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Purpose: To determine effectiveness of radiofrequency ablation for treatment of intrahepatic cholangiocarcinoma (iCCA) using a population-based database., Materials and Methods: Data was extracted from Surveillance, Epidemiology, and End Results database from 2000 to 2020 to include 194 patients who underwent ablation for iCCA. Patient demographics, overall survival (OS), and cancer-specific survival (CSS) were retrieved. Factors associated with survival were evaluated. Comparison between ablation and surgical resection (n=2653) or external beam radiotherapy (n=1068) were performed., Results: In the ablation group, atients diagnosed and treated after 2010 demonstrated improved OS than the 2000-2009 subgroup (mOS 32 versus 21 months, HR: 0.50 [95%CI: 0.33-0.75], p=0.001). Additional factors associated with OS included tumor size (≤3cm versus >3cm, p=0.049) and tumor stage (p<0.001). For patients diagnosed after 2010, the 1-, 3-, and 5-year OS were 82.8% (95%CI: 74.8-88.4%), 43.5% (95%CI: 33.5-53.1%), and 23.7% (95%CI: 15.3-33.5%), respectively. Patients with local disease (1-year OS: 87.8% [95%CI: 78.6-93.3%]) demonstrated improved OS than regional (1-year OS: 81.3% [95%CI: 52.5-93.5%]) and distant disease (50.2% [95%CI: 34.0-78.8%], p<0.001). For tumors ≤3cm, ablation and surgical resection offered comparable survival benefits (p=0.561), although both were better than radiotherapy (p<0.0001)., Conclusion: Survival of iCCA patients who underwent thermal ablation has improved over the last 10 years. For tumors ≤3cm, ablation could be as effective as resection with careful candidate selection, and may be considered as front line compared to radiotherapy in certain patient populations. Patient selection based on tumor size and disease stage could improve survival outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Background: With the advent of peptide receptor radionuclide therapy, the timing and sequence of surgery in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors merits further study. We hypothesized that surgery before peptide receptor radionuclide therapy might enhance its effectiveness in patients with metastatic gastroenteropancreatic neuroendocrine tumors., Methods: Eighty-nine patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors treated with 177 Lutetium-dotatate peptide receptor radionuclide therapy between 2018 and 2023 were included. Fifty-six patients underwent surgery (primary tumor resection and/or liver debulking) before peptide receptor radionuclide therapy and 33 patients did not. Primary outcome was progression-free survival according to Response Evaluation Criteria in Solid Tumors. Pretreatment dotatate positron emission tomography/computed tomography was used to calculate tumor volumes., Results: The surgery and no-surgery groups were well-matched. Median progression-free survival after peptide receptor radionuclide therapy was 15.6 months (interquartile range, 9.1-22.7 months) in the no-surgery group compared with 26.1 months (interquartile range, 12.7-38.1 months) in the surgery group (P = .04). On subgroup analysis, median progression-free survival was 18.1 months (interquartile range, 11.9-38.4 months) in patients who underwent primary tumor resection only compared with 26.2 months (interquartile range, 14.0-38.1 months) in patients who underwent liver debulking (P = .04). Tumor volume was lowest in patients who underwent liver debulking (median 146.07 mL 3 ) compared with no surgery (median 626.42 mL 3 ) (P = .001). On univariable analysis, a tumor volume <138.8 mL 3 was associated with longer progression-free survival (hazard ratio, 2.03; 95% confidence interval, 0.95-4.34, P = .05), with a median progression-free survival of 38.1 months (interquartile range, 16.9-41.3 months) compared with 17.8 months (interquartile range, 10.8-28.7 months)., Conclusion: Surgery may enhance the effectiveness of 177 Lutetium-dotatate in the treatment of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors. This positive effect may be the result of a lower tumor volume in patients after surgery. Our findings fortify the concept of using surgical debulking to improve systemic therapies such as peptide receptor radionuclide therapy., Competing Interests: Conflicts of Interest/Disclosure The authors have no potential conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) leads to ineffective chemotherapy and, consequently, delayed treatment, thereby contributing to poor prognosis. Glycolysis is an important intrinsic reason for gemcitabine resistance as it competitively inhibits gemcitabine activity by promoting deoxycytidine triphosphate accumulation in PDAC. However, biomarkers are lacking to determine which patients can benefit significantly from glycolysis inhibition under the treatment of gemcitabine activity, and a comprehensive understanding of the molecular mechanisms that promote glycolysis in PDAC will contribute to the development of a strategy to sensitize gemcitabine chemotherapy. In this study, we aimed to identify a biomarker that can robustly indicate the intrinsic resistance of PDAC to gemcitabine and guide chemotherapy sensitization strategies. After establishing gemcitabine-resistant cell lines in our laboratory and collecting pancreatic cancer and adjacent normal tissues from gemcitabine-treated patients, we observed that circRNA hsa&#95;circ&#95;0008383 (namely cNEK6) was highly expressed in the peripheral blood and tumor tissues of patients and xenografts with gemcitabine-resistant PDAC. cNEK6 enhanced resistance to gemcitabine by promoting glycolysis in PDAC. Specifically, cNEK6 prevented K48 ubiquitination of small ribonucleoprotein peptide A from the BTRC, a ubiquitin E3 ligase; thus, the accumulated SNRPA stopped PP2Ac translation by binding to its G-quadruplexes in 5' UTR of mRNA. mTORC1 pathway was aberrantly phosphorylated and activated owing to the absence of PP2Ac. The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy., (© 2024. The Author(s).)

Purpose: Online adaptive radiotherapy (oART) has high resource costs especially for head-and-neck (H&N) cancer, which requires recontouring complex targets and numerous organs-at-risk (OARs). ART systems provide auto-contours to help, we aim to explore the optimal level of editing automatic contours to maintain plan quality in a cone-beam-computed-tomography (CBCT)-based oART system for H&N. In this system influencer OAR contours are generated and reviewed first, which then drives the auto-contouring of the remaining OARs and targets., Methods and Materials: Three-hundred-and-forty-nine adapted fractions of forty-four H&N patients were retrospectively analyzed, with physician-edited OARs and targets. These contours and associated online adapted plans served as the gold standard for comparison. We simulated three contour editing workflows: (1) no editing of contours, (2) only editing the influencers, (3) editing the influencers and targets. The geometric difference was quantified with Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD). The dosimetric differences in target coverage and OAR doses were calculated between the gold standard and these three simulated workflows., Results: Workflow 1 resulted in significantly inferior contour quality for all OARs (mean DSC 0.85±0.17 and HD95 3.10±5.80mm), dosimetric data was hence not calculated for workflow 1. In workflow (2), the frequency of physician editing targets and remaining OARs were 80.8%-95.7% and 2.3% (brachial plexus)-67.7% (oral cavity) respectively, where the OAR differences were geometrically minor (mean DSC>0.95 with std≤0.09). However, due to the unedited target contours of workflow 2 (mean DSC 0.86-0.92 and mean HD95 2.56-3.30mm versus the ground-truth targets), plans were inadequate with insufficient coverage. In workflow (3) when both targets and influencers were edited (non-influencer OARs were unedited), over 95.5% of the adapted plans achieved the patient-specific dosimetry goals., Conclusion: The CBCT-based H&N oART workflow can be meaningfully accelerated by only editing the influencers and targets while omitting the remaining OARs without compromising the quality of the adaptive plans., Competing Interests: Declaration of competing interest David Sher received a research grant from Varian Medical Systems for a Phase II clinical trial of adaptive radiotherapy for head and neck cancer (DARTBOARD, NCT04883281). Mu-Han Lin and Justin Visak have a research agreement with Varian Medical Systems for an unrelated adaptive radiotherapy project., (Copyright © 2024. Published by Elsevier Inc.)

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer., (© 2024. The Author(s).)

Background: Lung cancer (LC) is a leading cause of cancer-related mortality, and immunotherapy (IO) has shown promise in treating advanced-stage LC. However, identifying patients likely to benefit from IO and monitoring treatment response remains challenging. This study aims to develop a predictive model for progression-free survival (PFS) in LC patients with IO based on clinical features and advanced imaging biomarkers., Materials and Methods: A retrospective analysis was conducted on a cohort of 206 LC patients receiving IO treatment. Pre-treatment computed tomography images were used to extract advanced imaging biomarkers, including intratumoral and peritumoral-vasculature radiomics. Clinical features, including age, gene status, hematology, and staging, were also collected. Key radiomic and clinical features for predicting IO outcomes were identified using a two-step feature selection process, including univariate Cox regression and chi-squared test, followed by sequential forward selection. The DeepSurv model was constructed to predict PFS based on clinical and radiomic features. Model performance was evaluated using the area under the time-dependent receiver operating characteristic curve (AUC) and concordance index (C-index)., Results: Combining radiomics of intratumoral heterogeneity and peritumoral-vasculature with clinical features demonstrated a significant enhancement (p < 0.001) in predicting IO response. The proposed DeepSurv model exhibited a prediction performance with AUCs ranging from 0.76 to 0.80 and a C-index of 0.83. Furthermore, the predicted personalized PFS curves revealed a significant difference (p < 0.05) between patients with favorable and unfavorable prognoses., Conclusions: Integrating intratumoral and peritumoral-vasculature radiomics with clinical features enabled the development of a predictive model for PFS in LC patients with IO. The proposed model's capability to estimate individualized PFS probability and differentiate the prognosis status held promise to facilitate personalized medicine and improve patient outcomes in LC., (© 2024. The Author(s).)

Introduction: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer., Methods: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity., Results: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure)., Conclusions: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer., Clinical Trial Registration: NCT02834013 (ClincialTrials.gov)., Plain Language Summary: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population., (© 2024 American Cancer Society.)

Background: Homologous recombination repair mutation (HRRm) status may guide risk-stratification and treatment decisions, including polyadenosine diphosphate-ribose polymerase inhibitor use, in advanced prostate cancer. Although HRRm prevalence has been reported in single-institution studies or clinical trials, real-world HRRm prevalence in diverse populations is unknown. We describe HRRm in the clinical setting using two real-world clinicogenomic databases: the Flatiron Health and Foundation Medicine, Inc. Clinico-Genomic Database (CGDB), a national electronic health record-derived database, and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE)., Methods: This cross-sectional analysis included 3757 individuals diagnosed with prostate cancer who had next generation sequencing (NGS) as standard of care. The CGDB included men with advanced/metastatic prostate cancer and genetic data included both germline and somatic pathogenic mutations. The GENIE analysis included men with prostate cancer whose received NGS as standard of care, but the data were filtered to include somatic mutations only. Due to key differences among databases, direct comparisons were not possible. Overall prevalence of HRRm was calculated and stratified by demographic and clinical characteristics., Results: HRRm prevalence (combined germline and somatic) in CGDB (n = 487) was 24.6% (95% CI 20.9-28.7%), with no major differences across demographic and disease characteristic subgroups. HRRm prevalence (somatic) in GENIE (n = 3270) was 11.0% (95% CI 10.0-12.1%), which varied between 9.5% and 18.4% across treatment centers., Conclusions: Approximately one-quarter of patients with advanced/metastatic prostate cancer in the CGDB had germline and/or somatic HRRm, which is consistent with clinical trials such as the PROfound study that used a similar NGS platform and algorithm to define HRRm. In the GENIE database, HRRm prevalence varied by treatment center or NGS platform. More research is needed to understand real-world HRRm prevalence variations., (© 2023. The Author(s).)

Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC., Competing Interests: JF: Consulting – Eisai, Foundation Medicine, Genentech, Guardant; Research funding institution – Abbvice, Genentech, Iterion, Omega Therapeutics; Research funding personal – NIH. AP: Medical advisory board – Genetech, Exelixis, AstraZeneca, Boston Scientific. CL: Consulting – AstraZeneca, Genentech, Histosonics, Incyte, Ipsen, QED, Transthera, Boston Scientific; Speaker – AstraZeneca, Incyte. Dr. Liao is an editorial board member of Frontiers in Oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Gujarathi, Franses, Pillai and Liao.)

Background: Peptide Receptor Radionuclide Therapy (PRRT), a form of Radioligand Therapy (RLT), and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). Data regarding comparative efficacy are lacking. Herein, we compare the efficacy of PRRT vs. CAPTEM as second-line/beyond regimens and treatment sequencing. Methods: Clinicopathologic, radiographic, and genomic data were captured for metastatic PNETs seen in our multi-disciplinary NET clinic between 2013 and 2023. The primary outcome was progression-free survival (PFS) after progression on a previous line of systemic therapy. The secondary outcomes were objective response rate (ORR), time to response (TTR), and overall survival (OS). Results: Fifty-nine cases were included. PFS was similar in the PRRT ( n = 29) and CAPTEM ( n = 30) groups (PRRT = 21.90 months vs. CAPTEM = 20.03 months; HR 0.99; p = 0.97). On subgroup analysis, PRRT had longer PFS in cases without extrahepatic metastases (26.47 months vs. 17.67 months; p = 0.03) and cases with a mutation in the MEN1, DAXX, and/or ATRX genes (28.43 months vs. 18.67 months; p = 0.03). PRRT had reduced PFS in patients with grade 3 disease (7.83 months vs. 16.33 months; p = 0.02). ORR did not vary significantly (34.78% vs. 40.91%; p = 0.67). CAPTEM responders showed shorter TTR (6.03 months vs. 11.15 months; p = 0.03). In patients who received both, OS did not vary based on the sequence (HR 1.20; p = 0.75). Conclusions: PFS, ORR, and OS are similar when using PRRT vs. CAPTEM as second-line-and-beyond therapy for patients with metastatic PNETs. However, patients with MEN1 , DAXX , and/or ATRX mutations or without extrahepatic metastases might better benefit from PRRT and patients with grade 3 disease from CAPTEM. Candidates for surgical debulking or with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to shorter TTR.

Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naïve repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.

Background: The study investigates the combined efficacy of subacromial hyaluronic acid (HA) injections and extracorporeal shockwave therapy (ESWT) in managing rotator cuff lesions without complete tears., Materials and Methods: Eligible patients were randomized into three groups: 3 HA injections combined with 2 sham ESWT (HA), 3 HA injections combined with 1 ESWT and 1 sham ESWT (HA + 1 ESWT), or 3 HA injections combined with 2 ESWT (HA + 2 ESWT) with an allocation ratio of 1:1:1. Visual Analogue Scale (VAS), Constant-Murley Score (CMS), range of motion (ROM), and muscle power of shoulder abduction (MP) were assessed pre-intervention and at 1, 3, 6, and 12 months post-initial HA injection. Shoulder magnetic resonance imaging (MRI) was conducted before and twelve months after the intervention., Results: All pertinent parameters showed no significant between-group differences at baseline but demonstrated significant within-group improvement throughout the study. The HA + 1 ESWT group demonstrated superior improvements in MP (P=0.011) and CMS (P=0.018) at 1 month, and in MP (P=0.014) and CMS (P=0.005) at 6 months, compared to the HA group. The HA + 2 ESWT group showed greater improvements in FF (P=0.027), IR (P=0.019), and SROM (P=0.025) at 1 month, and in ABD (P=0.022) at 6 months, compared to the HA group. Notably, the HA + 2 ESWT group exhibited greater improvements in FF (P=0.013), IR (P=0.019), and SROM (P=0.025) at 1 month, and in FF (P=0.007) at 3 months, than the HA + 1 ESWT group. Moreover, no deterioration in tendinopathy grading or tear status occurred in the HA + 1 ESWT group on MRI scans., Conclusion: ESWT provides additional benefits when combined with HA injections for patients with rotator cuff lesions lacking complete tears., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The mechanism of action of bispecific antibodies (bsAbs) directing T-cell immunity to solid tumors is incompletely understood. Here, we screened a series of CD3xHER2 bsAbs using extracellular matrix (ECM) embedded breast cancer tumoroid arrays exposed to healthy donor-derived T-cells. An initial phase of random T-cell movement throughout the ECM (day 1-2), was followed by a bsAb-dependent phase of active T-cell recruitment to tumoroids (day 2-4), and tumoroid killing (day 4-6). Low affinity HER2 or CD3 arms were compensated for by increasing bsAb concentrations. Instead, a bsAb binding a membrane proximal HER2 epitope supported tumor killing whereas a bsAb binding a membrane distal epitope did not, despite similar affinities and intra-tumoroid localization of the bsAbs, and efficacy in 2D co-cultures. Initial T-cell-tumor contact through effective bsAbs triggered a wave of subsequent T-cell recruitment. This critical surge of T-cell recruitment was explained by paracrine signaling and preceded a full-scale T-cell tumor attack., (© 2024. The Author(s).)

Background: Accurate segmentation of lung tumors on chest computed tomography (CT) scans is crucial for effective diagnosis and treatment planning. Deep Learning (DL) has emerged as a promising tool in medical imaging, particularly for lung cancer segmentation. However, its efficacy across different clinical settings and tumor stages remains variable., Methods: We conducted a comprehensive search of PubMed, Embase, and Web of Science until November 7, 2023. We assessed the quality of these studies by using the Checklist for Artificial Intelligence in Medical Imaging and the Quality Assessment of Diagnostic Accuracy Studies-2 tools. This analysis included data from various clinical settings and stages of lung cancer. Key performance metrics, such as the Dice similarity coefficient, were pooled, and factors affecting algorithm performance, such as clinical setting, algorithm type, and image processing techniques, were examined., Results: Our analysis of 37 studies revealed a pooled Dice score of 79 % (95 % CI: 76 %-83 %), indicating moderate accuracy. Radiotherapy studies had a slightly lower score of 78 % (95 % CI: 74 %-82 %). A temporal increase was noted, with recent studies (post-2022) showing improvement from 75 % (95 % CI: 70 %-81 %). to 82 % (95 % CI: 81 %-84 %). Key factors affecting performance included algorithm type, resolution adjustment, and image cropping. QUADAS-2 assessments identified ambiguous risks in 78 % of studies due to data interval omissions and concerns about generalizability in 8 % due to nodule size exclusions, and CLAIM criteria highlighted areas for improvement, with an average score of 27.24 out of 42., Conclusion: This meta-analysis demonstrates DL algorithms' promising but varied efficacy in lung cancer segmentation, particularly higher efficacy noted in early stages. The results highlight the critical need for continued development of tailored DL models to improve segmentation accuracy across diverse clinical settings, especially in advanced cancer stages with greater challenges. As recent studies demonstrate, ongoing advancements in algorithmic approaches are crucial for future applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Online adaptive radiotherapy relies on a high degree of automation to enable rapid planning procedures. The Varian Ethos intelligent optimization engine (IOE) was originally designed for conventional treatments so it is crucial to provide clear guidance for lung SAbR plans. This study investigates using the Ethos IOE together with adaptive-specific optimization tuning structures we designed and templated within Ethos to mitigate inter-planner variability in meeting RTOG metrics for both online-adaptive and offline SAbR plans., Methods: We developed a planning strategy to automate the generation of tuning structures and optimization. This was validated by retrospective analysis of 35 lung SAbR cases (total 105 fractions) treated on Ethos. The effectiveness of our planning strategy was evaluated by comparing plan quality with-and-without auto-generated tuning structures. Internal target volume (ITV) contour was compared between that drawn from CT simulation and from cone-beam CT (CBCT) at time of treatment to verify CBCT image quality and treatment effectiveness. Planning strategy robustness for lung SAbR was quantified by frequency of plans meeting reference plan RTOG constraints., Results: Our planning strategy creates a gradient within the ITV with maximum dose in the core and improves intermediate dose conformality on average by 2%. ITV size showed no significant difference between those contoured from CT simulation and first fraction, and also trended towards decreasing over course of treatment. Compared to non-adaptive plans, adaptive plans better meet reference plan goals (37% vs. 100% PTV coverage compliance, for scheduled and adapted plans) while improving plan quality (improved GI (gradient index) by 3.8%, CI (conformity index) by 1.7%)., Conclusion: We developed a robust and readily shareable planning strategy for the treatment of adaptive lung SAbR on the Ethos system. We validated that automatic online plan re-optimization along with the formulated adaptive tuning structures can ensure consistent plan quality. With the proposed planning strategy, highly ablative treatments are feasible on Ethos., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Objective: Aortic dissection, a rare but serious condition, requires timely diagnosis and treatment., Case Report: A case report involving a 33-year-old female with Stanford type B aortic dissection at 32 + 3 weeks gestational age highlights the importance of being alert to the symptoms and signs of this condition, particularly in patients with hypertension or a history of connective tissue disorders. The case report suggests a delivery first strategy followed by TEVAR procedure as the preferred approach for managing aortic dissection in pregnancy. This approach can alleviate pressure on the aorta, reduce the risk of rupture, and provide time for stabilization and preparation for the TEVAR procedure., Conclusion: The case report emphasizes the criticality of recognizing and treating aortic dissection in pregnant patients promptly, given its potential life-threatening impact on both mother and fetus., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery., (© 2024. The Author(s).)

Purpose: To assess the safety and effectiveness of using modified radiation lobectomy (mRL) to treat primary hepatic tumors located in the right hepatic lobe (Segments V-VIII) and to determine future liver remnant (FLR) hypertrophy., Materials and Methods: A retrospective review was performed at a single institution to include 19 consecutive patients (7 females, 12 males) who underwent single-session mRL for right-sided primary hepatic tumors: 15 received segmentectomy plus lobectomy (segmental dose of >190 Gy and lobar dose of >80 Gy); 4 were treated with the double-segmental approach (dominant segments of >190 Gy and nondominant segments of >80 Gy). Treated tumors included 13 hepatocellular carcinoma (HCC), 4 cholangiocarcinoma (CCA), and 2 mixed-type HCC-CCA with a median dominant tumor size of 5.3 cm (interquartile range [IQR], 3.7-7.3 cm). FLR of the left hepatic lobe was measured at baseline, T1 (4-8 weeks), T2 (2-4 months), T3 (4-6 months), and T4 (9-12 months)., Results: Objective tumor response and tumor control were achieved in 17 of the 19 (89.5%) and 18 of the 19 (94.7%) patients, respectively. FLR hypertrophy was observed at T1 (median, 47.8%; P = .025), T2 (median, 48.4%; P = .012), T3 (median, 50.4%; P = .015), and T4 (median, 59.1%; P < .001). Patients without cirrhosis demonstrated greater hypertrophy by 6 months (median, 55.8% vs 47.2%; P = .031). One patient developed a Grade 3 adverse event (ascites requiring paracentesis) at 1-month follow-up. Grade ≥2 serum toxicities were associated with worse baseline Child-Pugh Score, serum albumin, and total bilirubin (P < .05). Among 7 patients who underwent neoadjuvant mRL, 2 underwent resection and 1 received liver transplant., Conclusions: mRL appears safe and effective for treatment of right-sided primary hepatic tumors with the benefit of promoting FLR hypertrophy., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Despite current guidelines for tuberculosis (TB) control in health care settings, which focused on smear-positive cases, prevention of nosocomial TB transmission continues to be a challenge. Here, we report the results of the first hospital-wide prospective study applying interferon-gamma release assay to investigate the role of smear-negative, culture-positive index cases in nosocomial TB transmission., Methods: We prospectively identified cases of culture-confirmed smear-negative pulmonary TB receiving aerosol-generating procedures (AGPs) and cases of culture-confirmed smear-positive pulmonary TB admitted at a medical center. Nosocomial transmission was evaluated by screening their close contacts for latent TB infection (LTBI) using an interferon-gamma release assay., Results: A total of 93 smear-negative index receiving AGP and 122 smear-positive index were enrolled. Among them, 13 (14.0%) and 43 (35.2%) index cases, respectively, had secondary cases of LTBI (P < .001). Sputum smear negativity (adjusted odds ratio: 0.20 [0.08-0.48]) and AGP (sputum suction; adjusted odds ratio: 3.48 [1.34-9.05]) are independent factors of transmission. A similar proportion in the close contacts of the 2 index groups had LTBI (17 [15.3%] and 63 [16.0%], respectively), and the former index group contributed to 21.3% of the nosocomial transmission., Conclusions: Smear-negative, culture-positive index cases receiving AGPs could be as infectious as smear-positive index cases. Hospital TB control policy should also focus on the former group., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

The phytohormone ethylene is a major regulator of plant adaptive responses to flooding. In flooded plant tissues, ethylene quickly increases to high concentrations owing to its low solubility and diffusion rates in water. Ethylene accumulation in submerged plant tissues makes it a reliable cue for triggering flood acclimation responses, including metabolic adjustments to cope with flood-induced hypoxia. However, persistent ethylene accumulation also accelerates leaf senescence. Stress-induced senescence hampers photosynthetic capacity and stress recovery. In submerged Arabidopsis, senescence follows a strict age-dependent pattern starting with the older leaves. Although mechanisms underlying ethylene-mediated senescence have been uncovered, it is unclear how submerged plants avoid indiscriminate breakdown of leaves despite high systemic ethylene accumulation. We demonstrate that although submergence triggers leaf-age-independent activation of ethylene signaling via EIN3 in Arabidopsis, senescence is initiated only in old leaves. EIN3 stabilization also leads to overall transcript and protein accumulation of the senescence-promoting transcription factor ORESARA1 (ORE1) in both old and young leaves during submergence. However, leaf-age-dependent senescence can be explained by ORE1 protein activation via phosphorylation specifically in old leaves, independent of the previously identified age-dependent control of ORE1 via miR164. A systematic analysis of the roles of the major flooding stress cues and signaling pathways shows that only the combination of ethylene and darkness is sufficient to mimic submergence-induced senescence involving ORE1 accumulation and phosphorylation. Hypoxia, most often associated with flooding stress in plants, appears to have no role in these processes. Our results reveal a mechanism by which plants regulate the speed and pattern of senescence during environmental stresses such as flooding. Age-dependent ORE1 activity ensures that older, expendable leaves are dismantled first, thus prolonging the life of younger leaves and meristematic tissues that are vital to whole-plant survival., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI., Methods: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S)., Results: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased β-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001)., Conclusions: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice., (© 2024. The Author(s).)

Background: The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation., Methods: Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45 - MSCs., Results: Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD + ), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD + , with oral NAD + precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days., Conclusions: We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD + -a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars., (© 2024. The Author(s).)

The K + uptake system KtrAB is essential for bacterial survival in low K + environments. The activity of KtrAB is regulated by nucleotides and Na + . Previous studies proposed a putative gating mechanism of KtrB regulated by KtrA upon binding to ATP or ADP. However, how Na + activates KtrAB and the Na + binding site remain unknown. Here we present the cryo-EM structures of ATP- and ADP-bound KtrAB from Bacillus subtilis (BsKtrAB) both solved at 2.8 Å. A cryo-EM density at the intra-dimer interface of ATP-KtrA was identified as Na + , as supported by X-ray crystallography and ICP-MS. Thermostability assays and functional studies demonstrated that Na + binding stabilizes the ATP-bound BsKtrAB complex and enhances its K + flux activity. Comparing ATP- and ADP-BsKtrAB structures suggests that BsKtrB Arg417 and Phe91 serve as a channel gate. The synergism of ATP and Na + in activating BsKtrAB is likely applicable to Na + -activated K + channels in central nervous system., (© 2024. The Author(s).)

Objectives: To evaluate whether nephrotic syndrome (NS) and further corticosteroid (CS) use increase the risk of osteoporosis in Asian population during the period January 2000-December 2010., Design: Nationwide population-based retrospective cohort study., Setting: All healthcare facilities in Taiwan., Participants: A total of 28 772 individuals were enrolled., Interventions: 26 614 individuals with newly diagnosed NS between 2000 and 2010 were identified and included in out study. 26 614 individuals with no NS diagnosis prior to the index date were age matched as controls. Diagnosis of osteoporosis prior to the diagnosis of NS or the same index date was identified, age, sex and NS-associated comorbidities were adjusted., Primary Outcome Measure: To identify risk differences in developing osteoporosis among patients with a medical history of NS., Results: After adjusting for covariates, osteoporosis risk was found to be 3.279 times greater in the NS cohort than in the non-NS cohort, when measured over 11 years after NS diagnosis. Stratification revealed that age older than 18 years, congestive heart failure, hyperlipidaemia, chronic kidney disease, liver cirrhosis and NS-related disease including diabetes mellitus, hepatitis B infection, hepatitis C infection, lymphoma and hypothyroidism, increased the risk of osteoporosis in the NS cohort, compared with the non-NS cohort. Additionally, osteoporosis risk was significantly higher in NS patients with CS use (adjusted HR (aHR)=3.397). The risk of osteoporosis in NS patients was positively associated with risk of hip and vertebral fracture (aHR=2.130 and 2.268, respectively). A significant association exists between NS and subsequent risk for osteoporosis., Conclusion: NS patients, particularly those treated with CS, should be evaluated for subsequent risk of osteoporosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Conventional surveillance methods are poorly sensitive for monitoring appendiceal cancers (AC). This study investigated the utility of circulating tumor DNA (ctDNA) in evaluating systemic therapy response and recurrence after surgery for AC., Methods: Patients from two specialized centers who underwent tumor-informed ctDNA testing (Signatera) were evaluated to determine the association between systemic therapy and ctDNA detection. In addition, the accuracy of ctDNA detection during surveillance for the diagnosis of recurrence after complete cytoreductive surgery (CRS) for grade 2-3 ACs with peritoneal metastases (PM) was investigated., Results: In this cohort of 94 patients with AC, most had grade 2-3 tumors (84.0%) and PM (84.0%). Fifty patients completed the assay in the presence of identifiable disease, among which ctDNA was detected in 4 of 7 (57.1%), 10 of 16 (62.5%), and 19 of 27 (70.4%) patients with grade 1, 2, and 3 diseases, respectively. Patients who had recently received systemic chemotherapy had ctDNA detected less frequently (7 of 16 [43.8%] v 26 of 34 [76.5%]; odds ratio, 0.22 [95% CI, 0.06 to 0.82]; P = .02). Among 36 patients with complete CRS for grade 2-3 AC-PM, 16 (44.4%) developed recurrence (median follow-up, 19.6 months). ctDNA detection was associated with shorter recurrence-free survival (median 11.3 months v not reached; hazard ratio, 14.1 [95% CI, 1.7 to 113.8]; P = .01) and showed high accuracy for the detection of recurrence (sensitivity 93.8%, specificity 85.0%). ctDNA was more sensitive than carcinoembryonic antigen (62.5%), CA19-9 (25.0%), and CA125 (18.8%) and was the only elevated biomarker in four (25%) patients with recurrence., Conclusion: This study revealed a reduced ctDNA detection frequency after systemic therapy and accurate recurrence assessment after CRS. These findings underscore the role of ctDNA as a predictive and prognostic biomarker for grade 2-3 AC-PM management.

Tumor tissues often contain high extracellular adenosine, promoting an immunosuppressed environment linked to mesenchymal transition and immune evasion. Here, we show that loss of the epithelial transcription factor, GRHL2, triggers NT5E/CD73 ecto-enzyme expression, augmenting the conversion of AMP to adenosine. GRHL2 binds an intronic NT5E sequence and is negatively correlated with NT5E/CD73 in breast cancer cell lines and patients. Remarkably, the increased adenosine levels triggered by GRHL2 depletion in MCF-7 breast cancer cells do not suppress but mildly increase CD8 T cell recruitment, a response mimicked by a stable adenosine analog but prevented by CD73 inhibition. Indeed, NT5E expression shows a positive rather than negative association with CD8 T cell infiltration in breast cancer patients. These findings reveal a GRHL2-regulated immune modulation mechanism in breast cancers and show that extracellular adenosine, besides its established role as a suppressor of T cell-mediated cytotoxicity, is associated with enhanced T cell recruitment., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-β/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespan. Further, targeting FcRn by antisense oligonucleotide restores WAT integrity and metabolic health in aged mice. These findings pinpoint IgG as a hidden culprit in aging and enlighten a novel strategy to rejuvenate metabolic health., Competing Interests: Declaration of interests A patent application is pending by Columbia University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 ., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: To evaluate safety and effectiveness of selective internal radiation therapy (SIRT) using yttrium-90 for localized and locally advanced intrahepatic cholangiocarcinoma (iCCA)., Methods: A retrospective review was performed of patients with localized iCCA treated with SIRT at a single institution. Overall survival (OS), local tumor response, progression-free survival (PFS), and toxicity were collected. Stratified analysis was performed based on surgical resection. Predictor analysis of OS was performed using the Fine-Grey regression analysis model with patients bridged to surgery regarded as competing events., Results: A total of 28 consecutive patients with localized iCCA were treated with a total of 38 sessions of SIRT (17 segmental, 13 lobar, and 8 combined deliveries) and a mean dominant target dose per session of 238.4 ± 130.0 Gy. The cumulative radiologic response rate was 16/28 (57.1%) with a median PFS of 265 days. Median survival time (MST) was 22.9 months for the entire cohort with 1-year and 3-year survival of 78.4% and 45.1%, respectively. Ten patients (34.5%) were downstaged to surgical intervention (7 resection, 3 transplant) and showed longer OS (p = 0.027). The 1-year and 3-year OS for patients who received surgery were 100% and 62.5% (95% CI: 14.2-89.3%), respectively. Age (p = 0.028), Eastern Cooperative Oncology Group performance status (p = 0.030), and objective radiologic response (p=0.014) are associated with OS. Two ≥grade 3 hyperbilirubinemia, anemia, and one pleuro-biliary fistula occurred post-SIRT., Conclusions: SIRT for localized iCCA is safe and effective in achieving radiological response, downstaging to surgery and transplant, and resulting in pathologic necrosis., Clinical Relevance Statement: Selective internal radiation therapy should be considered for patients with localized and locally advanced intrahepatic cholangiocarcinoma., Key Points: • The effectiveness of radioembolization for intrahepatic cholangiocarcinoma (iCCA) can be underestimated given the inclusion of extrahepatic disease. • Radioembolization is safe and effective for local and locally advanced iCCA. Age, Eastern Cooperative Oncology Group performance status, and radiologic response are associated with survival. • Radioembolization should be considered for patients with localized and locally advanced iCCA., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient-derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF-κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis , the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 ( DACH1 ) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of B. anthracis . To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which B. anthracis LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing DACH1 gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as FOSB , ZFP36L1 , RUNX1 , FLI1 , AHR , and GFI1B genes may be positively regulated by DACH1 . Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34-megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis.

Background: Reported outcomes after surgical debulking in patients with advanced neuroendocrine tumor liver metastases (NETLM) are sparse., Methods: NETLM patients that underwent surgical debulking from 2019 to 2021 were reviewed. Trends in perioperative liver function, complications, symptom response, and progression-free survival were examined., Results: 1069 liver lesions were debulked from 53 patients using a combination of parenchymal-sparing resections (PSR) and ultrasound-guided microwave ablations (MWA). Post-operative transaminitis and thrombocytopenia were common, and severity correlated with increasing number of lesions. Laboratory markers for synthetic liver function did not differ according to the number of lesions debulked. 13% of patients sustained a Clavien-Dindo grade 3 or 4 complication which was not associated with the number of lesions targeted. All patients with preoperative symptoms had improvement after surgery. Median time to progression was 10.9 months., Conclusions: PSR with MWA for large numbers of NETLM is safe and effective for symptom control and does not affect synthetic liver function., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts nor competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Immunotherapy, particularly with checkpoint inhibitors, has revolutionized non-small cell lung cancer treatment. Enhancing the selection of potential responders is crucial, and researchers are exploring predictive biomarkers. Delta radiomics, a derivative of radiomics, holds promise in this regard. For this study, a meta-analysis was conducted that adhered to PRISMA guidelines, searching PubMed, Embase, Web of Science, and the Cochrane Library for studies on the use of delta radiomics in stratifying lung cancer patients receiving immunotherapy. Out of 223 initially collected studies, 10 were included for qualitative synthesis. Stratifying patients using radiomic models, the pooled analysis reveals a predictive power with an area under the curve of 0.81 (95% CI 0.76-0.86, p < 0.001) for 6-month response, a pooled hazard ratio of 4.77 (95% CI 2.70-8.43, p < 0.001) for progression-free survival, and 2.15 (95% CI 1.73-2.66, p < 0.001) for overall survival at 6 months. Radiomics emerges as a potential prognostic predictor for lung cancer, but further research is needed to compare traditional radiomics and deep-learning radiomics.

A rotator cuff tear is a prevalent ailment affecting the shoulder joint. The clinical efficacy of combined therapy remains uncertain for partial rotator cuff tears. In this study, we integrated extracorporeal shockwave therapy (ESWT) with platelet-rich plasma (PRP) injection, juxtaposed with PRP in isolation. Both cohorts exhibited significant improvements in visual analogue scale (VAS), Constant-Murley score (CMS), degrees of forward flexion, abduction, internal rotation, and external rotation, and the sum of range of motion (SROM) over the six-month assessment period. The application of ESWT in conjunction with PRP exhibited notable additional enhancements in both forward flexion ( p = 0.033) and abduction ( p = 0.015) after one month. Furthermore, a substantial augmentation in the range of shoulder motion (SROM) ( p < 0.001) was observed after six months. We employed isobaric tag for relative and absolute quantitation (iTRAQ) to analyze the differential plasma protein expression in serum samples procured from the two groups after one month. The concentrations of S100A8 ( p = 0.042) and S100A9 ( p = 0.034), known to modulate local inflammation, were both lower in the ESWT + PRP cohort. These findings not only underscore the advantages of combined therapy but also illuminate the associated molecular changes.

Background: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early breast cancer patients with low-burden axillary metastasis (≤ 2 positive nodes). This study aimed to determine the diagnostic performances of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and breast magnetic resonance imaging in detecting axillary lymph node (ALN) metastases and the reliability to predict ALN burden., Methods: A total of 275 patients with primary operable breast cancer receiving preoperative PET/CT and upfront surgery from January 2001 to December 2022 in a single institution were enrolled. A total of 244 (88.7%) of them also received breast MRI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET/CT and breast MRI were assessed. The predictive values to determine ALN burden were evaluated using radio-histopathological concordance., Results: PET/CT demonstrated a sensitivity of 53.4%, specificity of 82.1%, PPV of 65.5%, NPV of 73.5%, and accuracy of 70.9% for detecting ALN metastasis, and the corresponding values for MRI were 71.8%, 67.8%, 56%, 80.8%, and 69.2%, respectively. Combining PET/CT and MRI showed a significantly higher PPV than MRI (72.7% vs 56% for MRI alone, p = 0.037) and a significantly higher NPV than PET/CT (84% vs 73.5% for PET/CT alone, p = 0.041). For predicting low-burden axillary metastasis (1-2 positive nodes), the PPVs were 35.9% for PET/CT, 36.7% for MRI, and 55% for combined PET/CT and MRI. Regarding patients with 0-2 positive ALNs in imaging, who were indicated for SLNB, the predictive correctness was 96.1% for combined PET/CT and MRI, 95.7% for MRI alone, and 88.6% for PET/CT alone., Conclusions: PET/CT and breast MRI exhibit high predictive values for identifying low-burden axillary metastasis in patients with operable breast cancer with ≦ 2 positive ALNs on imaging., (© 2024. The Author(s).)

Water contamination caused by discharge of spent washes containing colorants remains controversial. In this study, rosin-derived strongly basic macroporous anion-adsorption resin (RSBMAR) was designed as an advanced adsorbent for scavenging caramel, the most recalcitrant colorant in spent washes. Toxicity tests suggest that RSBMAR is environmentally friendly and hardly threatens aquatic organisms. RSBMAR exhibits outstanding caramel capture efficiency because of its rich target quaternary ammonium (-R 4 N + ) and protonated tertiary amine (-R 3 NH + ) groups, abundant porous structure, large specific surface area, excellent thermal stability, and good sphericity. The caramel adsorption capacity of RSBMAR was 165.86 mg/g and the decolorization efficiency reached 96.75%. After five cycles, the spent RSBMAR maintained a high decolorization rate, indicating excellent renewability. Multiple characterizations indicated that caramel capture was largely mediated by charge interaction between -R 4 N + /-R 3 NH + (RSBMAR) and -RCOO - /-RCOOH (caramel), followed by H-bonds. Quantum chemical theory simulations, including electrostatic potential, local ionization energy, frontier molecular orbitals, and independent gradient model analyses, further visualized caramel capture mechanisms at atomic level. Hirshfeld surface analysis revealed that RSBMAR acts as both an H-bond donor and acceptor during caramel uptake. Dynamic adsorption was performed to treat real wastewater, laying the foundation for the industrial application of RSBMAR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed. Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Objectives: Angioarchitectural analysis of brain arteriovenous malformations (BAVMs) is qualitative and subject to interpretation. This study quantified the morphology of and signal changes in the nidal and perinidal areas by using MR radiomics and compared the performance of MR radiomics and angioarchitectural analysis in detecting epileptic BAVMs., Materials and Methods: From 2010 to 2020, a total of 111 patients with supratentorial BAVMs were retrospectively included and grouped in accordance with the initial presentation of seizure. Patients' angiograms and MR imaging results were analyzed to determine the corresponding angioarchitecture. The BAVM nidus was contoured on time-of-flight MR angiography images. The perinidal brain parenchyma was contoured on T2-weighted images, followed by radiomic analysis. Logistic regression analysis was performed to determine the independent risk factors for seizure. ROC curve analysis, decision curve analysis (DCA), and calibration curve were performed to compare the performance of angioarchitecture-based and radiomics-based models in diagnosing epileptic BAVMs., Results: In multivariate analyses, low sphericity (OR: 2012.07, p = .04) and angiogenesis (OR: 5.30, p = .01) were independently associated with a high risk of seizure after adjustment for age, sex, temporal location, and nidal volume. The AUC for the angioarchitecture-based, MR radiomics-based, and combined models was 0.672, 0.817, and 0.794, respectively. DCA confirmed the clinical utility of the MR radiomics-based and combined models., Conclusions: Low nidal sphericity and angiogenesis were associated with high seizure risk in patients with BAVMs. MR radiomics-derived tools may be used for noninvasive and objective measurement for evaluating the risk of seizure due to BAVM., Clinical Relevance Statement: Low nidal sphericity was associated with high seizure risk in patients with brain arteriovenous malformation and MR radiomics may be used as a noninvasive and objective measurement method for evaluating seizure risk in patients with brain arteriovenous malformation., Key Points: • Low nidal sphericity was associated with high seizure risk in patients with brain arteriovenous malformation. • The performance of MR radiomics in detecting epileptic brain arteriovenous malformations was more satisfactory than that of angioarchitectural analysis. • MR radiomics may be used as a noninvasive and objective measurement method for evaluating seizure risk in patients with brain arteriovenous malformation., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)