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Abstract This was a multicenter, single-arm, open-label, phase Ib/II study (NCT04255576), aimed to evaluate the efficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone (GCTB). JMT103 (2 mg/kg) was administered subcutaneously every four weeks, with loading doses on days 8 and 15. The primary endpoint was the objective tumor response rate (OTR) based on best response, defined as the proportion of patients who achieved elimination of at least 90% of the giant cells or radiologic complete or partial response per the modified Inverse Choi density/size (mICDS) or modified European Organization for Research and Treatment of Cancer (mEORTC) within 12 weeks. Secondary endpoints included objective response rate (ORR) per mICDS and mEORTC, and safety. A total of 139 patients were enrolled, and 135 were analyzed for efficacy. OTR, determined by the independent review committee (IRC) was 93.3% (95% CI 87.7-96.9). Treatment-related adverse events occurred in 90 (64.7%) patients, with hypophosphatemia and hypocalcemia being the most common. No serious treatment-related adverse events were observed. Thus, JMT103 demonstrates potential as a therapeutic option for GCTB.

Abstract While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

Background: As the most common primary malignant bone tumor in children and adolescents, osteosarcoma currently lacks an effective clinical cure. Focal adhesion plays a crucial role in tumor invasion, migration, and drug resistance by mediating communication between the extracellular matrix and tumor cells. This study investigated the prognostic features and immunotherapeutic relevance of focal adhesion pathway-related genes in osteosarcoma to aid in the development of new therapeutic options. Methods: We obtained mutational, transcriptomic, gene expression, and clinical data of osteosarcoma patients from the Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective (TARGET) databases. Differentially expressed genes were screened, followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Kaplan-Meier survival analysis was performed for genes related to the focal adhesion pathway, and multivariate Cox regression analysis was employed to construct a prognostic signature model. Genes such as SIGLEC15, TIGIT, CD274, HAVCR2, PDCD1, CTLA4, and LAG3 were extracted from the TARGET and CCLE databases for osteosarcoma patients and osteosarcoma cell lines, respectively，to observe the expression of immune checkpoint-related genes. Finally, qRT-PCR was used to verify the expression of these immune checkpoint-related genes in osteosarcoma cell lines. Results: In our study, 376 samples were analyzed, including 369 osteosarcoma samples and 7 normal tissue samples. We identified 50 up-regulated and 28 down-regulated differentially expressed genes. Among these, 10 Candidate genes relative to focal Adhesion were selected， and CAV1, ZYX, and ITGA5 were found to have a significant prognostic role based on survival analysis of osteosarcoma samples from the TARGET database. A predictive signature model related to the focal adhesion signaling pathway was constructed using these genes, and the AUCs of the 1-year, 3-year, and 5-year ROC curves were 0. 647, 0. 712, and 0. 717, respectively. The overall survival (OS) rate of osteosarcoma patients with high-risk scores was poorer than those with low-risk scores. Then, samples were divided into two subgroups based on the expression of the three genes, revealing significant differences in the expression of certain immune checkpoint-related genes between the subgroups. Additionally, above three genes and immune checkpoint-related genes in osteosarcoma cell lines were extracted from the CCLE database, showing high expression levels in eight osteosarcoma cell lines. We observed that CD274 and PDCD1LG2 were highly expressed in some osteosarcoma cell lines. Finally, the expression of CAV1, ZYX, ITGA5, CD80, CD274, and PDCD1LG2 in osteosarcoma cell lines was verified by qRT-PCR. Conclusions: Our study validated the prognostic role of three focal adhesion pathway-related genes (ZYX, CAV1, and ITGA5) in patients with osteosarcoma and constructed a prognostic signature model associated with the focal adhesion signaling pathway. We identified significant differences in the expression of multiple immune checkpoint-related genes among subgroups defined by the three genes. Additionally, CD274 and PDCD1LG2 showed higher expression in osteosarcoma cell lines characterized by these genes. These findings may aid in the selection of effective immunotherapy for specific osteosarcoma patients.

Abstract Background As the lethal bone tumor, osteosarcoma often frequently occurs in children and adolescents with locally destructive and high metastasis. Distinctive kinds of nanoplatform with high therapeutical effect and precise diagnosis for osteosarcoma are urgently required. Multimodal optical imaging and programmed treatment, including synergistic photothermal-chemodynamic therapy (PTT-CDT) elicits immunogenetic cell death (ICD) is a promising strategy that possesses high bio-imaging sensitivity for accurate osteosarcoma delineating as well as appreciable therapeutic efficacy with ignorable side-effects. Methods and results In this study, mesoporous Cu and Ce based oxide nanoplatform with Arg-Gly-Asp (RGD) anchoring is designed and successfully constructed. After loading with indocyanine green, this nanoplatform can be utilized for precisely targeting and efficaciously ablating against osteosarcoma via PTT boosted CDT and the closely following ICD stimulation both in vitro and in vivo. Besides, it provides off-peak fluorescence bio-imaging in the second window of near-infrared region (NIR II, 1000-1700 nm) and Magnetic resonance signal, serves as the dual-mode contrast agents for osteosarcoma tissue discrimination. Conclusion Tumor targeted Cu&Ce based mesoporous nanoplatform permits efficient osteosarcoma suppression and dual-mode bio-imaging that opens new possibility for effectively diagnosing and inhibiting the clinical malignant osteosarcoma.

Abstract Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47 + T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.

Abstract Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell‐derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non‐small cell lung cancer (NSCLC) cells, a hypoxia‐induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1‐eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1‐targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA‐mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.

Beta-Parvin (PARVB) is an actin-binding protein with functionality in extracellular matrix binding. Recent studies suggest its potential as a biomarker for various cancers, given its role in governing several malignancies. Yet, its involvement and modulatory mechanisms in malignant melanoma remain under-explored. In this research, we undertook a comprehensive pan-cancer analysis centered on PARVB. We probed its aberrant expression and prognostic implications, and assessed correlations between PARVB expression and immunocyte infiltration. This expression was subsequently corroborated using clinical samples. Both in vitro and in vivo, we discerned the functional ramifications of PARVB on melanoma. Furthermore, we scrutinized how HIF-1α/2α modulates PARVB and initiated a preliminary investigation into potential downstream pathways influenced by PARVB. Our results illuminate that elevated PARVB expression manifests across various tumors and significantly influences the prognosis of multiple cancers, emphasizing its peculiar expression and prognostic relevance in melanoma. Augmented PARVB levels were inversely proportional to immunocyte penetration in melanoma. Silencing PARVB curtailed cellular proliferation, migration, and invasion in vitro and decelerated tumor expansion in vivo. Notably, hypoxic conditions, triggering HIF-1α/2α activation, appear to elevate PARVB expression by anchoring to the hypoxia-specific responsive element within the PARVB promoter. Enhanced PARVB levels seem intertwined with the activation of cellular proliferation circuits and the damping of inflammatory trajectories. Collectively, these revelations posit PARVB as a potential prognostic indicator and therapeutic linchpin for malignant melanoma.

Abstract Introduction Soft tissue metastasis (STM) of cancers, encompassing skeletal muscle and subcutaneous tissue metastasis, is less common due to unique homeostatic conditions. With longer life expectancy and the advent of new imaging modalities, clinical physicians will increasingly encounter and manage such cases. This study retrospectively reviewed cases of STM in visceral cancers who underwent surgery at Fudan University Shanghai Cancer Center over a 7‐year period. Methods Data were collected through a comprehensive review of medical records, including demographic variables, primary tumor characteristics, surgical data, tumor pathology, and outcomes. Survival analysis was performed using Kaplan–Meier curves. Results The study included 77 cases with a median follow‐up period of 854 days. The most common primary tumor sites were the lung (11) and breast (10). The abdominal wall was the most frequent site of metastasis. The combination of visceral metastasis, age over 52 years, and a history of primary tumor correlates with a poorer prognosis. Surgical‐related metastases are associated with a higher degree of differentiation. Additionally, we have identified a better prognosis for patients with cancer of unknown primary (CUP) exhibiting potential resectable soft tissue metastases. Conclusion The combination of visceral metastasis, age over 52 years, and a history of primary tumor suggest a poorer prognosis. While no significant impact on survival was observed for patients with lymph node metastasis. Surgical‐related metastases are associated with a higher degree of differentiation. CUP patients with potentially resectable soft tissue metastases should be considered for surgical intervention.

Abstract Background Melanoma frequently harbors BRAF, NRAS, or KIT mutations which influence both tumor development and treatment strategies. For example, it is still controversial whether adjuvant anti‐PD‐1 monotherapy or BRAF/MEK inhibitors may better improve the survival for resected BRAF‐mutant melanoma. Furthermore, outcomes for melanoma with NRAS and KIT mutation receiving adjuvant immunotherapy remain unclear. Methods One hundred seventy‐four stage III melanoma patients who underwent radical surgery in Fudan University Shanghai Cancer Center (FUSCC) during January 2017 to December 2021 were included in this real‐world study. Patients were followed up until death or May 30th, 2022. Pearson's chi‐squared test or Fisher's exact test was performed for univariable analysis of the different category groups. Log‐rank analysis was used to identify the prognostic factors for disease‐free survival (DFS). Results There were 41 (23.6%) patients with BRAF mutation, 31 (17.8%) with NRAS mutation, 17 (9.8%) with KIT mutation, and 85 (48.9%) wild‐type patients without either genomic alteration of those three genes. Most ( n = 118, 67.8%) of them were acral melanoma, while 45 (25.9%) were cutaneous subtype, and 11 were (6.3%) primary unknown. Among them, 115 (66.1%) patients received pembrolizumab or toripalimab monotherapy as adjuvant therapy; 22 (12.6%) patients received high‐dose interferon (IFN), and 37 (21.3%) patients were just for observation. There was no statistical difference in clinicopathologic factors between anti‐PD‐1 group and IFN/OBS group. Of all the enrolled patients, anti‐PD‐1 group had a better DFS than IFN/OBS group ( p = 0.039). In anti‐PD‐1 group, patients with BRAF or NRAS mutations had poorer DFS than wild‐type group. No survival difference was found among patients harboring different gene mutations in IFN/OBS group. In wild‐type patients, anti‐PD‐1 group had a better DFS than IFN/OBS group ( p = 0.003), while no survival benefits were found for patients with BRAF, NRAS, or KIT mutations. Conclusion Although anti‐PD‐1 adjuvant therapy provides a better DFS in the general population and in wild‐type patients, patients with BRAF, KIT or, especially, NRAS mutation may not benefit further from immunotherapy than conventional IFN treatment or observation.

Abstract Background Sentinel lymph node biopsy (SLNB) helps to determine accurate pathological stages and facilitates strategies for regional disease control in melanoma. However, whether the number of biopsied sentinel lymph nodes (SLNs) influences the patients' survival is rarely investigated. Methods Acral or cutaneous melanoma patients with no history of nodal disease who received SLNB in Fudan University Shanghai Cancer Center (FUSCC) from January 1, 2017, to December 31, 2021 were retrospectively enrolled. Clinicopathological variables including Breslow index, ulceration, number of positive SLNs, SLN/non‐SLN status were analyzed. The pathologic nodal (pN) stage and pathological stage were defined. Results A total of 381 eligible patients were enrolled in this study, of whom 132 (34.7%) patients were diagnosed with SLN‐positive. The median number of biopsied SLNs was 2 (range: 1 to 20). Different numbers of biopsied SLNs did not influence the release‐free survival (RFS) of the general patients. However, patients with >2 SLNs had a longer RFS than those with 1–2 SLNs in T4, N1a group and those who rejected complete lymph node dissection (CLND). Conclusions In patients with T4 melanomas, N1a melanomas and those that did not undergo a CLND, the prognosis of those with three or more SLNs retrieved seemed to be improved.

Background: Osteosarcoma, the most common primary malignant bone tumor, is currently treated with surgery combined with chemotherapy, but the limited availability of targeted drugs contributes to a poor prognosis. Identifying effective therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. Methods: We screened the DepMap database to identify essential genes as potential therapeutic targets for osteosarcoma. Gene Set Enrichment Analysis (GSEA) was employed to elucidate the biological roles of these essential genes. Promising candidates were filtered through univariate and multivariate Cox analyses, as well as Kaplan-Meier survival analyses using the GSE21257-OSA and TARGET-OSA datasets. The functional role of the target gene was assessed through cell experiments. Additionally, an in situ nude mice model was established to observe the gene's function, and RNA sequencing was utilized to explore the underlying molecular mechanism. Results: A total of 934 essential genes were identified based on their effects (Chronos) using the DepMap database. These genes were primarily enriched in the ribosome pathway according to GSEA analysis. Among them, 195 genes were associated with the ribosome pathway. Rps28, Rps7, and Rps25 were validated as promising candidates following univariate and multivariate Cox analyses of the TARGET-OSA and GSE21257-OSA datasets. Kaplan-Meier survival analyses indicated Rps28 represented an especially promising target, with high expression correlating with poor prognosis. Knockdown of small ribosomal subunit protein eS28, the protein of Rps28, inhibited proliferation, migration, and invasion in both in vitro and in vivo experiments. Silencing RPS28 affected the MAPK signaling pathway in osteosarcoma. Conclusion: In summary, Rps28 has been identified as an essential gene for osteosarcoma cell survival and eS28 may serve as a potential vulnerability in osteosarcoma.

Abstract Background Visceral sarcoma is a rare malignancy with a poor prognosis. However, there is no recommended prognostic staging system for the malignant disease. Method We analyzed the data of patients diagnosed with primary soft tissue sarcoma (STS) of the abdomen and thoracic visceral organs between 2006 and 2017 at our hospital. Prognostic factors (size, tumor grade, and lymph node metastasis) were analyzed in our cohort (n = 203) and the SEER validation cohort (n = 5826). Results Tumor size, grade, and lymph node metastasis were important prognostic factors for visceral sarcoma in both our and the SEER cohorts. Based on these prognostic factors, we established a new staging system for visceral sarcoma, by which patients could be stratified into clinically meaningful and non‐overlapping stages in both our cohort and the SEER validation series. Moreover, the area under the curve (AUC) value of the staging system for 5‐year survival was 0.84 (95% CI: 0.78–0.89) in our series and 0.80 (95% CI: 0.79–0.81) in SEER series, respectively. In addition, compared with the widely used FIGO staging system for female genital sarcoma, the visceral sarcoma staging system could more effectively and reliably stratify patients into four different prognostic groups. Conclusions The visceral sarcoma staging system is applicable for STS of the abdomen and thoracic visceral organs and is better than the current FIGO staging system for female genital sarcoma and should be incorporated into the AJCC Cancer Staging Manual.

Abstract Background BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%–15% of acral or mucosal subtypes. Currently, immunotherapy with anti‐PD‐1 blockade and dual‐targeted therapy with Dabrafenib plus trametinib (D + T) target therapy have been approved as adjuvant therapies for Stage III melanoma with BRAF V600 mutation. According to their phase III clinical trials, 3‐year recurrence‐free survival (RFS) is around 60% for both types of treatment. However, early disease control was slightly more effective with targeted therapy than immunotherapy. With different drug approval deadlines in China, anti‐PD1 monotherapy, D + T combination, and Vemurafenib (V) monotherapy have all been used in real clinical practice as adjuvant settings for stage III BRAF‐mut melanoma in recent years. We conducted this retrospective study to evaluate the efficacy of different treatments in the Chinese melanoma population. Methods Patients who underwent radical surgery and were diagnosed as Stage III melanoma harboring BRAF V600 mutation by pathological report were retrospectively identified at Fudan University Shanghai Cancer Center from January 2017 to December 2021. Patients with mucosal melanoma, or with follow‐up of

Osteosarcoma (OS) is the third most common malignancy in adolescence. Currently, the treatments of OS confront great obstacles of tumor recurrence and critical bone defects after surgery, severely affecting the survival rates and living qualities of patients. Hence, it is urged to develop distinct biomaterials with both efficient tumor therapeutic and osteogenic functions. Although photothermal therapy (PTT) has aroused expanding interest, characterizing negligible invasiveness and high spatiotemporal adjustment, few studies discussed its drawbacks, such as thermal injury to adjacent normal tissue and exceeded laser power density, implying that focusing on sensitizing OS to PTT instead of simply elevating the laser power density may be a fresh way to enhance the PTT efficacy and attenuate the side/adverse effects. Herein, we successfully constructed 3D-printing silicene bioactive glass scaffolds with preferable PTT efficacy at the second near-infrared (NIR-II) biowindow and outstanding osteogenic biofunctions owing to the release of bioactive elements during degradation. Impressively, a histone demethylase inhibitor, IOX1, was introduced before PTT to sensitize OS to thermal therapy and minimize the side/adverse effects. This work offered a distinctive paradigm for optimizing the PTT efficacy of osteogenic scaffolds against OS with epigenetic modulation agents.

Background: Although there have been several risk factors reported for implant failure (IF), little consensus exists. Potential applicable measures to protect patients from IF are relatively few. This study aimed to discover new risk factors for IF and explore potential protective measures from IF after total spondylectomy for spinal tumors. Methods: A total of 145 patients undergoing total spondylectomy for thoracic and lumbar spinal tumors between 2010 and 2021 were included from three tertiary university hospitals. Patient demographic and surgical characteristics and follow-up outcomes were collected. Results: During a mean follow-up of 53.77 months (range, 12 to 149 months), 22 of 145 patients (15.17%) developed IF. Patients undergoing thoracolumbar junctional region (T12/L1) resection were more likely to develop IF compared to those undergoing surgery at other vertebral levels (HR = 21.622, 95% CI = 3.567–131.084, P = 0.001). Patients undergoing titanium mesh cage reconstruction were more likely to develop IF compared to patients undergoing expandable titanium cage reconstruction (HR = 8.315, 95% CI = 1.482–46.645, P = 0.016). Patients with bone cement augmentation around the cage were less likely to develop IF compared to those not receiving bone cement augmentation (HR = 0.015, 95% CI = 0.002–0.107, P

Abstract Background Fine‐needle aspiration (FNA) cytology is a rapid, inexpensive, and uncomplicated method. However, its role in the assessment of soft tissue lesions (STL) remains controversial, and its ability to guide surgical treatment remains unclear. This study investigated the positive predictive value (PPV) of FNA for detecting malignancy and its guiding role in the surgical treatment of STL. Methods We retrospectively reviewed 514 patients with STL who underwent preoperative FNA and surgical resection between March 2015 and August 2021. Imaging assessments confirmed that radical surgery was possible. The FNA results were compared with the final postoperative histopathology. Results Of the 514 patients with STL, 496 (mean age, 48.9 years; range, 21–91 years) were eligible for analysis, the male to female ratio was 111:100. According to the 496 FNA results, 90 (18.2%) were positive for malignancy, 84 (16.9%) were suspicious for malignancy, 80 (16.1%) were spindle cell present, and 242 (48.8%) were negative for malignant cells. Compared with postoperative histopathology, FNA correctly detected all 90 malignant lesions and 203 of the 242 benign lesions. A total of 39 false‐negative results were obtained. FNA showed an accuracy of 88.3%, sensitivity of 69.8%, specificity of 100%, negative predictive value (NPV) of 83.9%, and PPV of 100%. In the other seven validation cohorts (n = 1157), FNA had a consistently high PPV, with values all more than 93%. Conclusion Our results demonstrate that FNA has a high PPV for detecting malignancy. For patients with resectable lesions and malignant FNA, the core needle biopsy (CNB) step can be omitted with multidisciplinary evaluation, and subsequent radical surgery can be performed.

Abstract Objective S2‐alar‐iliac (S2AI) screw technique is widely used in spinal surgery, but it is rarely seen in the field of spinal tumors. The aim of the study is to report the preliminary outcomes of the freehand S2AI screw fixation after lumbosaral tumor resection. Methods The records of patients with lumbosacral tumor who underwent S2AI screw fixation between November 2016 to November 2020 at our center were reviewed retrospectively. Outcome measures included operative time, blood loss, complications, accuracy of screws, screw breach, and overall survival. Mean ± standard deviation or range was used to present continuous variables. Kaplan–Meier curve was used to present postoperative survival. Results A total of 23 patients were identified in this study, including 12 males and 11 females, with an average age of 47.3 ± 14.5 (range,15–73). The mean operation time was 224.6 ± 54.1 (range, 155–370 min). The average estimated blood loss was 1560.9 ± 887.0 (600–4000 ml). A total of 46 S2AI screws were implanted by freehand technique. CT scans showed three (6.5%) screws had penetrated the iliac cortex, indicating 93.5% implantation accuracy rate. No complications of iatrogenic neurovascular or visceral structure were observed. The average follow‐up time was 31.6 ± 15.3 months (range, 13–60 months). Two patients' postoperative plain radiography showed lucent zone around the screw. One patient underwent reoperation for wound delayed infection. At the latest follow‐up, eight patients had tumor‐free survival, 11 had survival with tumor, and four died of disease. Conclusion The freehand S2AI screw technique is reproducible, safe, and reliable in the management of lumbosacral spinal tumors.

Abstract Objective To investigate the clinical efficacy and safety of 3D printed artificial vertebral body for patients who underwent multilevel total en bloc spondylectomy (TES) and analyze whether it could reduce the incidence of implant subsidence. Methods This is a retrospective study. From January 2017 to May 2018, eight consecutive cases with spine tumor undergoing multilevel TES were analyzed. All patients underwent X‐ray and CT examinations to evaluate the stability of internal fixation during the postoperative follow‐up. Demographic, surgical details, clinical data, and perioperative complications was collected. Visual analog scale, Frankel score, and spinal instability neoplastic score (SINS) classification were also recorded. Results There were six cases of primary spinal tumor and two cases of metastatic spinal tumor. All patients achieved remarkable pain relief and improvement in neurological function. Five patients underwent operation through the posterior approach, one patient underwent operation through the anterior approach and the remaining two patients through a combined anterior and posterior approach. At the last follow‐up period, X‐rays showed that the 3D printed artificial vertebral body of all cases matched well, and the fixation was reliable. Hardware failure such as loosening, sinking, breaking, and displacement wasn't observed during the follow‐up period. Conclusion 3D printed customized artificial vertebral body can provide satisfying good clinical and radiological outcomes for patients who have undergone multilevel TES.

Understanding the mutation landscape of cancer may enable the development of more targeted therapies. Here, the authors sequence a panel of genes in a large Asian cohort and compare to American cohorts and find 64% of the Asian patients have actionable mutations.

Aims: Socioeconomic and racial disparities have been recognized as impacting the care of patients with cancer, however there are a lack of data examining the impact of these disparities on patients with bone sarcoma. The purpose of this study was to examine socioeconomic and racial disparities that impact the oncological outcomes of patients with bone sarcoma. Methods: We reviewed 4,739 patients diagnosed with primary bone sarcomas from the Surveillance, Epidemiology and End Results (SEER) registry between 2007 and 2015. We examined the impact of race and insurance status associated with the presence of metastatic disease at diagnosis, treatment outcome, and overall survival (OS). Results: Patients with Medicaid (odds ratio (OR) 1.41; 95% confidence interval (CI) 1.15 to 1.72) and uninsured patients (OR 1.90; 95% CI 1.26 to 2.86) had higher risks of metastatic disease at diagnosis compared to patients with health insurance. Compared to White patients, Black (OR 0.63, 95% CI 0.47 to 0.85) and Asian/Pacific Islander (OR 0.65, 95% CI 0.46 to 0.91) were less likely to undergo surgery. In addition, Black patients were less likely to receive chemotherapy (OR 0.67, 95% CI 0.49 to 0.91) compared to White patients. In patients with chondrosarcoma, those with Medicaid had worse OS compared to patients with insurance (hazard ratio (HR) 1.65, 95% CI 1.06 to 2.56). Conclusion: In patients with a bone sarcoma, the cancer stage at diagnosis varied based on insurance status, and racial disparities were identified in treatment. Further studies are needed to identify modifiable factors which can mitigate socioeconomic and racial disparities found in patients with bone sarcomas. Cite this article: Bone Joint Res 2022;11(5):278–291.

BackgroundGlioma is one of the most typical tumors in the central nervous system with a poor prognosis, and the optimal management strategy remains controversial. Lactate in the tumor microenvironment is known to promote cancer progression, but its impact on clinical outcomes of glioma is largely unknown.MethodsGlioma RNA-seq data were obtained from TCGA and GCGA databases. Lactate metabolism genes (LMGs) were then evaluated to construct an LMG model in glioma using Cox and LASSO regression. Immune cell infiltration, immune checkpoint gene expression, enriched pathways, genetic alteration, and drug sensitivity were compared within the risk subgroups. Based on the risk score and clinicopathological features, a nomogram was developed to predict prognosis in patients with glioma.ResultsFive genes (LDHA, LDHB, MRS2, SL16A1, and SL25A12) showed a good prognostic value and were used to construct an LMG-based risk score. This risk score was shown as an independent prognostic factor with good predictive power in both training and validation cohorts (p < 0.001). The LMG signature was found to be correlated with the expression of immune checkpoint genes and immune infiltration and could shape the tumor microenvironment. Genetic alteration, dysregulated metabolism, and tumorigenesis pathways could be the underlying contributing factors that affect LMG risk stratification. The patients with glioma in the LMG high-risk group showed high sensitivity to EGFR inhibitors. In addition, our nomogram model could effectively predict overall survival with an area under the curve value of 0.894.ConclusionWe explored the characteristics of LMGs in glioma and proposed an LMG-based signature. This prognostic model could predict the survival of patients with glioma and help clinical oncologists plan more individualized and effective therapeutic regimens.

Background: Langerhans cell histiocytosis (LCH) is a rare monoclonal histiocytic neoplasm. Little is known about clinical factors associated with LCH single- vs multi-system involvement at the time of diagnosis. Methods: Data on 1549 LCH patients diagnosed between years 2010 and 2018 were extracted from the Surveillance, Epidemiology and End Results Program. Patterns of single- vs multisystem involvement were examined using multivariable logistic regression analysis. Odd ratio (OR) and 95% confidence interval (CI) were reported. Results: 968 children and adolescents (0–19 years; median: 4 years) and 581 adults (≥20 years; median: 49 years) were included in the analysis. Multi-system LCH was reported for 30.9 % patients. Bone marrow (BM) (OR = 3.776; 95 %CI = 1.939–7.351; P

Abstract Burn injury is one of the potential causes of heterotopic ossification (HO), which is a rare but debilitating condition. The incidence ranges from 3.5 to 5.6 depending on body area. Burns that cover a larger percentage of the total body surface area (TBSA), require skin graft surgeries, or necessitate pulmonary intensive care are well-researched risk factors for HO. Since burns initiate such complex pathophysiological processes with a variety of molecular signal changes, it is essential to focus on HO in the specific context of burn injury to define best practices for its treatment. There are numerous key players in the pathways of burn-induced HO, including neutrophils, monocytes, transforming growth factor-β1-expressing macrophages and the adaptive immune system. The increased inflammation associated with burn injuries is also associated with pathway activation. Neurological and calcium-related contributions are also known. Endothelial-to-mesenchymal transition (EMT) and vascularization are known to play key roles in burn-induced HO, with hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) as potential initiators. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and radiotherapy are effective prophylaxes for HO. Limited joint motion, ankylosis and intolerable pain caused by burn-induced HO can be effectively tackled via surgery. Effective biomarkers for monitoring burn-induced HO occurrence and bio-prophylactic and bio-therapeutic strategies should be actively developed in the future.

Background: Synovial sarcoma (SS) is a rare and aggressive cancer that can come from distinct soft tissue types including muscle and ligaments. However, the transcriptomic landscape of SS is still poorly understood. This study aimed to systematically dissect the changes in SS transcriptome from different perspectives.Methods: We performed deep total RNA sequencing on ten paired Synovial sarcoma and tumor-adjacent tissues to systematically dissect the transcriptomic profile of SS in terms of gene expression, alternative splicing, gene fusion, and circular RNAs.Results: A total of 2,309 upregulated and 1,977 downregulated genes were identified between SS and tumor-adjacent tissues. Those upregulated genes could lead to the upregulation of the cell cycle, ribosome, and DNA replication pathways, while the downregulated genes may result in the downregulation of a set of metabolic biological processes and signaling pathways. Moreover, 2,511 genes (including 21 splicing factors) were differentially alternative spliced, indicating that the deregulation of alternative splicing could be one important factor that contributes to tumorigenesis. Additionally, we identified the known gene fusions of SS18-SSX1/SSX2 as well as 11 potentially novel gene fusions. Interestingly, 49 circular RNAs were differentially expressed and their parental genes could function in muscle contraction and muscle system processes.Conclusions: Collectively, our comprehensive dissection of the transcriptomic changes of SS from both transcriptional and post-transcriptional levels provides novel insights into the biology and underlying molecular mechanism of SS.

Abstract Background Lumbar degenerative spondylolisthesis (DS) has been a common disease that makes increasing patients to suffer from different degrees of low back pain and radicular symptoms. The Spinal Deformity Study Group (SDSG) and the Clinical and Radiographic Degenerative Spondylolisthesis (CARDS) systems are commonly used to classify the disease, and help to make a more detailed treatment plan. The objective of this study is to compare the reliability and reproducibility of SDSG and CARDS classifications, and to explore their clinical application value. Methods/design All 117 patients with L5/S1 lumbar DS were enrolled. Five experienced spine surgeons were selected to assess DS with SDSG and CARDS systems. Kappa (K) value was used to check the coefficient consistency for multi-factor and assess the inter- and intra-observer agreement. After 12 weeks, the analysis was repeated. Results The inter-observer reliability and intra-observer reproducibility of SDSG system were substantial with K values of 0.704 and 0.861, while those of CARDS system were substantial with values of 0.620 and 0.878. Conclusion SDSG system had better inter-observer reliability in comparison with CARDS system, and though CARDS system is more intuitive and simpler, it is more likely to produce deviations when using it. Both SDSG and CARDS systems show substantial agreement and have great significance in surgical strategy of L5/S1 lumbar DS, they can be widely used in clinical practice.

Melanoma is one of the most aggressive and heterogeneous life-threatening cancers. However, the heterogeneity of melanoma and its impact on clinical outcomes are largely unknown. In the present study, intra-tumoral heterogeneity of melanoma cell subpopulations was explored using public single-cell RNA sequencing data. Marker genes, transcription factor regulatory networks, and gene set enrichment analysis were further analyzed. Marker genes of each malignant cluster were screened to create a prognostic risk score, and a nomogram tool was further generated to predict the prognosis of melanoma patients. It was found that malignant cells were divided into six clusters by different marker genes and biological characteristics in which the cell cycling subset was significantly correlated with unfavorable clinical outcomes, and the Wnt signaling pathway-enriched subset may be correlated with the resistance to immunotherapy. Based on the malignant marker genes, melanoma patients in TCGA datasets were divided into three groups which had different survival rates and immune infiltration states. Five malignant cell markers (PSME2, ARID5A, SERPINE2, GPC3, and S100A11) were selected to generate a prognostic risk score. The risk score was associated with overall survival independent of routine clinicopathologic characteristics. The nomogram tool showed good performance with an area under the curve value of 0.802.

Abstract Background Whether non‐sentinel lymph node (SLN)‐positive melanoma patients can benefit from completion lymph node dissection (CLND) is still unclear. The current study was performed to identify the prognostic role of non‐SLN status in SLN‐positive melanoma and to investigate the predictive factors of non‐SLN metastasis in acral and cutaneous melanoma patients. Methods The records of 328 SLN‐positive melanoma patients who underwent radical surgery at four cancer centers from September 2009 to August 2017 were reviewed. Clinicopathological data including age, gender, Clark level, Breslow index, ulceration, the number of positive SLNs, non‐SLN status, and adjuvant therapy were included for survival analyses. Patients were followed up until death or June 30, 2019. Multivariable logistic regression modeling was performed to identify factors associated with non‐SLN positivity. Log‐rank analysis and Cox regression analysis were used to identify the prognostic factors for disease‐free survival (DFS) and overall survival (OS). Results Among all enrolled patients, 220 (67.1%) had acral melanoma and 108 (32.9%) had cutaneous melanoma. The 5‐year DFS and OS rate of the entire cohort was 31.5% and 54.1%, respectively. More than 1 positive SLNs were found in 123 (37.5%) patients. Positive non‐SLNs were found in 99 (30.2%) patients. Patients with positive non‐SLNs had significantly worse DFS and OS (log‐rank P

Abstract MicroRNAs (miRs) have shown tremendous potential to act as therapeutic targets for cancer treatment. In this context, the present study was designed to investigate the potential of miR-143 in the treatment of breast cancer. Results showed that miR-143 to be significantly (P

Osteosarcoma (OS) is the primary bone malignancy in children and adolescents, with a high incidence of lung metastasis and poor prognosis. Here, we report that growth hormone receptor (GHR) is overexpressed in OS samples compared with osteofibrous dysplasia. We subsequently demonstrated that GHR knockdown inhibited colony formation, promoted cell apoptosis and decreased the number of cells at G2/M phase in 143B and U2OS cells. Furthermore, knockdown of GHR inhibited tumor growth in vivo. Together, these findings indicate that GHR modulates cell proliferation and metastasis through the phosphoinositide 3‐kinase/AKT signaling pathway and may be suitable for use as a putative biomarker of OS.

Objective: To investigate risk factors of local recurrence of synovial sarcoma and the impact of local recurrence on survival.Methods: We retrospectively reviewed clinical data of patients with II to IIIB (AJCC8) synovial sarcoma who underwent surgery at our center between March 2005 and December 2016. Data relating clinicopathological factors, treatment and prognosis were collected. The impact of local recurrence on overall survival (OS), local recurrence-free survival (LRFS), and distant relapse-free survival (DRFS) were analyzed. The prognostic factors associated with local recurrence were also analyzed using Kaplan-Meier Curves and Cox regression analysis.Results: A total of 171 patients were included in this analysis. After a median follow-up of 48 months, 66 patients (38.6%) experienced local recurrence. The 5-year OS, LRFS, and DRFS rates of patients with local recurrence were 37.6, 6.1, and 24.1%, respectively. Multivariate analysis showed that larger initial tumors, multiple recurrences, positive resection margins, marginal resection, and lack of adjuvant therapy were associated with higher local recurrence.Conclusion: Local recurrence of synovial sarcoma is associated with distant metastasis and poor survival. Chemoradiation improves the prognosis of patients with local recurrence, in particular those for which recurrence occurs shortly after initial treatment.

ObjectivesMost non-metastatic cancer patients can harvest a preferable survival after surgical treatment, however, patients sometimes refuse the recommended cancer-directed surgery. It is necessary to uncover the factors associated with patent's decision in taking cancer surgery and explore racial/ethnic disparities in surgery refusal.MethodsBased on the Surveillance, Epidemiology and End Results (SEER)-18 program, we extracted data of non-metastatic cancer patients who didn't undergo surgery. Ten common solid cancers were selected. Four racial/ethnic categories were included: White, black, Hispanic, and Asian/Pacific Islander (API). Primary outcome was patient's refusal of surgery. Multivariable logistic regression models were used, with reported odds ratio (OR) and 95% confidence interval (CI).ResultsAmong 318,318 patients, the incidence of surgery refusal was 3.5%. Advanced age, female patients, earlier cancer stage, uninsured/Medicaid and unmarried patients were significantly associated with higher odds of surgery refusal. Black and API patients were more likely to refuse recommended surgery than white patients in overall cancer (black-white: adjusted OR, 1.18; 95% CI, 1.11–1.26; API-white: adjusted OR, 1.56; 95% CI, 1.41–1.72); those racial/ethnic disparities narrowed down after additionally adjusting for insurance type and marital status. In subgroup analysis, API-white disparities in surgery refusal widely existed in prostate, lung/bronchus, liver, and stomach cancers.ConclusionsPatient's socioeconomic conditions reflected by insurance type and marital status may play a key role in racial/ethnic disparities in surgery refusal. Oncological surgeons should fully consider the barriers behind patient's refusal of recommended surgery, thus promoting patient-doctor shared decision-making and guiding patients to the most appropriate therapy.

Objective: This study aimed to compare the outcomes between piecemeal spondylectomy and separation surgery for patients with spinal metastasis.Summary of Background Data: Piecemeal spondylectomy and separation surgery are two widely-used treatment options for spinal metastasis. However, no studies have compared the surgical outcomes between both treatment modalities.Methods: Patients with spinal metastasis who underwent piecemeal spondylectomy or separation surgery between August 2017 and April 2020 at our spine center were recruited. Demographic, preoperative, perioperative, and follow-up data were collected and analyzed. Kaplan–Meier analysis and the log-rank test were used to analyze overall survival (OS) and progression-free survival (PFS) in patients with spinal metastasis.Results: Overall, 26 patients were treated with piecemeal spondylectomy, and 29 underwent separation surgery with postoperative stereotactic radiosurgery. Both groups showed significant postoperative improvements in neurological status. The piecemeal spondylectomy group had significantly more blood loss (1784.62 ± 833.64 vs. 1165.52 ± 307.38 ml) and required longer operative time (4.76 ± 0.93 vs. 3.73 ± 1.15 h) than the separation surgery group. No significant difference in OS was found between the groups (P = 0.064); however, patients in the separation surgery group experienced less local recurrence than those in the piecemeal spondylectomy group (P = 0.0014). Notably, significant differences were detected in the development of complications between the groups (P = 0.029).Conclusion: Separation surgery led to less blood loss and reduced complications and had shorter operation time than piecemeal spondylectomy. Although no significant differences were found in OS between the groups, separation surgery was associated with better PFS compared with piecemeal spondylectomy. These findings suggest that separation surgery has some advantages over piecemeal spondylectomy for patients with spinal metastatic disease.

The use of adjuvant therapy has provided survival benefits in patients with advanced melanoma. This study aimed to explore the recurrence and prognosis of the PD-1 inhibitor, conventional interferon (IFN), or observation (OBS) on resected stage III acral and cutaneous melanoma patients through a retrospective analysis. Patients with resected stage III melanoma at Fudan University Shanghai Cancer Center from 2017 to 2021 were enrolled with all of their clinicopathologic characteristics collected. They were divided into three groups: PD-1 inhibitor, IFN, and OBS. Survival analyses were performed to indicate the significance of different adjuvant therapies. A total of 199 patients were enrolled (PD-1 n = 126; IFN n = 31; and OBS n = 42), with their median follow-up times being 21 months, 24 months, and 49 months, respectively. The PD-1 inhibitor significantly improved relapse-free survival (p = 0.027) and overall survival (p = 0.033) compared with conventional treatment (IFN+OBS). The superiority of the PD-1 inhibitor was witnessed in stage IIIC/D (p = 0.000) acral (p = 0.05) melanoma patients with ulceration (p = 0.011) or lymph node macrometastasis (p = 0.010). The PD-1 inhibitor significantly reduced local recurrence and systemic metastasis compared with conventional therapy (p = 0.002). In conclusion, adjuvant anti-PD-1 immunotherapy can achieve better survival outcomes in acral and cutaneous melanoma patients compared with conventional treatment, without considering adverse events. More clinical benefits were seen in later-stage acral melanoma patients with ulceration or lymph node macrometastasis.

The present study aimed to explore the prognostic value, function, and mechanism of CCNDBP1 in dedifferentiated liposarcoma (DDL). Immunohistochemistry staining was used to analyze the protein expression of CCNDBP1 in tissue specimens. After silencing CCNDBP1 in LPS853 and overexpressing CCNDBP1 in LPS510, CCK-8, clone formation, transwell migration, and invasion assays were used to detect cell proliferation, migration, and invasion ability. CCNDBP1-induced cell apoptosis was analyzed by flow cytometry. The altered expression of epithelial-mesenchymal transition (EMT)-related proteins were detected by Western blot. The methylation, gene expression, and clinical data of 58 samples with DDL were analyzed using the cancer genome atlas (TCGA) database. Low expression of CCNDBP1 was associated with a poor prognosis of patients with DDL and was considered an independent prognostic factor of the progression-free survival (PFS). CCNDBP1 significantly inhibited the clone formation, proliferation, migration, and invasion of cancer cells in vitro and promoted cancer cell apoptosis. CCNDBP1 could repress the pathological EMT, thereby inhibiting the malignant behaviors of DDL cells. The high degree of DNA methylation sites cg05194114 and cg22184989 could decrease the expression of CCNDBP1 and worsen the prognosis of DDL patients. This is the first study reporting that CCNDBP1 is a tumor suppressor gene of DDL and putative prognostic marker in DDL patients. CCNDBP1 might inhibit the ability of cell proliferation and invasion by repressing pathological EMT, and the expression of CCNDBP1 could be regulated by DNA methylation in DDL.

Background: Metaplastic or sarcomatoid carcinomas (MSCs) are rare epithelial malignancies with heterologous histological differentiation that can occur in different organs. The objective of the current study was to identify novel somatically mutated genes in MSCs from different organs.Methods: Whole-exome sequencing was performed in 16 paired MSCs originating from the breast (n = 10), esophagus (n = 3), lung (n = 2), and kidney (n = 1). In addition, we collected data on KMT2D mutations from eight independent cohorts (n = 195) diagnosed with MSCs derived from the breast (n = 83), liver (n = 8), esophagus (n = 15), lung (n = 10), and uterus or ovary (n = 79). The expression of KMT2D and its clinical significance were evaluated in our cohort.Results: The most frequently mutated genes were TP53 (13/16, 81%) and KMT2D (5/16,31%). We identified seven somatic KMT2D mutations in the exploratory cohort (n = 16 tumors), including three nonsense mutations, two frameshift indels, one missense mutation, and one splice site mutation. Interestingly, two patients showed double hits on KMT2D with nonsense mutations and frameshift indels. In the eight validation cohorts (n = 195), the average mutation rates for TP53 and KMT2D were 78% (152/195) and 13% (25/195), respectively. Two or more hits on KMT2D were also present in three validation cohorts. Furthermore, KMT2D mutations were associated with low expression of KMT2D, large tumor size and unfavorable prognosis.Conclusions: These findings provide clues for understanding the genetic basis of MSCs originating from different organs and implicate KMT2D alteration as a frequent pathogenic mutation, allowing provision of appropriate treatment for this rare malignant disease in the future.

3D-printed hemipelvic endoprosthesis is an emerging solution for personalized limb-salvage reconstruction after periacetabular tumor resection. Further clinical studies are still required to report its surgical characteristics, outcomes, benefits and drawbacks. Sixteen consecutive patients underwent periacetabular tumor wide resection and pelvic reconstruction with a 3D-printed hemipelvic endoprosthesis from 2018 to 2021. The surgical characteristics and outcomes are described. The mean follow-up duration was 17.75 months (range, 6 to 46 months). Five patients underwent surgery for type I + II resection and reconstruction, seven for type II + III resection and reconstruction, three for type II resection and reconstruction, and one for type I + II + IV resection and reconstruction. The incidence of postoperative complication was 12.5% (2/16) for deep venous thrombosis (DVT), 12.5% (2/16) for pneumonia, and 12.5% (2/16) for would deep or superficial infection. During follow-up, two patients (12.5%) suffered hip dislocation and underwent revision surgery. CT demonstrated an obvious prosthetic porous structure–bone fusion after follow-up of at least 6 months. At the final follow-up, 12 lived with no evidence of disease while four lived with disease; no patients experienced pain; and 15 had independent ambulation, with a mean Musculoskeletal Tumor Society (MSTS) score of 85.8% (range, 26.7% to 100%). 3D-printed hemipelvic endoprosthesis facilitates wide resection of periacetabular tumor and limb-salvage reconstruction, thus resulting in good oncological and functional outcomes. The custom-made nature is able to well mimic the skeletal anatomy and microstructure and promote osseointegration. Perioperative complications and rehabilitation exercise still need to be stressed for this engineering technology-assisted major orthopedic surgery.

Background/Aims: LncRNAs have been reported to be vital regulators of the progression of osteosarcoma, although the underlying mechanisms are not completely understood. Methods: The levels of MALAT1 and miR-129-5p expression were measured using qRT-PCR. Cell growth was determined using the CCK-8 and colony formation assays. Cell migration and invasion were detected using the wound healing and Transwell invasion assays, respectively. Tumor growth was determined with a xenograft model. Results: MALAT1 was significantly up-regulated in osteosarcoma tissues compared with adjacent non-tumor soft tissues. Overexpression of MALAT1 promoted osteosarcoma cell proliferation, migration, and invasion in vitro and enhanced tumor growth in a tumor xenograft mouse model. MALAT1 promoted osteosarcoma progression by modulating stem cell-like properties. Moreover, rescue experiment and luciferase reporter assay results indicated that MALAT1 modulates RET expression by sponging miR-129-5p in osteosarcomas. Furthermore, MALAT1 augmented the expression of downstream proteins of the RET-Akt pathway. MALAT1 was consistently significantly increased in osteosarcoma tissues and MALAT1 expression was positively correlated with tumor size and metastasis. High expression of MALAT1 was significantly associated with poor outcomes in patients with osteosarcomas. MALAT1 expression was positively related to RET and negatively related to miR-129-5p in osteosarcoma samples and xenograft tumors. MALAT1 functioned as an oncogenic lncRNA in osteosarcomas and was as an independent prognostic indicator. Conclusion: Our data revealed for the first time that MALAT1 increases stem cell-like properties by up-regulating RET via sponging miR-129-5p, and thus activates the PI3K-Akt signaling pathway and provides potential therapeutic targets for osteosarcoma treatment.