Staging of Liver Fibrosis Based on Energy Valley Optimization Multiple Stacking (EVO-MS) Model.

Currently, staging the degree of liver fibrosis predominantly relies on liver biopsy, a method fraught with potential risks, such as bleeding and infection. With the rapid development of medical imaging devices, quantification of liver fibrosis through image processing technology has become feasible. Stacking technology is one of the effective ensemble techniques for potential usage, but precise tuning to find the optimal configuration manually is challenging. Therefore, this paper proposes a novel EVO-MS model-a multiple stacking ensemble learning model optimized by the energy valley optimization (EVO) algorithm to select most informatic features for fibrosis quantification. Liver contours are profiled from 415 biopsied proven CT cases, from which 10 shape features are calculated and inputted into a Support Vector Machine (SVM) classifier to generate the accurate predictions, then the EVO algorithm is applied to find the optimal parameter combination to fuse six base models: K-Nearest Neighbors (KNNs), Decision Tree (DT), Naive Bayes (NB), Extreme Gradient Boosting (XGB), Gradient Boosting Decision Tree (GBDT), and Random Forest (RF), to create a well-performing ensemble model. Experimental results indicate that selecting 3-5 feature parameters yields satisfactory results in classification, with features such as the contour roundness non-uniformity (Rmax), maximum peak height of contour (Rp), and maximum valley depth of contour (Rm) significantly influencing classification accuracy. The improved EVO algorithm, combined with a multiple stacking model, achieves an accuracy of 0.864, a precision of 0.813, a sensitivity of 0.912, a specificity of 0.824, and an F1-score of 0.860, which demonstrates the effectiveness of our EVO-MS model in staging the degree of liver fibrosis.

NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Major Depressive Disorder (MDD) emerges as a complex psychosomatic condition, notable for its considerable suicidality and mortality rates. Increasing evidence suggests the efficacy of Chinese herbal medicine in mitigating depression symptoms and offsetting the adverse effects associated with conventional Western therapeutics. Notably, clinical trials have revealed the adjunctive antidepressant potential of Kaiyu Zhishen Decoction (KZD) alongside Western medication. However, the standalone antidepressant efficacy of KZD and its underlying mechanisms merit in-depth investigation. AIM OF THE STUDY: This research aims to elucidate the impact of KZD on MDD and delineate its mechanistic pathways through integrated network pharmacological assessments and empirical in vitro and in vivo analyses. MATERIALS AND METHODS: To ascertain the optimal antidepressant dosage and mechanism of KZD, a Chronic Unpredictable Mild Stress (CUMS)-induced depression model in mice was established to evaluate depressive behaviors. High-Performance Liquid Chromatography (HPLC) and network pharmacological approaches were employed to predict KZD's antidepressant mechanisms. Subsequently, hippocampal samples were subjected to 4D-DIA proteomic sequencing and validated through Western blot, immunofluorescence, Nissl staining, and pathway antagonist applications. Additionally, cortisol-stimulated PC12 cells were utilized to simulate neuronal damage, analyzing protein and mRNA levels of MAPK-related signals and cell proliferation markers. RESULTS: The integration of network pharmacology and HPLC identified kaempferol and quercetin as KZD's principal active compounds for MDD treatment. Proteomic and network pharmacological KEGG pathway analyses indicated the MAPK signaling pathway as a critical regulatory mechanism for KZD's therapeutic effect on MDD. KZD was observed to mitigate CUMS-induced upregulation of p-ERK/ERK, CREB, and BDNF protein expressions in hippocampal cells by attenuating oxidative stress, thereby ameliorating neuronal damage and exerting antidepressant effects. The administration of PD98059 counteracted KZD's improvements in depression-like behaviors and downregulated p-ERK/ERK and BDNF protein expressions in the hippocampus. CONCLUSIONS: This investigation corroborates KZD's pivotal, dose-dependent role in antidepressant activity. Both in vivo and in vitro experiments demonstrate KZD's capacity to modulate the ERK-CREB-BDNF signaling pathway by diminishing ROS expression induced by oxidative stress, enhancing neuronal repair, and thus, manifesting antidepressant properties. Accordingly, KZD represents a promising herbal candidate for further antidepressant research.

Artificial Intelligence-Driven Platform: Unveiling Critical Hepatic Molecular Alterations in Hepatocellular Carcinoma Development.

Since most Hepatocellular Carcinoma (HCC) typically arises as a consequence of long-term liver damage, the hepatic molecular characteristics are closely related to the occurrence of HCC. Gaining comprehensive information about the location, morphology, and hepatic molecular alterations related to HCC is essential for accurate diagnosis. However, there is a dearth of technological advancements capable of concurrently providing precise HCC diagnosis and discerning the accompanying hepatic molecular alterations. In this study, an integrated information system is developed for the pathological-level diagnosis of HCC and the revelation of critical molecular alterations in the liver. This system utilizes computed tomography/Surface-enhanced Raman scattering combined with an artificial intelligence strategy to establish connections between the occurrence of HCC and alterations in hepatic biomolecules. Employing artificial intelligence techniques, the SERS spectra from both healthy and HCC groups are successfully classified into two distinct categories with a remarkable accuracy rate of 91.38%. Based on molecular profiling, it is identified that the nucleotide-to-lipid signal ratio holds significant potential as a reliable indicator for the occurrence of HCC, thereby serving as a promising tool for prevention and therapeutic surveillance.

Characterization of the biological and transcriptomic landscapes of bone marrow-derived mesenchymal stem cells in patients with multiple myeloma.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) have been acknowledged as the most important stromal cells in the bone marrow (BM) microenvironment for physiologic hematopoiesis and the concomitant hematologic malignancies. However, the systematic and detailed dissection of the biological and transcriptomic signatures of BM-MSCs in multiple myeloma (MM) are largely unknown. METHODS: In this study, we isolated and identified BM-MSCs from 10 primary MM patients and 10 healthy donors (HD). On the one hand, we compared the multifaceted biological characteristics of the indicated two BM-MSCs, including biomarker expression pattern, multilineage differentiation potential, stemness and karyotyping, together with the cellular vitality and immunosuppressive property. On the other hand, we took advantage of RNA-SEQ and bioinformatics analysis to verify the similarities and differences at the transcriptomic level between MM-MSCs and HD-MSCs. RESULTS: As to biological phenotypes and biofunctions, MM-MSCs revealed conservation in immunophenotype, stemness and differentiation towards adipocytes and chondrocytes with HD-MSCs, whereas with impaired osteogenic differentiation potential, cellular vitality and immunosuppressive property. As to transcriptomic properties, MM-MSCs revealed multidimensional alterations in gene expression profiling and genetic variations. CONCLUSIONS: Overall, our date systematic and detailed reflected the multifaceted similarities and variations between MM-MSCs and HD-MSCs both at the cellular and molecular levels, and in particular, the alterations of immunomodulation and cellular viability of MM-MSCs, which wound benefit the further exploration of the pathogenesis and new drug application (NDA) of multiple myeloma from the view of BM-MSCs.

Is it necessary to extend fusion to L4 when correcting pediatric L5-S1 spondylolisthesis?

OBJECTIVE: The objective of this study was to investigate whether extending fusion to L4 is imperative in the surgical treatment of pediatric L5-S1 spondylolisthesis. METHODS: This retrospective analysis encompassed 68 pediatric cases of dysplastic L5-S1 spondylolisthesis who underwent posterior lumbar interbody fusion surgery at two hospitals. Patients were categorized into two groups based on the upper instrumented vertebra (group L4 and group L5). Data were collected from medical records and radiological images obtained preoperatively and at last follow-up. Radiographic parameters including slip percentage (SP), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), Spinal Deformity Study Group dysplastic lumbosacral angle (SDSG-LSA), pelvic tilt (PT), Dubousset's lumbosacral angle (Dub-LSA), sacral slope (SS), and severity index (SI) were measured. Surgery-related data and complication data were also collected. The incidence rates of complications were compared, including those of neurological deficit, adjacent-segment instability (ASI), and other complications. ASI was defined as progression of slippage > 3 mm or posterior opening > 5° in the adjacent segment. Clinical outcomes were assessed with the numeric rating scale (NRS) and the Oswestry Disability Index (ODI) scores. The follow-up period for all patients lasted a minimum of 2 years. RESULTS: Among all 68 patients, group L4 consisted of 15 patients and group L5 comprised 53 patients. The patients included in both groups had comparable baseline demographic characteristics and radiographic parameters. Postoperative SP and SDSG-LSA were significantly lower in group L5 (p < 0.05). No other postoperative radiographic differences were observed between groups. One patient in group L4 and 3 patients in group L5 experienced transient neurological deficits (p > 0.05). There were 13 cases of ASI in group L5 compared with none in group L4 (24.5% vs 0%, p > 0.05). Of the 13 patients with ASI, 4 underwent revision surgery due to L4-5 level instability and clinical symptoms. The remaining individuals exhibited no symptoms, and regular annual follow-up assessments are being conducted for all patients. The NRS and ODI scores at final follow-up did not exhibit any significant differences between the two groups. CONCLUSIONS: Fusion to L5 could achieve comparable satisfactory results to fixation to L4, albeit with increased likelihood of ASI. Extension of fusion to L4 may not be necessary for most patients with pediatric L5-S1 spondylolisthesis.

The outcome and predictive model of allogeneic hematopoietic stem cell transplantation among elderly patients with severe aplastic anemia from the Chinese Blood and Marrow Transplant Registry Group.

Not available.

Safety and effectiveness of halo gravity traction combined with traditional growing rods in severe early-onset scoliosis with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF-1) scoliosis can be difficult to treat without early detection. Correcting deformities while considering long-term growth in early-onset scoliosis (EOS) treatment is important. This study was performed to establish the safety and effectiveness of halo gravity traction (HGT) with traditional growing rods (TGRs) in NF-1 EOS. We retrospectively reviewed a cohort of 15 children (7 boys and 8 girls; mean age, 5.61 years) diagnosed with NF-1 EOS from October 2016 to March 2021. All patients underwent HGT before growing rod implantation. The growing rods were lengthened every 9-12 months, with a follow-up of 2-7 years. Cobb angle, thoracic kyphosis (TK), trunk shift (TS), sagittal vertebral axis and T1-S1 height were measured before operation, after traction, after operation and at last follow-up. Complications were also recorded. Fifteen patients with NF-1 EOS were treated with an average traction weight of 10.00 kg. After 29.20 days of HGT, the Cobb angle improved from 99.10° to 62.60°, TK from 79.33° to 55.04°, TS from 31.05 to 17.71 mm, sagittal vertebral axis from 42.07 to 25.63 mm and T1-S1 height from 27.50 to 29.70 cm (P < 0.05 for all). Postoperatively, compared with post-traction, the Cobb angle was 52.40° (P = 0.002) and TK was 44.54° (P = 0.004). No complications occurred during traction. Growing rod dislocation occurred in one patient and growing rod breakage in one patient. HGT combined with TGRs was well-tolerated and effective for treating severe NF-1 EOS. It significantly corrected the Cobb angle and TK, restored trunk balance, and increased spinal height with few complications.

One-Minute Preparation of Iron Foam-Drug Implant for Ultralow-Power Magnetic Hyperthermia-Based Combination Therapy of Tumors in Vivo.

The magnetic hyperthermia-based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)-drug implant is established in an ultra-facile and universal way for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra-high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large-scale preparation of IF-drug implants for biological application. As a proof of concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF-drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow-power combination therapy.

Safety and Accuracy of Robot-Assisted Cervical Screw Placement: A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to compare the accuracy and safety of robot-assisted (RA) cervical screw placement with conventional freehand (FH) technique. METHODS: Computer-based searches were conducted on various databases including PubMed, Embase, Cochrane Library, Web of Science, the China Biology Medicine, the China National Knowledge Infrastructure, and Wanfang Database. Inclusion criteria were studies reporting the use of RA techniques for cervical screw placement and providing data on safety and accuracy outcomes. Primary outcome indicators focused on the accuracy of screw placement, while secondary outcome indicators included operative time, intraoperative blood loss, length of hospital stay, complication rate, and radiation dose. Data from eligible studies were extracted and synthesized using a forest plot analysis. RESULTS: A total of 312 patients (1233 screws) from 6 studies were included, with 148 patients (47.4% with 567 screws) in the RA group. Perfect screw accuracy, as categorized by Gertzbein-Robbins grade A, was significantly superior with RA surgery compared to FH technique. RA screw implantation significantly reduced complication rates, intraoperative blood loss, length of hospitalization, and radiation dose compared to the conventional FH group. However, there was no statistically significant difference in surgery time between the RA and FH groups. CONCLUSIONS: RA surgery significantly improves the accuracy of cervical screw insertion and offers potential advantages in terms of reduced complications and blood loss, shorter hospital stays, and decreased radiation exposure. However, the impact on operative time remains uncertain. Further high-quality studies, including large-scale randomized controlled trials, are needed to strengthen the evidence base.

Analysis of poor prognostic factors for septic arthritis of the hip in children: a case series of 76 patients.

The clinical characteristics, treatment and outcomes of children with septic arthritis of the hip in our hospital were analyzed to identify the risk factors for a poor prognosis. The clinical data of 76 children with septic arthritis of the hip who were treated at our hospital from January 2010 to December 2020 were retrospectively analyzed. According to the most recent follow-up data, the patients were classified as good prognosis or poor prognosis. The differences between the two groups were analyzed. From January 2010 to December 2020, a total of 76 children with septic arthritis of the hip were admitted to our hospital, comprising 52 (68.4%) with a good prognosis and 24 (31.6%) with a poor prognosis. The risk of a poor prognosis was significantly higher in the group with time from onset to surgery >22 days than in the group with time from onset to surgery <11 days. The risk of poor prognosis in the group with C-reactive protein (CRP) > 100 mg/L was significantly higher than that in the group with CRP < 20 mg/L. Time from onset to surgery >14 days and CRP > 93 mg/L were the cutoff values for a poor prognosis. Significant elevation of CRP and prolonged time from onset to surgery in children with septic arthritis of the hip are risk factors for a poor prognosis. Early diagnosis and effective treatment are very important because delays in these factors can lead to a poor prognosis. Level of Evidence: Level II, retrospective study.

Identification of novel homozygous nonsense SLC10A7 variant causing short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis and surgical management of spine.

BACKGROUND: Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis is a rare, autosomal recessive, skeletal disorder first described in 2018. This syndrome starts with pre- and postnatal developmental delay, and gradually presents with variable facial dysmorphisms, a short stature, amelogenesis imperfecta, and progressive skeletal dysplasia affecting the limbs, joints, hands, feet, and spine. CASE PRESENTATION: We identified a homozygous novel nonsense mutation in exon 1 of SLC10A7 (NM_001300842.2: c.100G > T / p.Gly34*) segregating with the typical disease phenotype in a Han Chinese family. We reviewed the 12-year surgical treatment history with seven interventions on spine. CONCLUSION: To date, only 12 cases of the SLC10A7 mutation have been reported, mainly from consanguineous families. Our patient showed a relatively severe and broad clinical phenotype compared with previously reported cases. In this patient, annual check-ups and timely surgeries led to a good outcome.

Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors.

Inhibition of methionine adenosyltransferase 2A (MAT2A) has received significant interest because of its implication as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers. Here, we report the discovery of a series of 3H-pyrido[1,2-c]pyrimidin-3-one derivatives as novel MAT2A inhibitors. The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.

Protective effect of electroacupuncture at ST36 against damage of intestinal mucosa, oxidative stress and apoptosis induced by 5-FU chemotherapy in mice with colon cancer. / 电针"足三里"å‡è½»å¤§è‚ ç™Œå°é¼ åŒ–ç–—åŽè‚ é»è†œæŸä¼¤åŠå ¶å¯¹æ°§åŒ–åº”æ¿€å’Œç»†èƒžå‡‹äº¡çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) on intestinal mucosal damage, intestinal mucosal oxidative stress injury and apoptosis induced by 5-fluorouraeil (5-FU) chemotherapy in colorectal cancer-bearing mice. METHODS: Thirty male BALB/c mice were randomly divided into normal control, colorectal cancer (CT26), 5-FU, non-acupoint and ST36 groups, with 6 mice in each group. Except for those of the normal control group, mice of the remaining 4 groups received subcutaneous implantation of colorectal CT26 cell suspension (0.1 mL) in the right armpit for establishing colorectal cancer model. Rats of the 5-FU group, non-acupoint group and ST36 group were given with 5 mg/mL 5-FU solution once every 3 days for a total of 21 days. For mice of the non-acupoint group and ST36 group, EA (2 Hz, 1-2 mA) was applied to bilateral ST36 or non-acupoints (the bilateral sunken spots about 3 mm to the midpoint between the tail root and the anus) for 5 min after each intraperitoneal infusion of 5-FU, once every 3 days, for a total of 21 days. After the intervention, the diarrhea index was assessed. The length of colon (from the endpoint of cecum to the anal orifice) was measured. Histopathological changes of colonic mucosa were observed by H.E. staining, and the length of colonic villi was measured. The content of malondialdehyde (MDA), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) of colonic tissue were detected by thibabituric acid, xanthine oxidase and colorimetric method, respectively. The rate of cell apoptosis in the colonic tissue was measured by TUNEL assay. The positive expressions of Bax and Bcl-2 in colonic tissue were determined by immunohistochemistry. RESULTS: The CT26 model group didn't show any significant changes in the diarrhea index, colon length, colon villus length, MDA content, SOD and GSH-Px activities, colonic cell apoptosis rate, and Bax and Bcl-2 expression levels when compared with the normal group. Compared with the CT26 group, the 5-FU group had a remarkable increase in the diarrhea index, MDA content, colonic cell apoptosis rate and Bax expression level (P<0.01, P<0.05), and a marked decrease in the colon length, colon villus length, SOD and GSH-Px activities and Bcl-2 expression level (P<0.01), suggesting the side effects of administration of 5-FU. Compared with the 5-FU group, the diarrhea index, MDA content, colonic cell apoptosis rate and Bax expression level were markedly decreased (P<0.05, P<0.01) and those of the colon length, colon villus length, SOD and GSH-Px activities and Bcl-2 expression level were obviously increased (P<0.01) in the ST36 group. Compared with the 5-FU group, the non-acupoint group also had an increase in the colon villus length, SOD and GSH-Px activities (P<0.01, P<0.05) and a decrease in the cell apoptosis rate (P<0.01). CONCLUSIONS: EA at ST36 has a positive effect in reducing intestinal mucosal damage induced by 5-FU chemotherapy in cancer-bearing mice, which may be related to its function in relieving oxidative stress injury and inhibiting apoptosis of colonic tissue.

Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells.

ERα (estrogen receptor-α)-targeting PROTACs (PROteolysis TArgeting Chimeras) have emerged as a novel and promising modality for breast cancer therapeutics. However, ERα PROTACs-induced degradation in normal tissues raises concerns about potential off-tissue toxicity. Tumor microenvironment-responsive strategy provides potential for specific control of the PROTAC's on-target degradation activity. The glutathione (GSH) level has been reported to be significantly increased in tumor cells. Here, we designed a GSH-responsive ERα PROTAC, which is generated by conjugating an o-nitrobenzenesulfonyl group to the hydroxyl group of VHL-based ERα PROTAC through a nucleophilic substitution reaction. The o-nitrobenzenesulfonyl group as a protecting group blocks the bioactivity of ERα PROTAC (ER-P1), and that can be specifically recognized and removed by highly abundant GSH in cancer cells. Consequently, the GSH-responsive ERα PROTAC (GSH-ER-P1) exhibits significantly enhanced degradation of ERα in cancer cells compared to that in normal cells, leading to a remarkable inhibition of breast cancer cell proliferation and less toxic effects on normal cells. This study provides a potentially valuable strategy for breast cancer treatment using tumor microenvironment-responsive PROTACs.

Association between radiotherapy and prognosis in patients with small cell carcinoma of the bladder undergoing bladder-sparing surgery.

Background: Small cell carcinoma of the bladder is rare and has a poor prognosis. This study aimed to investigate whether radiotherapy after bladder-sparing surgery could improve the survival benefits of patients. Methods: This population-based retrospective cohort study used data from the Surveillance, Epidemiology, and End Results cohort in the United States to investigate small cell carcinoma of the bladder. Univariate and multivariate Cox regression analyses were used to identify significant risk factors influencing the clinical prognosis. A propensity score matching (PSM) algorithm was used to reduce the interference of confounding factors in each study group. The matched groups underwent Kaplan-Meier survival analysis to assess the potential survival benefits. Results: Univariate regression analysis demonstrated that age (P<0.001), tumour stage (T stage) (P=0.005), node stage (N stage) (P<0.001), chemotherapy (P<0.001), bone metastasis (P<0.001), liver metastasis (P<0.001), lung metastasis (P=0.005), tumour size (P=0.005), and radiotherapy (P<0.001) were related factors affecting survival. Multivariate regression analysis revealed that age (P=0.001), T stage (P=0.054), N stage (P<0.001), radiotherapy (P=0.010), chemotherapy (P<0.001), bone metastasis (P=0.007), and liver metastasis (P<0.001) were independent factors affecting survival. Moreover, survival analysis was performed on the PSM-matched groups, leading to the following findings: (1) the radiotherapy group exhibited a superior survival prognosis compared with the non-radiotherapy group (P<0.001); (2) the survival prognosis of individuals who underwent radiotherapy and chemotherapy was higher than that of those who underwent chemotherapy alone (P<0.001). Conclusion: The findings of this study suggest that radiotherapy improves survival benefits for patients with small cell carcinoma of the bladder who undergo bladder-sparing surgery. Furthermore, radiotherapy combined with chemotherapy demonstrates a greater survival benefit compared with chemotherapy alone. The results underscore the importance of considering radiotherapy as a valuable treatment option for such patients, highlighting its potential benefits in improving their overall prognosis.

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

Scoliosis risk factors and outcomes in children with dysplastic spondylolisthesis undergoing surgical reduction and fixation.

Purpose: To explore scoliosis risk factors and outcomes in children with dysplastic spondylolisthesis undergoing surgical reduction and internal fixation. Methods: We retrospectively analyzed 56 children with dysplastic spondylolisthesis who underwent surgical reduction and internal fixation. Patients were grouped according to presence of scoliosis before surgery. Radiographic parameters measured before surgery included pelvic incidence, pelvic tilt, sacral slope, coronal Cobb angle, slip percentage, Dubousset's lumbosacral angle, lumbar lordosis, sagittal vertical axis, and Spinal Deformity Study Group index. Groups were compared using logistic regression. Receiver operating characteristic analysis was performed to determine the optimal Spinal Deformity Study Group index cut-off value. All patients were followed up for at least 2 years. Results: The scoliosis group comprises 36 patients (mean age: 9.6 ± 2.7 years), while the no scoliosis group comprises 20 (mean age: 9.1 ± 2.4 years). Slip percentage and Spinal Deformity Study Group index were significantly higher in the scoliosis group (p < 0.01). Sacral slope and pelvic incidence were lower in the scoliosis group (p < 0.05). Univariate logistic regression analysis showed that slip percentage, Spinal Deformity Study Group index, pelvic incidence, and sacral slope were significantly associated with scoliosis. In the multivariate logistic regression analysis, only Spinal Deformity Study Group index was an independent risk factor for scoliosis. The optimal cut-off value for Spinal Deformity Study Group index was 0.288. Mean Cobb angle decreased from 20.3° ± 8.8° before surgery to 8.5° ± 8.9° at last follow-up; the mean scoliosis correction rate was 59.3%. Conclusion: Severe S1 dysplasia and high slip percentage may be risk factors for developing scoliosis in patients with dysplastic spondylolisthesis. Scoliosis resolved spontaneously after spondylolisthesis reduction and fixation in most patients. Level of evidence: 3.

Impact of Early Natural Killer Cell Reconstitution on the Outcomes of T Cell-Replete Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Early immune reconstitution is crucial to successful outcomes after allogeneic stem cell transplantation (allo-HSCT). However, in T cell-replete HSCT, the impact of natural killer (NK) cells on transplantation outcome and the factors influencing early NK cell reconstitution remain unclear. Methods: In this retrospective study, we analyzed 128 patients with hematological malignancies who received the first T cell-replete allo-HSCT between May 2019 and September 2021. After application of a conditioning regimen, prophylaxis for graft versus host disease (GVHD), and engraftment, the patients received prevention and treatment procedures for cytomegalovirus (CMV) reactivation. NK cells, T lymphocytes and B lymphocytes in peripheral blood were collected and analyzed at 30, 60, 90, 135 and 180 days after transplantation to observe immune cell reconstitution. Overall survival (OS), relapse-free survival (RFS), minimal residual disease (MRD), relapse, and non-relapse mortality (NRM) were evaluated. SPSS 25.0 and R version 4.2.1 were used for statistical analysis. Results: In patients with rapid NK recovery (NK cell count at 30 days post-HSCT [NK30] >165/µL and 60 days post-HSCT [NK60] >265/µL), we observed lower rates of NRM, CMV reactivation and acute GVHD (aGVHD). Multivariate analysis indicated that a lower NK30 (≤165/µL) was an independent factor associated with inferior OS and RFS. The NK30 and NK60 in patients with CMV reactivation and aGVHD after transplantation were significantly lower than those in patients without these complications. In addition, CD107a expression in NK cells was also significantly lower in patients who experienced aGVHD. Correlation analysis did not find an inhibitory effect of T-lymphocyte subset reconstitution on NK cells in the early stage after transplantation. Conclusion: Rapid NK cell reconstitution early after allo-HSCT had protective effects on NRM and survival. Promoting early NK cell reconstitution represents a new approach to improving the outcomes of allo-HSCT.