rather than by global judgments of modality superiority.