Arginine-linked HPV-associated E7 displaying bacteria-derived outer membrane vesicles as a potent antigen-specific cancer vaccine.

BACKGROUND: Bacteria-based cancer therapy have demonstrated innovative strategies to combat tumors. Recent studies have focused on gram-negative bacterial outer membrane vesicles (OMVs) as a novel cancer immunotherapy strategy due to its intrinsic properties as a versatile carrier. METHOD: Here, we developed an Human Papillomavirus (HPV)-associated E7 antigen displaying Salmonella-derived OMV vaccine, utilizing a Poly(L-arginine) cell penetrating peptide (CPP) to enhance HPV16 E7 (aa49-67) H-2 Db and OMV affinity, termed SOMV-9RE7. RESULTS: Due to OMV's intrinsic immunogenic properties, SOMV-9RE7 effectively activates adaptive immunity through antigen-presenting cell uptake and antigen cross-presentation. Vaccination of engineered OMVs shows immediate tumor suppression and recruitment of infiltrating tumor-reactive immune cells. CONCLUSION: The simplicity of the arginine coating strategy boasts the versatility of immuno-stimulating OMVs that can be broadly implemented to personalized bacterial immunotherapeutic applications.

Antimicrobial Resistance and Molecular Characterization of Escherichia coli from Healthy Chickens in Shandong, China from 2009 to 2014.

Antimicrobial resistance (AMR) is a great threat to animal and public health. Here, we conducted a surveillance of Escherichia coli isolated from healthy chickens during 2009-2014 to identify the characteristics of AMR. A total of 351 (95.64%) E. coli isolates were obtained from 367 healthy chicken fecal samples collected from 6 farms located in Shandong Province, China. The susceptibility to 10 antimicrobials, the prevalence of antibiotic resistance genes (ARGs), phylogenetic clustering, and multilocus sequence typing were evaluated. The isolates exhibited high resistant rates (>95%) to ampicillin, cefotaxime, ciprofloxacin, ceftiofur, and enrofloxacin. The most prevalent ARGs were blaCTX-M (36.36%), aac(6')-Ib-cr (30.79%), qnrS (29.62%), oqxAB (27%), mcr-1 (15.83%), blaTEM (9.09%), qnrC (3.52%), qnrD (0.88%), and qepA (0.29%). Phylogenetic clustering analysis indicated that the most prevalent group was group D (37.89%), followed by group B1 (34.76%), A (24.22%), and B2 (3.13%). Fifty-seven sequence types (STs) were identified among the 124 blaCTX-M-positive strains, and the dominant STs were ST354 (13.71%), ST117 (5.65%), ST155, ST2309, and ST2505 (4.84% each). There was a significant association between 17 pairs of AMR phenotypes, 14 pairs of ARGs, and 11 pairs of AMR-ARGs. The strongest association was found between ST602 and qnrC (odds ratios: 22.2). This study implied that E. coli isolated from healthy chickens could potentially serve as a reservoir of AMR and ARGs, and significant associations exist among AMR, ARGs, phylogenetic groups, and STs. Our study highlighted the need for routine surveillance of AMR in healthy chickens, and promoting appropriate antibiotic use and implementing regular monitoring of resistance in broilers are crucial for fostering the development of the poultry industry and safeguarding public health.

Exploring the Diagnostic and Prognostic Significance of Alkaline Phosphatase on Neutrophil Surface Membrane in Patients with Sepsis.

Background: Sepsis, characterized by life-threatening organ dysfunction, stems from an unregulated host response. Timely identification is pivotal for enhancing the prognosis of sepsis patients. Objective: This study aims to explore the diagnostic and prognostic values of alkaline phosphatase on the surface membrane of neutrophils (mNAP) in peripheral blood among sepsis patients. Design: The study employed a retrospective design. Setting: This study was conducted at Donghai County People's Hospital. Participants: A total of 180 sepsis patients were selected and categorized into the sepsis shock group (n=45) and the sepsis non-shock group (n=135). Additionally, 35 patients with non-infectious systemic inflammatory response syndrome served as the control group. Interventions: mNAP was assessed via flow cytometry, while serum procalcitonin (PCT) and C-reactive protein (CRP) levels were measured through immunoassay. Primary Outcome Measures: (1) Changes in mNAP, PCT, and CRP. (2) Correlation of mNAP with CRP and PCT in sepsis patients. (3) Diagnostic values of mNAP, PCT, and CRP in sepsis. Results: Statistically significant differences in mNAP, PCT, and CRP were observed between the sepsis shock group, the sepsis non-shock group, and the control group (P = .000). The median value of mNAP (22627 Ab/c) in the 28-day death group was significantly higher than that (5100 Ab/c) in the survival group (P = .000). Spearman rank correlation analysis indicated a positive correlation between mNAP, PCT, and CRP in sepsis patients (P < .01). Conclusions: Both mNAP and PCT exhibit superior diagnostic specificity and sensitivity compared to CRP. While mNAP demonstrates similar sensitivity to PCT in diagnosing sepsis, its diagnostic specificity surpasses that of PCT. mNAP holds promise as a novel marker for the diagnosis and prognosis of sepsis.

Development of a fluorescent ligand that can illuminate nuclear G-quadruplexes and modulate oncogene expression.

In this study, we developed a promising dual-function fluorescent ligand termed KS-1 by a slight structural modification on a reported carbazole-based scaffold. KS-1 was then found to mainly bind and illuminate the nuclear DNA G-quadruplexes (G4s) in a sandwich-like interacting mode, and also effectively modulate the oncogene expression through a G4-mediated manner. Furthermore, KS-1 was proved to inhibit cancer cell growth either in 2D monolayer cells or 3D multicellular tumor spheroids. To be noted, this ligand could overcome the shortcomings of other reported dual-function ligands that appeared to accumulate in the lysosomes or mitochondria, and may be used as a theranostic agent in the future.

[Clinical study of ear keloids with surgical excision and intraoperative low-energy X-ray irradiation therapy].

Objective:To explore the clinical efficacy of surgical excision combined with low-energy X-ray irradiation in the treatment of ear keloids. Methods:Clinical data of 32 cases of ear keloid lesions that received surgical treatment alone or surgery combined with radiotherapy from March 2019 to November 2022 in the Department of Otorhinolaryngology Head and Neck Surgery of the Tianjin First Central Hospital were retrospectively analyzed. Among them, 10 cases received radiotherapy and 22 cases did not receive radiotherapy. The radiotherapy group received irradiation with a large divided dose of 50 kV low-energy X-rays. The mode of fractionation radiotherapy was as follows: the first was 10 Gy of intraoperative radiation therapy and the second was 8 Gy on the 3rd postoperative day for a total of 18 Gy. The local efficacy and skin radiation reaction were observed at a follow-up of 8-52 months. Results:The median follow-up was 26 months, and as of the date of the last follow-up, 9 cases were cured and 1 case was ineffective in the radiotherapy group, with an effective rate of 90.0%, while 9 cases were cured and 13 cases were ineffective in the no-radiotherapy group, with an effective rate of 40.9%. The recurrence of ear keloids was not related to the side, site, or etiology of the patient's onset（P>0.05）. Recurrence was related to whether or not the patients received radiotherapy（χ²=4.885, P<0.05）, and the recurrence rate in the radiotherapy group（10.0%） was significantly lower than that in the non-radiotherapy group（59.1%）. Conclusion:Surgical excision combined with low-energy X-ray irradiation therapy is an effective method of treating keloids in the ear, especially with intraoperative radiation therapy can achieve more satisfactory results.

Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Anti-pancreatic cancer activity of cassane diterpenoids isolated from the seeds of Caesalpinia sappan mediated by autophagy activation via ROS/AMPK/mTORC1 pathway.

Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC50 value of 18.13 ± 0.63 µM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which is demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.

Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic ß-cell survival and function.

Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, we examined multiple variants that influence SLC30A8 allele-specific expression. Epigenomic mapping has previously identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighboring genes. Here, we show that deletion of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-ßH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves glucose-stimulated insulin secretion. While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21, or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.

Retinal detachment with multiple macrocysts in Stickler syndrome: case report and review of the literature.

Background: Stickler syndrome is a hereditary connective tissue disorder associated with ocular, orofacial, musculoskeletal, and auditory impairments. Its main clinical characteristics include retinal detachment, hearing loss, and midface underdevelopment. In clinical practice, macrocyst is rarely reported in retinal detachment cases with Stickler syndrome. Case presentation: We report the case of a 7-year-old child who developed a rhegmatogenous retinal detachment (RRD) in the right eye, accompanied by multiple peripheral macrocysts. The detachment was successfully surgically repaired with vitrectomy, retinal laser photocoagulation, cryotherapy and silicone oil tamponade. During the operation, a mini-retinectomy in the outer layer of each macrocyst was made for vesicular drainage and retinal reattachment. Genetic testing identified a pathogenic point mutation variant (c.1693C>T; p.Arg565Cys) in exon 26 of the COL2A1 gene. Six-months after the operation, the retina remained attached with improvement of best corrected visual acuity to 20/200. Conclusion: Patients with Stickler syndrome may develop RRD of different severity. Macrocyst is rarely reported in previous literature of Stickler syndrome. In this case report, we share our experience in treating with multiple macrocysts in RRD and emphasize the importance of periodic follow-up for patients with Stickler syndrome.

Validation of the Chinese Version of Penn Alcohol Craving Scale for Patients With Alcohol Use Disorder.

OBJECTIVE: The Penn Alcohol Craving Scale (PACS) is a five-item, single-dimension questionnaire that is used to measure a patient's alcohol craving. We sought to develop the Chinese version of the PACS (PACS-C) and assess its reliability and validity. METHODS: A total of 160 Taiwanese patients with alcohol use disorder were enrolled in this study. The internal consistency and concurrent validity of the PASC-C with the visual analogue scale (VAS) for craving, the Yale-Brown Obsessive Compulsive Scale for heavy drinking (YBOCS-hd), and the Severity of Alcohol Dependence Questionnaire (SADQ) were assessed. The test-retest reliability of the PASC-C was evaluated 1 day after the baseline measurements. Confirmatory factor analysis (CFA) was performed to examine the psychometric properties of the PACS-C. RESULTS: The PACS-C exhibited good internal consistency (Cronbach's α=0.95) and test-retest reliability (r=0.97). This scale showed high correlations with the VAS (r=0.81) and YBOCS-hd (r=0.81 and 0.79 for the obsession and compulsion subscales, respectively), and moderate correlation with the SADQ-C (r=0.47). Furthermore, CFA results revealed that the PACS-C had good fit indices under various models. CONCLUSION: The PACS-C appears to be a reliable and valid tool for assessing alcohol craving in patients with alcohol use disorder in Taiwan.

Toxin gene detection and antibiotic resistance of Clostridium perfringens from aquatic sources.

Clostridium perfringens is a zoonotic opportunistic pathogen that produces toxins that can cause necrotic enteritis and even "sudden death disease". This bacterium is widely distributed in the intestines of livestock and human, but there are few reports of distribution in aquatic animals (Hafeez et al., 2022). In order to explore the isolation rate of C. perfringens and the toxin genes they carry, 141 aquatic samples, including clams (Ruditapes philippinarum), oysters (Ostreidae), and mud snails (Bullacta exerata Philippi), were collected from the coastal areas of Shandong Province, China. C. perfringens strains were tested for cpa, cpb, etx, iap, cpb2, cpe, netB, and tpeL genes. 45 clam samples were boiled at 100 °C for 5 min before bacteria isolation. 80 strains were isolated from 141 samples with the positive rate being 57 %.And the positive rates of cooked clams was 87 % which was higher than the average. In detection of 8 toxin genes, all strains tested cpa positive, 3 strains netB positive, and 2 cpb and cpe, respectively. 64 strains were selected to analyze the antibiotic resistance phenotype of 10 antibiotics. The average antibiotic resistance rates of the strains to tetracycline, clindamycin, and ampicillin were 45 %, 20 %, and 16 % respectively, and the MIC of 4 strains to clindamycin was ≥128 µg/mL. A high isolation rate of C. perfringens from aquatic animals was shown, and it was isolated from boiled clams for the first time, in which cpe and netB toxin genes were detected for the first time too. The toxin encoded by cpe gene can cause food poisoning of human, thus the discoveries of this study have certain guiding significance for food safety. Antibiotics resistant C. perfringens of aquatic origin may arise from transmission in the terrestrial environment or from antibiotic contamination of the aquaculture environment and is of public health significance.

Deep-potential enabled multiscale simulation of gallium nitride devices on boron arsenide cooling substrates.

High-efficient heat dissipation plays critical role for high-power-density electronics. Experimental synthesis of ultrahigh thermal conductivity boron arsenide (BAs, 1300 W m-1K-1) cooling substrates into the wide-bandgap semiconductor of gallium nitride (GaN) devices has been realized. However, the lack of systematic analysis on the heat transfer across the GaN-BAs interface hampers the practical applications. In this study, by constructing the accurate and high-efficient machine learning interatomic potentials, we perform multiscale simulations of the GaN-BAs heterostructures. Ultrahigh interfacial thermal conductance of 260 MW m-2K-1 is achieved, which lies in the well-matched lattice vibrations of BAs and GaN. The strong temperature dependence of interfacial thermal conductance is found between 300 to 450 K. Moreover, the competition between grain size and boundary resistance is revealed with size increasing from 1 nm to 1000 µm. Such deep-potential equipped multiscale simulations not only promote the practical applications of BAs cooling substrates in electronics, but also offer approach for designing advanced thermal management systems.

Effect of outer membrane vesicles of Lactobacillus pentosus on Tau phosphorylation and CDK5-Calpain pathway in mice.

Alzheimer's disease (AD) stands as a neurodegenerative disorder causing cognitive decline, posing a significant health concern for the elderly population in China. This study explored the effects of outer membrane vesicles (OMVs) from the gut microbiota of AD patients on learning and memory abilities and Tau protein phosphorylation in mice. In contrast to the OMVs from healthy controls and the PBS treatment group, mice treated with AD-OMVs exhibited notable declines in learning and memory capabilities, as evidenced by results from the Morris water maze, Y-maze, and novel object recognition tests. Immunohistochemistry and Western blot assessments unveiled elevated levels of hyperphosphorylated Tau in the cortex and hippocampus of mice treated with AD-OMVs. However, there were no alterations observed in the total Tau levels. In addition, AD-OMVs treated mice showed increased neuroinflammation indicated by elevated astrocytes and microglia. Molecular mechanism studies demonstrated that AD-OMVs could activate GSK3ß, CDK5-Calpain and NF-κB pathways in mice hippocampus. These studies suggest AD patient gut microbiota derived OMVs can promote host Tau phosphorylation and improved neuroinflammation.

Discovery of a triphenylamine-based ligand that targets mitochondrial DNA G-quadruplexes and activates the cGAS-STING immunomodulatory pathway.

Stabilization of G-quadruplex (G4) structures in mitochondria leads to the damage of mitochondrial DNA (mtDNA), making mtDNA G4s a promising target in the field of cancer therapy in recent years. Damaged mtDNA released into the cytosol can stimulate cytosolic DNA-sensing pathways, and cGAS-STING pathway is a typical one with potent immunostimulatory effects. A few small molecule ligands of mtDNA G4s are identified with antitumor efficacy, but little is known about their results and mechanisms on immunomodulation. In this study, we engineered a series of triphenylamine-based analogues targeting mtDNA G4s, and A6 was determined as the most promising compound. Cellular studies indicated that A6 caused severe mtDNA damage. Then, damaged mtDNA stimulated cGAS-STING pathway, resulting in the following cytokine production of tumor cells and the maturation of DCs. In vivo experiments certified that A6 exerted suppressive influences on tumor growth and metastasis in 4T1 cell-bearing mice by the regulation of TME, including the remodeling of macrophages and the activation of T cells. To our knowledge, it is the first time to report a ligand targeting mtDNA G4s to activate the cGAS-STING immunomodulatory pathway, providing a novel strategy for the future development of mtDNA G4-based antitumor agents.

Nocturnal Pressure Controlled Ventilation Improves Sleep Efficiency in Patients Receiving Mechanical Ventilation.

BACKGROUND: Patients receiving mechanical ventilation commonly experience sleep fragmentation. The present meta-analysis compared the effects of pressure controlled ventilation (PCV) and pressure support ventilation (PSV) on sleep quality. METHODS: We conducted a search of the PubMed, Embase, and Cochrane Library databases for studies published before November 2023. In this meta-analysis, individual effect sizes were standardized, and the pooled effect size was determined by using random-effects models. The primary outcome was sleep efficiency. The secondary outcomes were wakefulness, percentages of REM (rapid eye movement) sleep and stages 3 and 4 non-REM sleep, the fragmentation index, and the incidence of apneic events. RESULTS: This meta-analysis examined 4 trials that involved 67 subjects. Sleep efficiency was significantly higher in the PCV group than in the PSV group (mean difference 15.57%, 95% CI 8.54%-22.59%). Wakefulness was significantly lower in the PCV group than in the PSV group (mean difference -18.67%, 95% CI -30.29% to -7.04%). The percentage of REM sleep was significantly higher in the PCV group than in the PSV group (mean difference 2.32%, 95% CI 0.20%-4.45%). Among the subjects with a tendency to develop sleep apnea, the fragmentation index was significantly lower in those receiving PCV than PSV (mean difference -40.00%, 95% CI -51.12% to -28.88%). The incidence of apneic events was significantly lower in the PCV group than in the PSV group (risk ratio 0.06, 95% CI 0.01-0.45). CONCLUSIONS: Compared with PSV, PCV may improve sleep quality in patients receiving nocturnal mechanical ventilation.

Discovering New Substrates of a UDP-Glycosyltransferase with a High-Throughput Method.

UDP-glycosyltransferases (UGTs) form a large enzyme family that is found in a wide range of organisms. These enzymes are known for accepting a wide variety of substrates, and they derivatize xenobiotics and metabolites for detoxification. However, most UGT homologs have not been well characterized, and their potential for biomedical and environmental applications is underexplored. In this work, we have used a fluorescent assay for screening substrates of a plant UGT homolog by monitoring the formation of UDP. We optimized the assay such that it could be used for high-throughput screening of substrates of the Medicago truncatula UGT enzyme, UGT71G1, and our results show that 34 of the 159 screened compound samples are potential substrates. With an LC-MS/MS method, we confirmed that three of these candidates indeed were glycosylated by UGT71G1, which includes bisphenol A (BPA) and 7-Ethyl-10-hydroxycamptothecin (SN-38); derivatization of these toxic compounds can lead to new environmental and medical applications. This work suggests that UGT homologs may recognize a substrate profile that is much broader than previously anticipated. Additionally, it demonstrates that this screening method provides a new means to study UDP-glycosyltransferases, facilitating the use of these enzymes to tackle a wide range of problems.

Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

BACKGROUND: Bone metastasis in advanced cancer is challenging because of pain, functional issues, and reduced life expectancy. Treatment planning is complex, with consideration of factors such as location, symptoms, and prognosis. Prognostic models help guide treatment choices, with Skeletal Oncology Research Group machine-learning algorithms (SORG-MLAs) showing promise in predicting survival for initial spinal metastases and extremity metastases treated with surgery or radiotherapy. Improved therapies extend patient lifespans, increasing the risk of subsequent skeletal-related events (SREs). Patients experiencing subsequent SREs often suffer from disease progression, indicating a deteriorating condition. For these patients, a thorough evaluation, including accurate survival prediction, is essential to determine the most appropriate treatment and avoid aggressive surgical treatment for patients with a poor survival likelihood. Patients experiencing subsequent SREs often suffer from disease progression, indicating a deteriorating condition. However, some variables in the SORG prediction model, such as tumor histology, visceral metastasis, and previous systemic therapies, might remain consistent between initial and subsequent SREs. Given the prognostic difference between patients with and without a subsequent SRE, the efficacy of established prognostic models-originally designed for individuals with an initial SRE-in addressing a subsequent SRE remains uncertain. Therefore, it is crucial to verify the model's utility for subsequent SREs. QUESTION/PURPOSE: We aimed to evaluate the reliability of the SORG-MLAs for survival prediction in patients undergoing surgery or radiotherapy for a subsequent SRE for whom both the initial and subsequent SREs occurred in the spine or extremities. METHODS: We retrospectively included 738 patients who were 20 years or older who received surgery or radiotherapy for initial and subsequent SREs at a tertiary referral center and local hospital in Taiwan between 2010 and 2019. We excluded 74 patients whose initial SRE was in the spine and in whom the subsequent SRE occurred in the extremities and 37 patients whose initial SRE was in the extremities and the subsequent SRE was in the spine. The rationale was that different SORG-MLAs were exclusively designed for patients who had an initial spine metastasis and those who had an initial extremity metastasis, irrespective of whether they experienced metastatic events in other areas (for example, a patient experiencing an extremity SRE before his or her spinal SRE would also be regarded as a candidate for an initial spinal SRE). Because these patients were already validated in previous studies, we excluded them in case we overestimated our result. Five patients with malignant primary bone tumors and 38 patients in whom the metastasis's origin could not be identified were excluded, leaving 584 patients for analysis. The 584 included patients were categorized into two subgroups based on the location of initial and subsequent SREs: the spine group (68% [399]) and extremity group (32% [185]). No patients were lost to follow-up. Patient data at the time they presented with a subsequent SRE were collected, and survival predictions at this timepoint were calculated using the SORG-MLAs. Multiple imputation with the Missforest technique was conducted five times to impute the missing proportions of each predictor. The effectiveness of SORG-MLAs was gauged through several statistical measures, including discrimination (measured by the area under the receiver operating characteristic curve [AUC]), calibration, overall performance (Brier score), and decision curve analysis. Discrimination refers to the model's ability to differentiate between those with the event and those without the event. An AUC ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An AUC of 0.7 is considered clinically acceptable discrimination. Calibration is the comparison between the frequency of observed events and the predicted probabilities. In an ideal calibration, the observed and predicted survival rates should be congruent. The logarithm of observed-to-expected survival ratio [log(O:E)] offers insight into the model's overall calibration by considering the total number of observed (O) and expected (E) events. The Brier score measures the mean squared difference between the predicted probability of possible outcomes for each individual and the observed outcomes, ranging from 0 to 1, with 0 indicating perfect overall performance and 1 indicating the worst performance. Moreover, the prevalence of the outcome should be considered, so a null-model Brier score was also calculated by assigning a probability equal to the prevalence of the outcome (in this case, the actual survival rate) to each patient. The benefit of the prediction model is determined by comparing its Brier score with that of the null model. If a prediction model's Brier score is lower than the null model's Brier score, the prediction model is deemed as having good performance. A decision curve analysis was performed for models to evaluate the "net benefit," which weighs the true positive rate over the false positive rate against the "threshold probabilities," the ratio of risk over benefit after an intervention was derived based on a comprehensive clinical evaluation and a well-discussed shared-decision process. A good predictive model should yield a higher net benefit than default strategies (treating all patients and treating no patients) across a range of threshold probabilities. RESULTS: For the spine group, the algorithms displayed acceptable AUC results (median AUCs of 0.69 to 0.72) for 42-day, 90-day, and 1-year survival predictions after treatment for a subsequent SRE. In contrast, the extremity group showed median AUCs ranging from 0.65 to 0.73 for the corresponding survival periods. All Brier scores were lower than those of their null model, indicating the SORG-MLAs' good overall performances for both cohorts. The SORG-MLAs yielded a net benefit for both cohorts; however, they overestimated 1-year survival probabilities in patients with a subsequent SRE in the spine, with a median log(O:E) of -0.60 (95% confidence interval -0.77 to -0.42). CONCLUSION: The SORG-MLAs maintain satisfactory discriminatory capacity and offer considerable net benefits through decision curve analysis, indicating their continued viability as prediction tools in this clinical context. However, the algorithms overestimate 1-year survival rates for patients with a subsequent SRE of the spine, warranting consideration of specific patient groups. Clinicians and surgeons should exercise caution when using the SORG-MLAs for survival prediction in these patients and remain aware of potential mispredictions when tailoring treatment plans, with a preference for less invasive treatments. Ultimately, this study emphasizes the importance of enhancing prognostic algorithms and developing innovative tools for patients with subsequent SREs as the life expectancy in patients with bone metastases continues to improve and healthcare providers will encounter these patients more often in daily practice. LEVEL OF EVIDENCE: Level III, prognostic study.

Psoas muscle area is an independent survival prognosticator in patients undergoing surgery for long-bone metastases.

BACKGROUND: Predictive analytics is gaining popularity as an aid to treatment planning for patients with bone metastases, whose expected survival should be considered. Decreased psoas muscle area (PMA), a morphometric indicator of suboptimal nutritional status, has been associated with mortality in various cancers, but never been integrated into current survival prediction algorithms (SPA) for patients with skeletal metastases. This study investigates whether decreased PMA predicts worse survival in patients with extremity metastases and whether incorporating PMA into three modern SPAs (PATHFx, SORG-NG, and SORG-MLA) improves their performance. METHODS: One hundred eighty-five patients surgically treated for long-bone metastases between 2014 and 2019 were divided into three PMA tertiles (small, medium, and large) based on their psoas size on CT. Kaplan-Meier, multivariable regression, and Cox proportional hazards analyses were employed to compare survival between tertiles and examine factors associated with mortality. Logistic regression analysis was used to assess whether incorporating adjusted PMA values enhanced the three SPAs' discriminatory abilities. The clinical utility of incorporating PMA into these SPAs was evaluated by decision curve analysis (DCA). RESULTS: Patients with small PMA had worse 90-day and 1-year survival after surgery (log-rank test p < 0.001). Patients in the large PMA group had a higher chance of surviving 90 days (odds ratio, OR, 3.72, p = 0.02) and 1 year than those in the small PMA group (OR 3.28, p = 0.004). All three SPAs had increased AUC after incorporation of adjusted PMA. DCA indicated increased net benefits at threshold probabilities >0.5 after the addition of adjusted PMA to these SPAs. CONCLUSIONS: Decreased PMA on CT is associated with worse survival in surgically treated patients with extremity metastases, even after controlling for three contemporary SPAs. Physicians should consider the additional prognostic value of PMA on survival in patients undergoing consideration for operative management due to extremity metastases.