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BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Primárias Desconhecidas , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Primárias Desconhecidas/mortalidade , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gencitabina , Perfilação da Expressão Gênica , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Carboplatina/administração & dosagem , China , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Adulto Jovem , AdolescenteRESUMO
PURPOSE: Medulloblastoma is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. Recent transcriptional studies have shown that medulloblastomas comprise at least four molecular subgroups, each with distinct demographics, genetics, and clinical outcomes. Medulloblastoma subtyping has become critical for subgroup-specific therapies. The use of gene expression assays to determine the molecular subgroup of clinical specimens is a long-awaited application of molecular biology for this pediatric cancer. METHODS: In the current study, we established a medulloblastoma transcriptome database of 460 samples retrieved from three published datasets (GSE21140, GSE37382, and GSE37418). With this database, we identified a 23-gene signature that is significantly associated with the medulloblastoma subgroups and achieved a classification accuracy of 95.2%. RESULTS: The 23-gene signature was further validated in a long-term cohort of 142 Chinese medulloblastoma patients. The 23-gene signature classified 21 patients as WNT (15%), 41 as SHH (29%), 16 as Group 3 (11%), and 64 as Group 4 (45%). For patients of WNT, SHH, Group 3, and Group 4, 5-year overall-survival rate reached 80%, 62%, 27%, and 47%, respectively (p < 0.0001), meanwhile 5-year progression-free survival reached 80%, 52%, 27%, and 45%, respectively (p < 0.0001). Besides, SHH/TP53-mutant tumors were associated with worse prognosis compared with SHH/TP53 wild-type tumors and other subgroups. We demonstrated that subgroup assignments by the 23-gene signature and Northcott's NanoString assay were highly comparable with a concordance rate of 96.4%. CONCLUSIONS: In conclusion, we present a novel gene signature that is capable of accurately and reliably assigning FFPE medulloblastoma samples to their molecular subgroup, which may serve as an auxiliary tool for medulloblastoma subtyping in the clinic. Future incorporation of this gene signature into prospective clinical trials is warranted to further evaluate its clinical.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Humanos , Criança , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Transcriptoma/genética , Estudos Prospectivos , Neoplasias Cerebelares/genética , ChinaRESUMO
The advent of internet of things (IoT) technology has ushered in a new dawn for the digital realm, offering innovative avenues for real-time surveillance and assessment of the operational conditions of intricate mechanical systems. Nowadays, mechanical system monitoring technologies are extensively utilized in various sectors, such as rotating and reciprocating machinery, expansive bridges, and intricate aircraft. Nevertheless, in comparison to standard mechanical frameworks, large amusement facilities, which constitute the primary manned electromechanical installations in amusement parks and scenic locales, showcase a myriad of structural designs and multiple failure patterns. The predominant method for fault diagnosis still relies on offline manual evaluations and intermittent testing of vital elements. This practice heavily depends on the inspectors' expertise and proficiency for effective detection. Moreover, periodic inspections cannot provide immediate feedback on the safety status of crucial components, they lack preemptive warnings for potential malfunctions, and fail to elevate safety measures during equipment operation. Hence, developing an equipment monitoring system grounded in IoT technology and sensor networks is paramount, especially considering the structural nuances and risk profiles of large amusement facilities. This study aims to develop customized operational status monitoring sensors and an IoT platform for large roller coasters, encompassing the design and fabrication of sensors and IoT platforms and data acquisition and processing. The ultimate objective is to enable timely warnings when monitoring signals deviate from normal ranges or violate relevant standards, thereby facilitating the prompt identification of potential safety hazards and equipment faults.
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The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM). This study aimed to present an atlas of MM-TME in disease progression and explore TME-directed therapeutic strategies. We performed single-cell RNA sequencing (scRNAseq) in samples from different disease stages. We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments. We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8+ T cells and reprogramming of macrophages (MPs). The reprogrammed tumour-associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores. We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand-receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA-CD47 pathway suppressing phagocytosis and the CD74-MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes. We designed a dual-MP-targeted strategy by combining an anti-CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo. We drafted alterations in MM-TME during disease progression and unravelled TAM's reprogramming. The dual MP-targeted approach blocking both CD47 and MIF showed potent antitumour effects.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/patologia , Linfócitos T CD8-Positivos , Macrófagos/metabolismo , Fagocitose , Progressão da Doença , Microambiente TumoralRESUMO
BACKGROUND: Osteosarcoma (OS) is the most frequent and aggressive primary malignant sarcoma among adolescents and chemotherapy has not substantially progressed for decades. New insights into OS development and therapeutic strategies are urgently needed. METHODS: We analyzed integrated single-cell transcriptomes, bulk RNA-seq, and microarray data from Gene Expression Omnibus (GEO) datasets. We also used Weighted Gene Co-expression Network Analysis (WGCNA), Gene set enrichment analysis (GSEA), and Gene set variation analysis (GSVA), along with Simple ClinVar and Enrichr web servers. RESULTS: The findings of integrated single-cell analysis showed that OS arises from imperfect osteogenesis during development. Novel abnormalities comprised deficient TGFß and P53 signal pathways, and cell cycle pathway activation, and a potentially new driver mutation in the interferon induced transmembrane protein 5 (IFITM5) that might function as a pathogenic factor in OS. Osteosarcoma is characterized by oncocyte heterogeneity, especially in immunogenic and adipocyte-like subtypes that respectively promote and hamper OS treatment. Etoposide is a promising chemotherapeutic that provides palliation by affecting the subtype of OS and correcting the abnormal pathways. CONCLUSION: Various abnormal signal pathways play indispensable roles in OS development. We explored the heterogeneity and underlying mechanisms of OS and generated findings that will assist with OS assessment and selecting optimal therapies.
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Neoplasias Ósseas , Osteossarcoma , Sarcoma , Adolescente , Humanos , Neoplasias Ósseas/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Transdução de Sinais/genética , Sarcoma/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Although immune checkpoint blockade (ICB) therapy has brought survival benefits to patients with specific cancer types, most of cancer patients remain refractory to the ICB therapy, which is largely attributed to the immunosuppressive tumor microenvironment. Thereby, it is urgent to profile key molecules and signal pathways responsible for modification of tumor microenvironment. METHODS: Multiple databases of esophageal squamous cell carcinoma (ESCC) were integratively analyzed to screen candidate genes responsible for infiltration of CD8+ T cells. Expression of pescadillo ribosomal biogenesis factor 1 (PES1) in clinical ESCC samples was examined by qRT-PCR, western blotting, and immunohistochemistry. The mechanisms of PES1 were investigated via RNA sequencing and mass spectrometry followed by immunoprecipitation and proximity ligation assay. The clinical and therapeutic significance of PES1 in ESCC was comprehensively investigated using ESCC cells and mouse model. RESULTS: PES1 was significantly upregulated and correlated with poor prognosis in ESCC patients. PES1 knockdown decreased ESCC cell growth in vitro and in vivo and enhanced the efficacy of ICB therapy in mouse model, which was established through subcutaneous inoculation with ESCC cells. Analyses on RNA sequencing and mass spectrometry suggested that PES1 expression was negatively correlated with IL15 and ILF3 was one of the PES1-associated proteins. It has been known that ILF3 interacts with and stabilizes IL15 mRNA to increase IL15 protein level. Our data further indicated that PES1 interfered with the interaction between ILF3 and IL15 mRNA and impaired ILF3-mediated stabilization of IL15 mRNA, which eventually reduced the protein level of IL15. Interestingly, the inhibitory effect of ICB therapy boosted by PES1 knockdown dramatically antagonized by knockdown of IL15, which suppressed the tumor-infiltrated CD8+ T cells in ESCC. Finally, we confirmed the relationships among PES1, IL15, and CD8+ T cell infiltration in 10 locally advanced ESCC patients receiving ICB neoadjuvant therapy and demonstrated that ICB therapy would be more effective in those with low expression of PES1. CONCLUSIONS: Altogether, our findings herein provided novel insights on biological function and clinical significance of PES1 and suggested that high expression of PES1 could suppress ILF3-IL15 axis-mediated immunosurveillance and promote resistance to ICB through restraining tumor-infiltrated CD8+ T cells.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Camundongos , Linfócitos T CD8-Positivos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/terapia , Imunoterapia , Interleucina-15/farmacologia , Interleucina-15/uso terapêutico , Microambiente Tumoral , Proteínas de Ligação a RNA/metabolismo , Proteínas do Fator Nuclear 90/metabolismoRESUMO
BACKGROUND: Salvage esophagectomy, indicated for some patients with locally recurrent/persistent disease after definitive chemoradiotherapy (dCRT), reportedly has high postoperative complications. This study aims to compare the safety and efficacy of dCRT followed by salvage esophagectomy (DCRE) with planned esophagectomy after neoadjuvant chemoradiotherapy (NCRE) in esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively reviewed all locally advanced ESCC patients treated with DCRE or NCRE at Shanghai Chest Hospital from 2018 to 2021. Propensity score matching (PSM) was used to balance baseline differences. DCRE is defined as esophagectomy for recurrent/persistent disease after dCRT. RESULTS: A total of 302 patients (41 for DCRE and 261 for NCRE) were included. The median interval of chemoradiotherapy-to-surgery was 47d in NCRE, 43d and 440d in DCRE of persistent disease (n = 24) and recurrence (n = 17), respectively. DCRE was observed with advanced ypT stage (63% vs 38%), poorer differentiation (32% vs 15%) and more lymphovascular invasion (29% vs 11%) compared with NCRE (all p < 0.05). The above factors were comparable between the two groups after PSM (all p > 0.05). There were no significant differences before and after PSM in postoperative complications over Clavien-Dindo grade III (e.g., respiratory failure and anastomotic leak), 30/90-day postoperative mortality, and survival. CONCLUSION: Through a standardized surgical procedure in a high-volume center, DCRE exhibited comparable postoperative complications and prognosis with NCRE.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/cirurgia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Estudos Retrospectivos , Esofagectomia/métodos , Pontuação de Propensão , Terapia de Salvação/métodos , China , Quimiorradioterapia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Células Epiteliais/patologia , Resultado do TratamentoRESUMO
STUDY DESIGN: A Bayesian network meta-analysis. OBJECTIVE: Spinal cord injury (SCI) can profoundly influence human health and has been linked to lifelong disability. More high-level evidence-based medical research is expected to evaluate the value of stem cells and biomaterial scaffold material therapy for SCI. METHODS: We performed a comprehensive search of Web of Science, Cochrane databases, Embase, and PubMed databases. 18 randomized controlled trials including both scaffolds and BMSCs were included. We performed a Bayesian network meta-analysis to compare the motor functional recovery efficacy of different scaffolds with BMSCs in rat SCI. RESULTS: In our Bayesian network meta-analysis, the motor functional recovery was found to benefit from scaffolds, BMSCs, and BMSCs combined with scaffolds, but the scaffold and BMSC groups had similar motor functional recovery efficacy, and the BMSCs combined with scaffolds group appeared to show better efficacy than BMSCs and scaffolds alone. Subgroup analysis showed that BMSCs+fibrin, BMSCs+ASC, BMSCs+gelatine, and BMSCs+collagen were the best four treatments for SCI in rat models. CONCLUSIONS: These Bayesian network meta-analysis findings strongly indicated that BMSCs combined with scaffolds is more effective to improve motor functional recovery than BMSCs and scaffolds alone. The fibrin, gelatine, ASC, and collagen may be favourable scaffolds for the injured spinal cord and that scaffolds with BMSCs could be a promising option in regeneration therapy for patients with SCI.
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Transplante de Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Ratos , Humanos , Animais , Traumatismos da Medula Espinal/terapia , Ratos Sprague-Dawley , Teorema de Bayes , Metanálise em Rede , Medula Espinal , Colágeno/farmacologia , Recuperação de Função Fisiológica , Células da Medula ÓsseaRESUMO
Recent advances in roller coasters accelerate the creation of complex tracks to provide stimulation and excitement for humans. As the main load-bearing component, tracks are prone to damage such as loose connecting bolts, paint peeling, corroded sleeper welds, corroded butt welds, reduced track wall thickness and surface cracks under complex environments and long-term alternating loads. However, inspection of the roller coaster tracks, especially the high-altitude rolling tracks, is a crucial problem that traditional manual detection methods have difficulty solving. In addition, traditional inspection is labor-intensive, time-consuming, and provides only discrete information. Here, a concept of the multifunctional detection robot with a mechanical structure, electrical control system, camera, electromagnetic ultrasonic probes and an array of eddy current probes for detecting large roller coaster tracks is reported. By optimizing the design layout, integrating multiple systems and completing machine testing, the multifunctional roller coaster track detection robot exhibits outstanding performance in track appearance, thickness and crack detection. This study provides great potential for intelligent detection in amusement equipment, railcar, train and so on.
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OBJECTIVE: To compare perioperative and long-term outcomes of robot-assisted minimally invasive esophagectomy (RAMIE) and conventional minimally invasive esophagectomy (MIE) in the treatment for patients with esophageal squamous cell carcinoma (ESCC). SUMMARY BACKGROUND DATA: RAMIE has emerged as an alternative to traditional open or thoracoscopic approaches. Efficacy and safety of RAMIE and MIE in the surgical treatment for ESCC remains uncertain given the lack of high-level clinical evidence. METHODS: The RAMIE trial was designed as a prospective, multicenter, randomized, controlled clinical trial that compares the efficacy and safety of RAMIE and MIE in the treatment of resectable ESCC. From August 2017 to December 2019, eligible patients were randomly assigned to receive either RAMIE or MIE performed by experienced thoracic surgeons from 6 high-volume centers in China. Intent-to-treat analysis was performed. RESULTS: Significantly shorter operation time was taken in RAMIE (203.8 vs 244.9 min, P<0.001). Compared with MIE, RAMIE showed improved efficiency of thoracic lymph node dissection in patients who received neoadjuvant therapy (15 vs 12, P = 0.016), as well as higher achievement rate of lymph node dissection along the left recurrent laryngeal nerve (79.5% vs 67.6%, P = 0.001). No difference was found in blood loss, conversion rate, and R0 resection. The 90-day mortality was 0.6% in each group. Overall complications were similar in RAMIE (48.6%) compared with MIE (41.8%) (RR, 1.16; 95% CI, 0.92-1.46; P = 0.196). Besides, the rate of major complications (Clavien-Dindo classification ≥ III) was also comparable (12.2% vs 10.2%, P = 0.551). RAMIE showed similar incidences of pulmonary complications (13.8% vs 14.7%; P = 0.812), anastomotic leakage (12.2% vs 11.3%; P = 0.801), and vocal cord paralysis (32.6% vs 27.1%, P = 0.258) to MIE. CONCLUSIONS: Early results demonstrate that both RAMIE and MIE are safe and feasible for the treatment of ESCC. RAMIE can achieve shorter operative duration and better lymph node dissection in patients who received neoadjuvant therapy. Long-term results are pending for further follow-up investigations. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT03094351.
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Boehmeria , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Robótica , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia/métodos , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.
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Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço , Biomarcadores Tumorais/genética , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodosRESUMO
BACKGROUND: Preoperative chemoradiotherapy (CRT) with CROSS regimen has been the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The addition of programmed cell death protein 1 (PD-1) inhibitor to preoperative CRT may further improve oncologic results. Preoperative camrelizumab plus chemotherapy has been demonstrated as a promising treatment modality based on results of the phase II NICE study (ChiCTR1900026240). METHODS: The NICE-2 study is designed as a three-arm, multicenter, prospective, randomized, phase II clinical trial, comparing camrelizumab plus chemotherapy (IO-CT) and camrelizumab plus CRT (IO-CRT) versus CRT as preoperative treatment for locally advanced ESCC. A total of 204 patients will be recruited from 8 Chinese institutions within 1.5 years. The primary endpoint is pathological complete response (pCR) rate and secondary endpoints include event-free survival (EFS), R0 resection rate, and adverse events. DISCUSSION: This is the first prospective randomized controlled trial to explore commonly used neoadjuvant treatments in clinical practice, which will provide high-level evidence of neoadjuvant treatment for patients with locally advanced ESCC. The purpose of this study is to establish the optimal modality of IO-CT, IO-CRT and CRT as preoperative treatment for locally advanced ESCC. The Institution Review Committee approved this study protocol in August 2021 and patient enrollment was started in September 2021. TRIAL REGISTRATION: ClinicalTrial.gov: NCT05043688 (August 29, 2021). The trial was prospectively registered.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/métodos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Terapia Neoadjuvante , Estudos ProspectivosRESUMO
Multiple myeloma (MM) is an incurable plasma cell malignancy, and International Staging System (ISS) is used to predict the outcomes of MM patients. However, ISS stage is imperfect, and there might exist other factors correlated with prognosis of MM patients. Expression profiles and clinical information of 340 newly diagnosed MM patients from GEO database and 105 newly diagnosed MM patients from our hospital were analyzed, and LASSO regression was used to screen genes associated with both overall survival and progression-free survival of MM patients. Nomogram was constructed to predict outcomes of MM patients. Then, CCK8 and transwell assays were used to evaluate the proliferation and migration ability of MM cells; flow cytometry was performed to verify whether MM cells underwent necroptosis. Quantitative real-time PCR and western blot were performed to evaluate gene expressions. We found that KIAA1191 was associated with both overall survival and progression-free survival of MM patients. Furthermore, KIAA1191 high expression suppressed the proliferation and migration of MM cells; upregulated the expression of RIP1, RIP3, and CYLD, and restored the TNF-α/z-VAD-induced necroptosis. Besides, KIAA1191 overexpression had a synergistic effect with bortezomib on the proliferation capability of MM cells.
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Regulação Neoplásica da Expressão Gênica , Oxigenases de Função Mista/genética , Mieloma Múltiplo/genética , Necroptose , Movimento Celular , Proliferação de Células , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Prognóstico , Células Tumorais CultivadasRESUMO
BACKGROUND: This study aimed to identify the results of the quality assessment and the learning curve of robot-assisted minimally invasive McKeown esophagectomy (RAMIE-MK). METHODS: The study retrospectively reviewed the data of 400 consecutive patients with esophageal cancer who underwent RAMIE-MK by a single surgeon from November 2015 to March 2019. Cumulative summation analysis of the learning curve was performed. The patients were divided into decile cohorts of 40 cases to minimize demographic deviations and to maximize the power of detecting statistically significant changes in performance. RESULTS: The 90-day mortality rate for all the patients was 0.5% (2 cases). The authors' experience was divided into the ascending phase (40 cases), the plateau phase (175 cases), and the descending phase (185 cases). After 40 cases, significant improvements in operative time (328 vs. 251 min; P = 0.019), estimated blood loss (350 vs. 200 ml; P = 0.031), and conversion rates (12.5% vs. 2.5%; P < 0.001) were observed. After 80 cases, a decrease in the rates of anastomotic leakage (22.5% vs. 8.1%; P = 0.001) and vocal cord palsy (31.3% vs. 18.4%; P = 0.024) was observed. The number of harvested lymph nodes increased after 40 cases (13 vs. 23; P < 0.001), especially for lymph nodes along the recurrent laryngeal nerve (3.0 vs. 6.0; P < 0.001). CONCLUSIONS: The learning phase of RAMIE-MK consists of 40 cases, and quality outcomes can be improved after 80 procedures. Several turning points related to the optimization of surgical outcomes can be used as benchmarks for surgeons performing RAMIE-MK.
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Neoplasias Esofágicas , Procedimentos Cirúrgicos Robóticos , Robótica , Neoplasias Esofágicas/cirurgia , Esofagectomia , Humanos , Curva de Aprendizado , Estudos RetrospectivosRESUMO
BACKGROUND: The incidence of multiple primary malignant tumors (MPMTs) is rising due to the development of screening technologies, significant treatment advances and increased aging of the population. For patients with a prior cancer history, identifying the tumor origin of the second malignant lesion has important prognostic and therapeutic implications and still represents a difficult problem in clinical practice. METHODS: In this study, we evaluated the performance of a 90-gene expression assay and explored its potential diagnostic utility for MPMTs across a broad spectrum of tumor types. Thirty-five MPMT patients from Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University and Fudan University Shanghai Cancer Center were enrolled; 73 MPMT specimens met all quality control criteria and were analyzed by the 90-gene expression assay. RESULTS: For each clinical specimen, the tumor type predicted by the 90-gene expression assay was compared with its pathological diagnosis, with an overall accuracy of 93.2% (68 of 73, 95% confidence interval 0.84-0.97). For histopathological subgroup analysis, the 90-gene expression assay achieved an overall accuracy of 95.0% (38 of 40; 95% CI 0.82-0.99) for well-moderately differentiated tumors and 92.0% (23 of 25; 95% CI 0.82-0.99) for poorly or undifferentiated tumors, with no statistically significant difference (p-value > 0.5). For squamous cell carcinoma specimens, the overall accuracy of gene expression assay also reached 87.5% (7 of 8; 95% CI 0.47-0.99) for identifying the tumor origins. CONCLUSIONS: The 90-gene expression assay provides flexibility and accuracy in identifying the tumor origin of MPMTs. Future incorporation of the 90-gene expression assay in pathological diagnosis will assist oncologists in applying precise treatments, leading to improved care and outcomes for MPMT patients.
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Hydrophobic/oleophilic sponges are excellent absorbent materials for oil contaminant removal. However, the application is limited in dealing with surfactant stabilized O/W emulsions. The water in the emulsion isolates the contact between the sponge and oil droplets. Consequently, the oil absorption efficiency is not ideal. Herein, to improve the oil absorption efficiency from anionic surfactant stabilized O/W emulsions, water responsive hybrid sponges were reported. To prepare such sponges, water soluble poly(N,N-dimethylaminoethylmethacrylate) (PDMAEMA) was introduced into polydimethylsiloxane (PDMS) sponges using table salt as a template and multi-walled carbon nanotubes (MWCNTs) as mechanical reinforcement in a one-pot method. Upon contact with an O/W emulsion, the water soluble PDMAEMA chain rose to the surface of the sponge, turning the hydrophobic surface into hydrophilic. Next, the tertiary amine groups in PDMAEMA ionized in water and carried positive charges which would cause the coagulation of oil droplets. Finally, the coagulated oil droplets were absorbed immediately by the oleophilic inner part of the sponge through the wicking effect. As a result, a Janus interface was generated in situ and sustained. Such material design synergistically contributed to a satisfactory hexadecane (HD) absorption efficiency of 178 ± 4% in 25 min. In contrast, the PDMS-MWCNT1.0% sponge could only absorb 9.8 ± 0.2% HD. Moreover, these sponges also presented robust mechanical performance and reusability, offering a new route for oil/water separation and oil pollution remediation in open water.
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BACKGROUND: We analyzed the pathological characteristics and recurrence pattern of cN0 submucosal esophageal cancer after esophagectomy and conducted risk stratification to determine the feasibility of performing endoscopic resection for cN0pT1b esophageal squamous cell malignancies. METHODS: We retrospectively enrolled 167 patients who underwent right-sided transthoracic esophagectomy and extended thoracic/abdominal two-field lymphadenectomy. Patients with pathologically confirmed lymph node metastasis or tumor recurrence constituted the high-risk group for endoscopic submucosal resection, and the remainder were defined as low risk. Factors affecting lymphatic metastasis and long-term recurrence were identified by univariate and multivariate analyses. RESULTS: Postoperative pathology showed that five patients (5/167; 3%) had lymph node metastases. Follow-up ranged from 12-60 months, with a median of 29 months. A total of 17 patients (10.2%) had recurrences during follow-up, including three patients with pathologic nodal metastasis (pN +) found at surgery. Invasion depth, differentiation, and tumor size differed significantly in high-risk patients. Overall 3-year survival rates were 94.2% (low-risk) and 40.9% (high-risk) (p < 0.01). Twenty-one patients with sm1 cancer, high tumor differentiation, and tumor length < 2 cm had no lymph node metastasis or lymphovascular invasion, and none of these patients experienced recurrence. CONCLUSIONS: Endoscopic submucosal resection alone may be feasible for patients with small (≤ 2 cm) clinically N0 submucosal esophageal squamous cell carcinoma with low invasion depth (sm1) and higher differentiation, but prospective studies are required for confirmation. Other patients require surgical resection with extended two-field thoracic/abdominal lymphadenectomy.
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Endoscopia/métodos , Neoplasias Esofágicas/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Chirality is ubiquitous in nature with primary cellular functions that include construction of right-/left-handed helix and selective communications among diverse biomolecules. Of particularly intriguing are the chiral peptide-based materials that can be deliberately designed to change physicochemistry properties via tuning peptide sequences. Critically, understanding their chiral effects are fundamental for the development of novel materials in chemistry and biomedicine fields. Here, we review recent researches on chirality in peptide-based materials, summarizing relevant typical chiral effects towards recognition, amplification, and induction. Driven forces for the chiral discrimination in affinity interaction as well as the handedness preferences in supramolecular structure formation at both the macroscale and microscale are illustrated. The implementation of such chirality effects of artificial copolymers, assembled aggregates and their composites in the fields of bioseparation and bioenrichment, cell incubation, protein aggregation inhibitors, chiral smart gels, and bionic electro devices are also presented. At last, the challenges in these areas and possible directions are pointed out. The diversity of chiral roles in the origin of life and chirality design in different organic or composite systems as well as their applications in drug development and chirality detection in environmental protection are discussed.
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Peptídeos , Polímeros , Sequência de Aminoácidos , Géis , EstereoisomerismoRESUMO
Dielectric metasurfaces, which are capable of manipulating incident light, have been a novel branch of flat optics. This modulation ability is realized by nanostructures with space-variant geometrical parameters such as height and diameter. Therefore, accurate profile measurement of metasurfaces is of great importance. White-light scanning interferometry is widely used for profile measurement. The step height is retrieved by locating the envelope's peak. However, spurious fringes attached to the desired fringes were observed at the measured area near the edge of nanostructures. Their amplitude distributions vary with the density of nanostructures as well as distance to the edge. Further, anomalous coherence signals with two fringe envelopes are produced, which result in inaccurate measurement results. We attributed this phenomenon to the complex light modulation by the nanostructures. When referring to the anomalous coherence signals for the top of the nanostructures, one envelope is produced by the top, and the other is produced by the bottom; however, it is difficult to distinguish these two, which is the same case for the bottom of the nanostructures. To automatically solve these obstacles, a signal processing method, which integrates the image segmentation technology to identify and divide the anomalous coherence signals, along with a Morlet wavelet transform to extract the fringe envelope, suitable for any measured area of the dielectric metasurface, is proposed. One metasurface belt consisting of seven kinds of nanopillars with varying arrayed densities that produce different coherence signals is measured. The diameter distribution ranges from 500 to 1250 nm with a constant height of 1850 nm. The local periods in the X and Y directions are 3020 and 1740 nm, respectively. Measurement results demonstrate the validity of the proposed method for spurious fringes processing.
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The upregulation of programmed cell death-ligand 1 (PD-L1) and continuous mutation of EGFR could induce chemoresistance in somatic cancers, however, the molecular mechanism of oncogene ABL1 in regulating the expression of PD-L1 in lung adenocarcinoma (LAD) remains unclear. In addition, the therapeutic effect of STAT3 and PD-L1 inhibitors in LAD is not fully understood. The ABL1 lentiviruses were used to transfect LAD cell lines (H1975, PC-9) with different EGFR mutation subtypes. Next, the expression of the JAK/STAT3 and PD-L1 pathway was detected followed by the treatment with STAT3 and PD-L1 inhibitors. Lastly, we observed the apoptosis and expression of STAT3 and PD-L1 before and after treatments in transfected and knocked down cell lines. The expression of ABL1 was upregulated by more than 3.71-fold and the expression of PD-L1 increased by 4.85-fold in lung cancer tissues compared with para-cancer tissues (both p<0.01), the ABL1 could induce upregulation of PD-L1 in LAD cell lines. Furthermore, the STAT3 inhibitor might induce more apoptosis than the PD-L1 inhibitor in both H1975 and PC-9 cell lines (both p<0.01) The STAT3 inhibitor combined with PD-L1 inhibitor had a synergistic effect on the PC-9 cell line, and the antagonistic effect was observed on the H1975 cell line. Furthermore, the expression of PD-L1 decreased almost equally after the PD-L1 inhibitor combined with a STAT3 inhibitor, or the STAT3 inhibitor alone (p>0.05). In addition, the STAT3 and PD-L1 decreased significantly after the STAT3 inhibitor compared with other treatments on the H1975 cell line (both p<0.01). To conclude, the EGFR mutation subtypes might influence the therapeutic efficacy in the treatment with PD-L1 inhibitor combined with STAT3 inhibitor on LAD cell lines.