Survival and functional outcomes after hemiarthroplasty in children with proximal tibial osteosarcoma.

BACKGROUND: Treatment options for correcting limb-length discrepancy after limb-salvage reconstruction for proximal tibial osteosarcoma in children have several limitations. Therefore, we aimed to evaluate the feasibility, complications, prognosis, and clinical outcomes of reconstruction using hemiarthroplasty after tumor resection in pediatric patients with proximal tibial osteosarcoma. METHODS: We conducted a comprehensive retrospective analysis of the data of pediatric patients with osteosarcoma of the proximal tibia who underwent surgery between December 2008 and November 2018 at our center. We enrolled 49 consecutive patients who underwent hemiarthroplasty. The cruciate ligaments of all patients were reconstructed using special spacers, and the medial and lateral collateral ligaments of the knee and joint capsule were reconstructed using a mesh. Postoperatively, if the unequal length of both lower limbs exceeded 4 cm or knee instability occurred, a second-stage surgery was performed for limb lengthening and replacing the distal femoral prosthesis. We analyzed the oncological prognosis, complications of hemiarthroplasty, postoperative stability, and postoperative function. RESULTS: The follow-up period ranged between 11 and 159 months, with a median of 84 (62, 129) months. The overall 5-year survival rate was 83.2%. Thirty-nine patients survived at the end of the follow-up period with 34 prostheses (87.2%). The overall prosthesis survival rate was 87.4% after 5 years, indicating the long-term benefits of the procedure. Limb length was measured in 28 adult patients. The average limb-length discrepancy was 33 ± 15 mm with a median of 33 mm (21, 47); the femur and tibia caused a discrepancy of 8.5 ± 9.9 mm and 24.8 ± 15.5 mm, respectively. The patients had 30-135° of knee motion, with a mean of 82 ± 24°. The femoral tibial angle was greater on the affected side than on the healthy side, with a mean difference of 4.5°±3.6°. The Musculoskeletal Tumor Society (MSTS) score was 25 ± 3. Five patients underwent second-stage distal femoral prosthesis replacement, with mean MSTS scores of 24 ± 2 and 28 ± 1 before and after second-stage surgery, respectively. CONCLUSIONS: Hemiarthroplasty in children reduces limb-length discrepancy in adulthood by rebuilding cruciate ligaments, lateral collateral ligaments, and the joint capsule, thereby improving knee stability.

Structural characterization and immune activity evaluation of a polysaccharide from Lyophyllum Decastes.

An innovative acidic hydrolysate fingerprinting workflow was proposed for the characterization of Lyophyllum Decastes polysaccharide (LDP) by ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The crude polysaccharides were firstly separated and purified by using DE-52 column and the BRT GPC purification system, respectively. The molecular weight and monosaccharide content of homogeneous polysaccharides were ascertained by utilizing HPGPC and ion chromatography separately. Secondly, the linkage of LDP was identified by methylation analysis and 1D/2D NMR spectra. The UPLC-MS/MS was used to scan and identify the acidic hydrolysate products of LDP using the PGC column. The oligosaccharides were collected by chromatography and identified by mass spectrometry. Thirdly, the expression of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I was measured in order to assess the immunological activity of LDP. Besides, the targeted receptors identification of polysaccharides was performed by screening the expression of TLRs family protein. The results showed that oligosaccharide fragments with different molecular weights can be obtained by partial hydrolysis, which further verified that the structures of LDP polysaccharides was a 1-6-linked ß-glucan. Moreover, the LDP polysaccharide can up-regulate the content of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I and plays an important immunoregulation role through TLRs family.

Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy.

Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.

A new simple index for characterizing the labile heavy metal concentration in soil by diffusive gradients in thin films technique.

Diffusive gradients in thin films technique (DGT) is recognized as a more reliable method for determining labile heavy metal (HM) concentration in soil than traditional destructive methods. However, the current DGT measurement index, CDGT, theoretically underestimates the true labile concentration (Clabile) of HMs in soil and lacks direct comparability with the conventional soil HM content indices due to unit differences. Here, we proposed CDGT-W, a new simple index which is defined as the HM accumulation in the binding layer, normalized to the weight of soil (optimized water content = 100% of the maximum water holding capacity) filled in the open cavity-type DGT device over a specified deployment time (optimized time = 24 h). The procedure for measuring CDGT-W is analogous to that of CDGT but includes precise determination of water content (water/dry soil) and the mass of soil filled in the cavity. We conducted measurements of Cu, Pb, Cr(Ⅵ) and As(V) as CDGT-W, CDGT, solution concentration (Csoln), and CaCl2 extractable concentration (CCaCl2) on three soils with a diverse range of HM concentrations. CDGT-W showed significant linear correlations with all other tested indexes. The ratios of CDGT-W to CCaCl2 varied between 0.30 and 0.98 for all HM-soil combinations with only one exception, a range much greater than CDGT/Csoln (typically <0.1) but lower than 1. This suggested that CDGT-W may more accurately reflect Clabile than CDGT (theoretically underestimates Cliable) and CCaCl2(likely overestimates Cliable). Additionally, CDGT-W measurements for these four HMs exhibited a broad measure concentration range and a low detection limit (mg/kg level). Consequently, CDGT-W may offer a more reliable alternative to CDGT for characterizing Clabile in unsaturated soils.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity.

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor ECOG performance status with relapsed or refractory large B-cell lymphoma after 2 or more lines of prior therapy.

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

Structurally diverse deformed phenanthrenes from Strophioblachia fimbricalyx with cytotoxic activities by inducing cell apoptosis.

A group of phenanthrene derivatives with different deformed types, including four previously undescribed derivatives (1-4), an undescribed natural product (5) and five known compounds (6-10), were isolated from the leaves and stems of Strophioblachia fimbricalyx by molecular networking based on UPLC-MS/MS method. Their structures were established by 1D/2D NMR spectroscopy, HRESIMS, quantum chemistry calculation, and single crystal X-ray diffraction. In biogenic pathways, series of deformed phenanthrenes were all suspected to be derived from 6/6/6 tricyclic phenanthrenes with a gem-dimethyl unit in one ring as characteristic components of Strophioblachia. Fimbricalyxone (1) and trigoxyphin M (6) with a 6/6/5 tricyclic carbon skeleton were reported for the first time from the genus and fimbricalyxanhydride C (2) is the first example of anhydride type bearing a rare 8,9-oxycycle. All the isolates were evaluated for their cytotoxic activity against three tumor cell lines, and compounds 8 and 10 exhibited significant activity with IC50 values of 4.65-9.02 µM, and the structure-activity relationship of the deformed phenanthrenes was discussed. In addition, the X-ray structure of 8 and 10 and the antineoplastic activity of 10 are reported herein for the first time. Trigohowilol G (10) inhibiting the proliferation of A549 cells might be related to cell cycle distribution and the induction of S phase arrest, and it induced cell apoptosis through Bad/Bax/Cleaved PARP1 pathway.

An innovative staged prosthetic lengthening reconstruction strategy for osteosarcoma-related leg discrepancy.

Correction of leg length discrepancy (LLD) in skeletally mature patients with osteosarcoma was rarely reported and quite challenging. This study aimed to propose a treatment strategy of staged lengthening and reconstruction with a standard static prosthesis to address LLD and restore limb function. It also evaluated the effectiveness of the strategy in terms of leg lengthening, functional outcomes, and complications. The strategy for lengthening included three stages. In stage 1, the previous prosthesis was removed and an external fixator with a temporary rod-cement spacer was placed. In this stage, the external fixator was used to lengthen the limb to the appropriate length. In stage 2, the external fixator was removed and the old rod-cement spacer was replaced with a new one. In stage 3, the rod-cement spacer was removed and the standard static prosthesis was planted. Nine skeletally mature distal femoral osteosarcoma patients with unacceptable LLD were treated in our institution from 2019 to 2021. We performed a chart review on nine patients for the clinical and radiographic assessment of functional outcomes, LLD, and complications. The mean (range) leg lengthening was 7.3 cm (3.6-15.6). The mean (range) LLD of the lower limbs decreased from 7.6 cm (4.1-14.2) before the lengthening to 0.3 cm (- 0.3 to 2.1) at the final follow-up with statistical significance (P = 0.000). The mean (range) Musculoskeletal Tumor Society score improved from 30.3% (16.7%-53.3%) before the lengthening to 96.3% (86.7%-100%) at the final follow-up with statistical significance (P = 0.000). Three patients (33.3%) had a minor complication; none needed additional surgical intervention. In the short term, the current staged lengthening and reconstruction with standard static prosthesis provided satisfactory functional outcomes and LLD correction with few complications. The long-term effects of this method need further exploration.

Real-World Outcomes with Chimeric Antigen Receptor T Cell Therapies in Large B Cell Lymphoma: A Systematic Review and Meta-Analysis.

Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.

A comparative study of reconstruction modalities after knee joint-preserving tumor resection: reconstruction with a custom-made endoprosthesis versus reconstruction with a liquid nitrogen-inactivated autologous bone graft.

BACKGROUND: This study evaluated the feasibility, complications, graft survival rate, and clinical outcomes of joint-preserving resection using a custom-made endoprosthesis and liquid nitrogen-inactivated autologous bone graft reconstruction in patients with malignant bone tumors around the knee joint. METHODS: We retrospectively analyzed 23 consecutive patients who underwent joint preservation surgery between 2008 and 2018 at our center. The study cohort included 13 patients who underwent custom-made endoprosthesis reconstruction and 10 who underwent liquid nitrogen-inactivated autologous bone graft reconstruction. The resected bone length, distance between the resection line and the joint, intraoperative blood loss, operation time, complications, and MSTS were compared between the two groups. RESULTS: The median follow-up time was 68.5 months in the endoprosthesis group and 65.3 months in the inactivated autograft group. There were no significant differences in baseline characteristics, resected bone length, distance between the resection line and the joint, or intraoperative blood loss between the two groups. The operative time was longer in the inactivated bone graft group than in the endoprosthesis group (p < 0.001). The endoprosthesis group had more complications (six patients) and reoperations due to complications (five) than the inactivated autograft group (one), but there was no significant difference in the incidence of complications between the two groups (p = 0.158). The inactivated autograft group had one patient with type 1b complications, while the endoprosthesis group had one with type 1b complications, one with type 2b complications, and one with type 4a complications. One patient in the endoprosthesis group with type 5a complications experienced two soft tissue recurrences. The overall 5-year survival rate was 86.5% and the graft survival and final limb salvage rates were 100% in both groups. After the follow-up period, the mean MSTS scores were 91% ± 7% in the endoprosthesis group and 94% ± 6% in the inactivated autograft group, with no significant difference (p = 0.280). CONCLUSION: Joint-preserving resection is a reliable and effective tumor resection method that can achieve good postoperative function. There were no significant differences in the incidence of complications, overall survival rate, or graft survival rate between the two groups.

A Retrospective Observational Study on Disease Characteristics and Treatment Patterns of Giant Cell Tumor of the Bone in China.

Aims: Giant cell tumor of the bone (GCTB) is associated with considerable morbidity. As GCTB epidemiological data for China are limited, this study is aimed at describing the disease characteristics of GCTB in China and establishing the historical context for its treatment before recent advances in treatment options. Methods: The disease characteristics, treatment patterns, and local GCTB recurrence rate after primary surgery for GCTB were evaluated in this single-center, retrospective, noninterventional, observational study of patients treated for GCTB at Ji Shui Tan Hospital, Beijing, from 2009 to 2016 based on medical chart review. Patients with unmet need were defined as those whose surgical treatment was difficult or who had to undergo high-morbidity surgery. Results: Among the 668 patients with a primary GCTB diagnosis, 578 (86.5%) of target lesions were in the extremities, and 89 (13.3%) were in the pelvic or axial bone. Of these, 173 (25.9%) were characterized as having an unmet need. Almost all GCTB patients received surgical treatment at both primary diagnosis (666/668 (99.7%)) and last disease recurrence (196/200 (98.0%)). Additionally, about one-third of patients received nonsurgical treatment at primary diagnosis (205/668 (30.7%)) and disease recurrence (67/200 (33.5%)), with neoadjuvant therapy being the most common treatment. The rate of high-morbidity surgery increased for recurrent disease (65/200 (32.5%)) compared with primary diagnosis (111/668 (16.6%)). The 2-year cumulative incidence of postoperative disease recurrence was 29.2%, in line with rates observed in prior studies. Conclusion: As many patients with primary and recurrent disease received high-morbidity surgery, more effective treatments are needed.

GMRS Oncological Prosthesis with a Porous Coating Collar: A Good Option for Revision of Aseptic Loosening in the Lower Extremity.

BACKGROUND: Revisions for oncological prosthesis are especially challenging due to the limited bone quantity and poor quality that the patients still possess. The aims of this study were to ask (1) what is the cumulative survival of the Global Modular Replacement System (GMRS) prosthesis after revision? and (2) what are the long-term functional outcomes of these patients? METHODS: We retrospectively reviewed 16 patients who developed aseptic loosening of a lower extremity prosthesis. There were nine males and seven females with a mean age of 28 years (range, 14-55 years). The 5-year and 8-year survivorship of the prosthesis were calculated. Function outcome was evaluated according to the score of the Musculoskeletal Tumor Society (MSTS). RESULTS: At a mean of 90 months follow-up (range, 52-118 months), the cumulative survival of all revision prosthesis was 94% at both 5 and 8 years. There were two prosthesis failures including one infection and one repeated aseptic loosening. At the last follow-up, except for the infection case, 93.3% (14/15) of the patients did not develop repeated aseptic loosening. The mean MSTS score was 27.7 (range, 24-30). CONCLUSIONS: GMRS prosthesis demonstrated significant satisfactory long-term outcomes for revisions of lower extremity oncological prosthesis.

Dioscin induces M1 macrophage polarization through Connexin-43 Channels in Tumor-associated-macrophages-mediated melanoma metastasis.

BACKGROUND: Tumor-associated macrophages (TAMs) are important constituent parts of tumor microenvironment that connected with tumor metastasis in melanoma. Connexin 43 (Cx43) was expressed in all the immune cells which modulated different aspects of immune response. However, the concrete molecular mechanism maintains unclear. PURPOSE: The study aimed to find a natural drug monomer effectively reversed the polarity of tumor-associated macrophages inhibiting melanoma metastasis and improving survival time. METHODS: Flow cytometry was used to determine the effects of dioscin on the macrophage phenotype. Western bolt and ELISA were performed to explore the underlying mechanism of dioscin and a co-culture experiment in vitro was applied to assess the role of dioscin on TAMs-mediated melanoma proliferation, invasion and migration. Moreover, in vivo melanoma metastasis models were established for examining effects of dioscin on TAMs-mediated melanoma metastasis. RESULTS: Dioscin repolarized macrophages from M2 towards M1-like phenotype. Dioscin suppressed M2-like phenotype macrophages through enhanced the expression and transport function of Cx43. Furthermore, the stimulation IFN-γ/STAT1 pathway and suppression IL-4/JAK2/STAT3 pathway were major mechanism of dioscin. Importantly, dioscin suppressed Cx43G21R mutation TAMs induced proliferation, invasion, migration and metastasis of melanoma cells. It worthily noting that dioscin ameliorated tumor-associated-macrophages-mediated melanoma metastasis in vitro and vivo. CONCLUSION: Dioscin re-polarized macrophages from M2 to M1 phenotype through activation of Cx43-gap-junction-intercellular-communications (Cx43-GJs)/IFN-γ/STAT1 pathway and inhibition of Cx43-GJs/IL-4/JAK2/STAT3 suppressing migration, invasion and metastasis of melanoma, which provided a theoretical and experimental basis for treating melanoma metastasis.

Inulin-type fructans obtained from Atractylodis Macrocephalae by water/alkali extraction and immunoregulatory evaluation.

Two homogenous polysaccharides extracted from Atractylodes macrocephala Koidz. were investigated by water extraction (AMP-FW) and alkali solution extraction (AMP-FA) after purification by anion exchange column and size exclusion chromatography. The molecular weight of AMP-FW and AMP-FA were 2874 Da and 3438 Da, respectively, estimated by high performance gel permeation chromatography (HPGPC). The monosaccharide compositions of AMP-FW and AMP-FA were glucose and fructose at a molar ratio of 0.11:0.89 determined by high performance anion exchange chromatography (HPAEC). The functional groups, glycosidic linkages and the chemical structure were characterized by FT-IR, GC-MS and NMR, which comprehensively indicated a similar inulin-type fructan structure of the two polysaccharides from A. macrocephala. However, the scanning electron microscopy (SEM) results showed different microstructures that irregular lamellar shape for the AMP-FW and spheroid shape for the AMP-FA. The further studies on immunomodulation showed that AMP-FW at 50 µg/mL could significantly (P < 0.05) stimulate RAW 264.7 cells by enhancing the mRNA expression of TNF-α and IL-1ß, which had a relative high immunomodulatory potential when compared to AMP-FA. Their activation on different toll-like receptors (TLR) also indicated their different roles in the immunoregulation. Overall, these findings reported here will serve as the basis for further structure-activity relationship studies.

Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance.

OBJECTIVE: The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection. DESIGN: We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice. RESULTS: The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment. CONCLUSIONS: Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.

Chinese expert consensus on the diagnosis and treatment of bone metastasis in lung cancer (2022 edition).

Lung cancer is the leading cause of cancer-related deaths worldwide. Bone is a common metastatic site of lung cancer, about 50% of bone metastatic patients will experience skeletal related events (SREs). SREs not only seriously impact the quality of life of patients, but also shorten their survival time. The treatment of bone metastasis requires multi-disciplinary therapy (MDT) and development of individualized treatment plan. In order to standardize the diagnosis and treatment of bone metastasis in lung cancer, the expert group of the MDT Committee of the Chinese Medical Doctor Association has developed the expert consensus on the diagnosis and treatment of lung cancer bone metastasis.

Expression and prognosis analysis of PAQR5 in kidney cancer.

Progestin and adipoQ receptor 5 (PAQR5) affects the development of various malignancies and is specifically expressed in kidney. However, the role of PAQR5 in renal carcinoma remains unclear. We assessed the state of PAQR5 expression in kidney renal clear cell carcinoma (KIRC) by The Cancer Genome Atlas and Gene Expression Omnibus datasets. Moreover, immunohistochemistry was performed to observe the expressions of PAQR5 protein in tumor tissues. The relationships between PAQR5 expression and clinical characteristics were investigated by UALCAN. Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter were used to analyze the effect of PAQR5 expression levels on overall survival and relapse-free survival (RFS). The re lationships between clinical characteristics and survival were also evaluated by univariate and multifactorial Cox regression. Gene Ontology term analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis were performed on PAQR5 to explain the enrichment pathways and functions. Protein and protein interactions were explained by GeneMANIA and STRING. We also explored the relevance of PAQR5 to tumor immune cell infiltration and immunomodulatory molecules by TIMER and GEPIA. Finally, we explored the correlation of PAQR5 with the pathway proteins STATs, HIF-1α, and mTOR using the GSE40435 dataset. PAQR5 expression was low in KIRC and correlated significantly with clinical characteristics including cancer stage, tumor grade, and nodal metastasis status. Low PAQR5 expression was significantly associated with poorer survival. Cox regression analysis indicated that upregulation of PAQR5 was an independent factor for a good prognosis of KIRC. PAQR5 downregulation was associated mainly with STAT3 target upregulation, tumorigenesis, and poor differentiation. PAQR5 expression also correlated positively with B cells, neutrophils, macrophages, and dendritic cells and negatively with the infiltration of FOXP3+ Treg cells and the immune checkpoint molecules PD-1, CTLA4, and LAG3. Moreover, PAQR5 expression in KIRC was negatively correlated with the pathway proteins STAT1/2/3/4/5A, HIF-1α, and mTOR. PAQR5 is an excellent predictor of KIRC prognosis and may be a potential molecular therapeutic target.

[Application of three-dimensional printing technology in treatment of limb bone tumors].

With the developing of three-dimensional (3D) printing technology, it is widely used in the treatment of bone tumors in the clinical orthopedics. Because of the great individual differences in the location of bone tumor, resection and reconstruction are difficult. Based on 3D printing technology, the 3D models can be prepared to show the anatomical part of the disease, so that the surgeons can create a patient-specific operational plans based on better understand the local conditions. At the same time, preoperative simulation can also be carried out for complex operations and patient-specific prostheses can be further designed and prepared according to the location and size of tumor, which may have more advantages in adaptability. In this paper, the domestic and international research progress of 3D printing technology in the treatment of limb bone tumors in recent years were reviewed and summarized.

Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States.

Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.