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BackgroundThe aim of this study was to analyze the impact of the number and extranodal extension (ENE) of positive parotid lymph nodes (LNs) on distant metastasis in parotid cancer.MethodsPatients with surgically treated parotid cancer were retrospectively enrolled. The hazard ratios (HRs) of the number and ENE of positive parotid LNs on distant metastasis-free survival (DMFS) were evaluated.ResultsIn the Cox model, the groups with zero and one positive LN had comparable 10-year DMFS, but those with two positive LNs had an HR of 2.11 (95% CI: 1.36–5.29), and those with three or more positive LNs had an HR of 3.31 (95% CI: 2.05–8.43). The presence of ENE in parotid LNs did not impact the DMFS (p = 0.462; HR: 2.17; 95% CI: 0.84–6.17).ConclusionParotid LN metastasis was associated with decreased DMFS; this effect was mainly driven by the number of positive LNs rather than ENE.

Prostate cancer is the only human malignancy that generates predominantly osteoblastic bone metastases, and osteoblastic bone metastases account for more than 90% of osseous metastases of prostate cancer. Prostate-specific antigen (PSA) plays an important role in the osteoblastic bone metastasis of prostate cancer, which can promote osteomimicry of prostate cancer cells, suppress osteoclast differentiation, and facilitate osteoblast proliferation and activation at metastatic sites. In the meantime, it can activate osteogenic factors, including insulin-like growth factor, transforming growth factor β2 and urokinase-type plasminogen activator, and meanwhile suppress osteolytic factors such as parathyroid hormone-related protein. To recapitulate, PSA plays a significant role in the osteoblastic predominance of prostate cancer bone metastasis and bone remodeling by regulating multiple cells and factors involved in osseous metastasis.

BackgroundPostoperative ileus (POI) is a common complication following abdominal surgery, which can lead to significant negative impacts on patients’ well-being and healthcare costs. However, the efficacy of current treatments is not satisfactory. The purpose of this study was to evaluate the therapeutic effects of acupuncture intervention and explore the regulation of acupoint selection for treating POI in colorectal cancer (CRC) patients.MethodsWe searched eight electronic databases to identify randomized controlled trials (RCTs) on acupuncture for POI in CRC and conducted a meta-analysis. Subsequently, we utilized the Apriori algorithm and the Frequent pattern growth algorithm, in conjunction with complex network and cluster analysis, to identify association rules of acupoints.ResultsThe meta-analysis showed that acupuncture led to significant reductions in time to first defecation (MD=-20.93, 95%CI: -25.35, -16.51; I2 = 93.0%; p < 0.01; n=2805), first flatus (MD=-15.08, 95%CI: -18.39, -11.76; I2 = 96%; p < 0.01; n=3284), and bowel sounds recovery (MD=-10.96, 95%CI: -14.20, -7.72; I2 = 94%; p < 0.01; n=2043). A subgroup analysis revealed that acupuncture not only reduced the duration of POI when administered alongside conventional care but also further expedited the recovery of gut function after colorectal surgery when integrated into the enhanced recovery after surgery (ERAS) pathway. The studies included in the analysis reported no instances of serious adverse events associated with acupuncture. We identified Zusanli (ST36), Shangjuxu (ST37), Neiguan (PC6), Sanyinjiao (SP6), Xiajuxu (ST39), Hegu (LI4), Tianshu (ST25), and Zhongwan (RN12) as primary acupoints for treating POI. Association rule mining suggested potential acupoint combinations including {ST37, ST39}≥{ST36}, {PC6, ST37}≥{ST36}, {SP6, ST37}≥{ST36}, and {ST25, ST37}≥{ST36}.ConclusionMeta-analysis indicates acupuncture’s safety and superior effectiveness over postoperative care alone in facilitating gastrointestinal recovery. Machine-learning approaches highlight the importance of the lower He-sea points, including Zusanli (ST36) and Shangjuxu (ST37), in treating POI in CRC patients. Incorporating additional acupoints such as Neiguan (PC6) (for pain and vomiting) and Sanyinjiao (SP6) (for abdominal distension and poor appetite) can optimize treatment outcomes. These findings offer valuable insights for refining treatment protocols in both clinical and experimental settings, ultimately enhancing patient care.

BackgroundThe association between clear cell renal cell carcinoma (ccRCC) and disulfidoptosis remains to be thoroughly investigated.MethodsWe conducted multiple bioinformatics analyses, including prognostic analysis and cluster analysis, using R software. Additionally, we utilized Quantitative Real-time PCR to measure RNA levels of specific genes. The proliferation of ccRCC was assessed through CCK8 and colony formation assays, while the invasion and migration of ccRCC cells were evaluated using the transwell assay.ResultsIn this study, utilizing data from multiple ccRCC cohorts, we identified molecules that contribute to disulfidoptosis. We conducted a comprehensive investigation into the prognostic and immunological roles of these molecules. Among the disulfidoptosis-related metabolism genes (DMGs), LRPPRC, OXSM, GYS1, and SLC7A11 exhibited significant correlations with ccRCC patient prognosis. Based on our signature, patients in different groups displayed varying levels of immune infiltration and different mutation profiles. Furthermore, we classified patients into two clusters and identified multiple functional pathways that play important roles in the occurrence and development of ccRCC. Given its critical role in disulfidoptosis, we conducted further analysis on SLC7A11. Our results demonstrated that ccRCC cells with high expression of SLC7A11 exhibited a malignant phenotype.ConclusionsThese findings enhanced our understanding of the underlying function of DMGs in ccRCC.

Gastric cancer is one of the most serious malignant tumor and threatens the health of people worldwide. Its heterogeneity leaves many clinical problems unsolved. To treat it effectively, we need to explore its heterogeneity. Single-cell transcriptome sequencing, or single-cell RNA sequencing (scRNA-seq), reveals the complex biological composition and molecular characteristics of gastric cancer at the level of individual cells, which provides a new perspective for understanding the heterogeneity of gastric cancer. In this review, we first introduce the current procedure of scRNA-seq, and discuss the advantages and limitations of scRNA-seq. We then elaborate on the research carried out with scRNA-seq in gastric cancer in recent years, and describe how it reveals cell heterogeneity, the tumor microenvironment, oncogenesis and metastasis, as well as drug response in to gastric cancer, to facilitate early diagnosis, individualized therapy, and prognosis evaluation.

BackgroundArtificial intelligence (AI) discrimination models using single radioactive variables in recognition algorithms of lung nodules cannot predict lung cancer accurately. Hence, we developed a clinical model that combines AI with blood test variables to predict lung cancer.MethodsBetween 2018 and 2021, 584 individuals (358 patients with lung cancer and 226 individuals with lung nodules other than cancer as control) were enrolled prospectively. Machine learning algorithms including lasso regression and random forest (RF) were used to select variables from blood test data, Logistic regression analysis was used to reconfirm the features to build the nomogram model. The predictive performance was assessed by performing the receiver operating characteristic (ROC) curve analysis as well as calibration, clinical decision and impact curves. A cohort of 48 patients was used to independently validate the model. The subgroup application was analyzed by pathological diagnosis.FindingsA total of 584 patients were enrolled (358 lung cancers, 61.30%,226 patients for the control group) to establish the model. The integrated model identified eight potential factors including carcinoembryonic antigen (CEA), AI score, Pro-Gastrin Releasing Peptide (ProGRP), cytokeratin 19 fragment antigen21-1(CYFRA211), squamous cell carcinoma antigen(SCC), indirect bilirubin(IBIL), activated partial thromboplastin time(APTT) and age. The area under the curve (AUC) of the nomogram was 0.907 (95% CI, 0.881-0.929). The decision and clinical impact curves showed good predictive accuracy of the model. An AUC of 0.844 (95% CI, 0.710 - 0.932) was obtained for the external validation group.ConclusionThe nomogram model integrating AI and clinical data can accurately predict lung cancer, especially for the squamous cell carcinoma subtype.

Virtual Touch Tissue Quantification (VTQ) offers several advantages in the diagnosis of various lung diseases. Chemokine expression levels, such as CXCL13, play a vital role in the occurrence and development of tumors and aid in the diagnosis process. The purpose of this study was to evaluate the combined value of VTQ and changes in CXCL13 expression levels for the diagnosis of lung tumors. A total of 60 patients with thoracic nodules and pleural effusion were included, with 30 of them having malignant pleural effusion (based on pathology) and the remaining 30 having benign thoracic nodules and pleural effusion. The relative expression level of CXCL13 was measured in the collected pleural effusions using Enzyme-Linked Immunosorbent Assay (ELISA). The relationship between CXCL13 expression levels and various clinical features was analyzed. A Receiver Operating Characteristic (ROC) curve analysis was conducted on the VTQ results and relative expression levels of CXCL13, and the areas under the curve, critical values, sensitivity, and specificity were calculated. Multivariate analysis incorporating multiple indicators was performed to determine the accuracy of lung tumor diagnosis. The results showed that the expression levels of CXCL13 and VTQ were significantly higher in the lung cancer group compared to the control group (P < 0.05). In the Non-Small Cell Lung Cancer (NSCLC) group, CXCL13 expression levels increased with later TNM staging and poorer tumor differentiation. The expression level of CXCL13 in adenocarcinoma was higher than that in squamous cell carcinoma. The ROC curve analysis revealed that CXCL13 had an area under the curve (AUC) of 0.74 (0.61, 0.86) with an optimal cut-off value of 777.82 pg/ml for diagnosing lung tumors. The ROC curve analysis of VTQ showed an AUC of 0.67 (0.53, 0.82) with a sensitivity of 60.0% and a specificity of 83.3%, and an optimal diagnostic cut-off of 3.33 m/s. The combination of CXCL13 and VTQ for diagnosing thoracic tumors had an AUC of 0.842 (0.74, 0.94), which was significantly higher than either factor alone. The results of the study demonstrate the strong potential of combining VTQ results with chemokine CXCL13 expression levels for lung tumor diagnosis. Additionally, the findings suggest that elevated relative expression of CXCL13 in cases of malignant pleural effusion caused by non-small cell lung cancer may indicate a poor prognosis. This provides promising potential for using CXCL13 as a screening tool and prognostic indicator for patients with advanced lung cancer complicated by malignant pleural effusion.

ObjectiveThe efficacy of concurrent chemoradiotherapy (CRT) after induction chemotherapy (IC) in the treatment of esophageal squamous cell carcinoma (ESCC) remains unclear. The purpose of this study was to explore the efficacy of IC in patients with ESCC.Methods124 patients with ESCC receiving CRT were included. Patients were divided into IC+CRT group and CRT group. Short-term and long-term efficacy as well as survival time of the two groups were compared, influencing factors of IC efficacy were investigated, and overall survival (OS) and progression-free survival (PFS) between the two groups were compared in different subgroups.ResultsThere was no significant difference in the objective response rate (ORR) between the two groups. After IC, the ORR was higher in patients with single-drug concurrent chemotherapy weekly and patients with effective IC. In the long-term efficacy, advanced clinical stage patients had a shorter PFS compared to early-stage patients, and chemoradiotherapy mode ameliorates patients’ PFS. OS and PFS of IC+CRT group were longer than that of CRT group in both tumor diameter

MALT lymphoma is an extranodal B-cell lymphoma of the marginal zone of mucosa-associated lymphoid tissue (MALT), caused by malignant transformation of B-cells in the marginal zone. In this work, we aim to explore the potential relationship between MALT lymphoma and DLBCL. Vaccines derived from messenger ribonucleic acid (mRNA) may provide satisfactory results. Despite being a promising treatment option, immunotherapy isn’t widely used in treating renal cell carcinoma, as only a few patients respond to the treatment. The Cancer Genome Atlas (TCGA) analysis revealed gene expression profiles and clinical information. Antigen-presenting cells infiltrated the immune system using TIMER tool (http://timer.cistrome.org/). GDSC (Genomics of Drug Sensitivity in Cancer) data were used to estimate drug sensitivity. Immune-related genes were associated with a better prognosis in MALT lymphoma patients and higher levels of antigen-presenting cells. There is a significant relationship between these immune subtypes and immunological checkpoints, immunogenic cell death regulators, and prognostic variables for MALT lymphoma patients. In this study, we provide a theoretical foundation for the development of mRNA vaccines and suggest that KLHL14 could potentially be used as antigens to develop mRNA vaccines for MALT lymphoma.

Radiotherapy plays an irreplaceable and unique role in treating thoracic tumors, but the occurrence of radiation-induced lung injury has limited the increase in tumor target doses and has influenced patients’ quality of life. However, the introduction of functional lung imaging has been incorporating functional lungs into radiotherapy planning. The design of the functional lung protection plan, while meeting the target dose requirements and dose limitations of the organs at risk (OARs), minimizes the radiation dose to the functional lung, thus reducing the occurrence of radiation-induced lung injury. In this manuscript, we mainly reviewed the lung ventilation or/and perfusion functional imaging modalities, application, and progress, as well as the results based on the functional lung protection planning in thoracic tumors. In addition, we also discussed the problems that should be explored and further studied in the practical application based on functional lung radiotherapy planning.

Estrogen receptor α (ERα) is the dominant tumorigenesis driver in breast cancer (BC), and ERα-positive BC (ERα+ BC) accounts for more than two-thirds of BC cases. MOF (males absent on the first) is a highly conserved histone acetyltransferase that acetylates lysine 16 of histone H4 (H4K16) and several non-histone proteins. Unbalanced expression of MOF has been identified, and high MOF expression predicted a favorable prognosis in BC. However, the association of MOF with ERα and the regulatory mechanisms of MOF in ERα signaling remain elusive. Our study revealed that the expression of MOF is negatively correlated with that of ERα in BC. In ERα+ BC cells, MOF overexpression downregulated the protein abundance of ERα in both cytoplasm and nucleus, thus attenuating ERα-mediated transactivation as well as cellular proliferation and in vivo tumorigenicity of BC cells. MOF promoted ERα protein degradation through CUL4B-mediated ubiquitin–proteasome pathway and induced HSP90 hyperacetylation that led to the loss of chaperone protection of HSP90 to ERα. We also revealed that suppression of MOF restored ERα expression and increased the sensitivity of ERα-negative BC cells to tamoxifen treatment. These results provide a new insight into the tumor-suppressive role of MOF in BC via negatively regulating ERα action, suggesting that MOF might be a potential therapeutic target for BC.

Urothelial carcinomas (UCs) are malignant tumors that arise from the lower and upper urinary tract and are characterized by multiple recurrences. Aristolochic acid (AA) is a potent nephrotoxin and human carcinogen associated with UC. East Asian populations with a high UC prevalence have an unusual genome-wide AA-induced mutational pattern. To address the genomic differences and clonal relatedness between primary and recurrent tumors in the UCs with AA pattern, we investigated the genomic differences and tumor microenvironment (TME) of AA and non-AA UCs. 17 UC patients were recruited, with nine documented AA exposure. Eleven of them showed recurrence. After-surgery tissues of primary and paired recurrent tumors were collected. Capture-based targeted deep sequencing was performed using a commercial panel consisting of 520 cancer-related genes. Tumor-infiltrating lymphocytes (TILs) were identified with an immunofluorescence-based microenvironment analysis panel (MAP). Hierarchical clustering based on the COSMIC signatures confirmed two significant subtypes: AA Sig and non-AA Sig. AA Sig was associated with AA-containing herbal drug intake, recurrence, and higher tumor mutation burden (TMB). The clonal architecture of UCs revealed three types of clonal evolution patterns. Non-AA Sig cohort showed shared clonal origin of primary and recurrent tumors. AA Sig showed heterogeneity and had multiple independent origins. Recurrent tumors as second primary tumors in AA Sig showed immunoreactive TME, indicating a better response with immune checkpoint inhibitor therapy. The AA mutational signature and unique immune profiles are helpful molecular markers to distinguish AA exposure from other carcinogens. These results also provide new insights into the origin of recurrent UCs that could affect treatment strategies.

As an abundant component of tumor microenvironment, cancer-associated fibroblasts (CAFs) are heterogeneous cell populations that play important roles in tumor development, progression and therapeutic resistance. Multiple sources of cells can be recruited and educated to become CAFs, such as fibroblasts, mesenchymal stem cells and adipocytes, which may explain the phenotypic and functional heterogeneity of CAFs. It is widely believed that CAFs regulate tumor progression by remodeling extracellular matrix, promoting angiogenesis, and releasing soluble cytokines, making them a promising cancer therapy target. In this review, we discussed about the origin, subpopulation, and functional heterogeneity of CAFs, with particular attention to recent research advances and clinical therapeutic potential of CAFs in cancer.

Kidney renal clear cell carcinoma (KIRC) represents one of the most fatal cancers, usually showing malignant progression and a high tumor recurrence rate. The urokinase-type plasminogen activator receptor (PLAUR) plays a critical role in the initiation and progression of several cancers, including KIRC. However, the function and mechanism of PLAUR in patients with KIRC are still unclear and require further investigation. In the present study, we first explored the expression profile and prognostic values of PLAUR in pan-cancer based on The Cancer Genome Atlas and Genotype-Tissue Expression databases. PLAUR was upregulated in multiple cancers and was significantly associated with poor overall survival and disease-free survival only in patients with KIRC. Subsequently, the PVT1/SNHG15-hsa-miR-532-3p axis was identified as the most potential upstream regulatory network of PLAUR in KIRC. In addition, PLAUR expression was closely associated with tumor-infiltrating immune cells, tumor immunity biomarkers, and immunomodulator expression. Furthermore, we constructed a multiple-gene risk prediction signature according to the PLAUR-related immunomodulators (PRIs). A prognostic nomogram was then developed to predict the 1-, 3-, and 5-year survival probabilities of individuals. In conclusion, our study identified the PVT1/SNHG15-hsa-miR-532-3p-PLAUR axis and a prognostic signature of PRIs, which could be a reference for future clinical research.

BackgroundIntegration of 4D-CT ventilation function images into esophageal cancer radiation treatment planning aimed to assess dosimetric differences between different functional lung (FL) protection strategies and radiotherapy techniques.MethodsA total of 15 patients with esophageal cancer who had 4D-CT scans were included. Lung ventilation function images based on Jacobian values were obtained by deformation image registration and ventilation imaging algorithm. Several different plans were designed for each patient: clinical treatment planning (non-sparing planning), the same beam distribution to FL-sparing planning, three fixed-beams FL-sparing intensity-modulated radiation therapy (IMRT) planning (5F-IMRT, 7F-IMRT, 9F-IMRT), and two FL-sparing volumetric modulated arc therapy (VMAT) planning [1F-VMAT (1-Arc), 2F-VMAT (2-Arc)]. The dosimetric parameters of the planning target volume (PTV) and organs at risk (OARs) were compared and focused on dosimetric differences in FL.ResultsThe FL-sparing planning compared with the non-sparing planning significantly decreased the FL-Dmean, V5-30 and Lungs-Dmean, V10-30 (Vx: volume of receiving ≥X Gy), although it slightly compromised PTV conformability and increased Heart-V40 (P< 0.05). The 5F-IMRT had the lowest PTV-conformability index (CI) but had a lower Lungs and Heart irradiation dose compared with those of the 7F-IMRT and 9F-IMRT (P< 0.05). The 2F-VMAT had higher PTV-homogeneity index (HI) and reduced irradiation dose to FL, Lungs, and Heart compared to those of the 1F-VMAT planning (P< 0.05). The 2F-VMAT had higher PTV conformability and homogeneity and decreased FL-Dmean, V5-20 and Lungs-Dmean, V5-10 but correspondingly increased spinal cord-Dmean compared with those of the 5F-IMRT planning (P< 0.05).ConclusionIn this study, 4D-CT ventilation function image-based FL-sparing planning for esophageal cancer can effectively reduce the dose of the FL. The 2F-VMAT planning is better than the 5F-IMRT planning in reducing the dose of FL.

BackgroundEverolimus has been approved in China for adult patients with TSC-AML (tuberous sclerosis associated renal angiomyolipomas) not requiring immediate surgery and has been previously shown to be an effective treatment option for TSC-AML in the Chinese populationMethodsThis is an open label, single arm, multi-center Phase IV post-approval commitment study to further assess the safety and efficacy of everolimus in patients with TSC-AML who do not require immediate surgical intervention. The primary outcome was to evaluate the safety of everolimus while the secondary outcome was to evaluate AML response.ResultsTreatment with everolimus was associated with a clinically meaningful best overall AML response rate of 70% (95% CI: 53.5, 83.4). Of the 38 evaluable patients, 37 (97%) patients experienced a reduction in the sum of volumes of target angiomyolipoma lesions relative to baseline. At Week 12 (n=38), the median percentage change in sum of target AML volume was −56.60%, which further changed by -59.96% at Week 24 (n=38), and by −64.41% at Week 48 (n=22). Throughout the study, renal function remained relatively stable. Patients with TSC associated lymphangiomyomatosis (LAM) (N=13) demonstrated a lower than expected rate of decline in pulmonary function tests (PFTs). Everolimus was generally well tolerated with no significant safety findings in Chinese patients. Most of the adverse events were of grade 1-2, and manageable with appropriate dose adjustments and supportive therapies. There were no treatment discontinuation due to AE and no treatment death was reported.ConclusionsBased on the efficacy and safety data presented in this study, the overall clinical benefit/risk assessment further supports the use of everolimus as a viable treatment option for Chinese patients with TSC-AML.

BackgroundRenal clear cell cancer (ccRCC) is one of the most common cancers in humans. Thus, we aimed to construct a risk model to predict the prognosis of ccRCC effectively.MethodsWe downloaded RNA sequencing (RNA-seq) data and clinical information of 539 kidney renal clear cell carcinoma (KIRC) patients and 72 normal humans from The Cancer Genome Atlas (TCGA) database and divided the data into training and testing groups randomly. Pyroptosis-related lncRNAs (PRLs) were obtained through Pearson correlation between pyroptosis genes and all lncRNAs (p 0.3). Univariate and multivariate Cox regression analyses were then performed to select suitable lncRNAs. Next, a novel signature was constructed and evaluated by survival analysis and ROC analysis. The same observation applies to the testing group to validate the value of the signature. By gene set enrichment analysis (GSEA), we predicted the underlying signaling pathway. Furthermore, we calculated immune cell infiltration, immune checkpoint, the T-cell receptor/B-cell receptor (TCR/BCR), SNV, and Tumor Immune Dysfunction and Exclusion (TIDE) scores in TCGA database. We also validated our model with an immunotherapy cohort. Finally, the expression of PRLs was validated by quantitative PCR (qPCR).ResultsWe constructed a prognostic signature composed of six key lncRNAs (U62317.1, MIR193BHG, LINC02027, AC121338.2, AC005785.1, AC156455.1), which significantly predict different overall survival (OS) rates. The efficiency was demonstrated using the receiver operating characteristic (ROC) curve. The signature was observed to be an independent prognostic factor in cohorts. In addition, we found the PRLs promote the tumor progression via immune-related pathways revealed in GSEA. Furthermore, the TCR, BCR, and SNV data were retrieved to screen immune features, and immune cell scores were calculated to measure the effect of the immune microenvironment on the risk model, indicating that high- and low-risk scores have different immune statuses. The TIDE algorithm was then used to predict the immune checkpoint blockade (ICB) response of our model, and subclass mapping was used to verify our model in another immunotherapy cohort data. Finally, qPCR validates the PRLs in cell lines.ConclusionThis study provided a new risk model to evaluate ccRCC and may be pyroptosis-related therapeutic targets in the clinic.

BackgroundImmunotherapies represented by immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. A large part of the population has both cancer and psoriasis but is usually excluded from ICI clinical trials because of the dysregulated activation of the immune system. This is the first study to evaluate the safety and efficacy of ICI therapy in patients with cancer and preexisting psoriasis.MethodsPubMed, EMBASE, Cochrane, and MEDLINE databases were searched from inception through February 2022. Observational studies on patients with cancer and confirmed psoriasis before ICI initiation were included. Outcomes included the incidence of psoriasis flares, de novo immune-related adverse events (irAEs), discontinuation rate due to flare/de novo irAEs, and efficacy of ICI therapy. Clinical manifestations, management, and outcomes for adverse events (AEs) were systematically reviewed. All pooled analyses were based on a random-effects model using Stata software. Meta-regression and subgroup analyses were performed to identify sources of heterogeneity.ResultsTwelve studies involving 191 patients were included. The pooled incidence of psoriasis flares was 45.0% (95% CI: 31.1%-58.9%, I2 = 71.7%) and 44.9% (95% CI: 29.0%–60.7%, I2 = 71.8%) for de novo irAEs. The tumor type, psoriasis subtype, ICI class, and country were the main sources of heterogeneity. Grade 3–4 flares occurred in 10.8% (95% CI: 5.3%–16.3%) of patients, and about 16.6% (95% CI: 10.7%–22.5%) of patients experienced grade 3–4 de novo irAEs. The estimated incidence of ICI discontinuation due to AE was 18.5% (95% CI: 6.1%–30.8%, I2 = 68.7%). The median times to develop flare and de novo irAEs were 44 and 63 days, respectively. Endocrinopathies and colitis were the most common de novo irAEs. Conventional therapy is effective for most AEs. The estimated objective response rate (ORR) of ICIs was 38.1% (95% CI: 11.8%–64.3%, I2 = 81.7%), and the disease control rate (DCR) was 64.5% (95% CI: 55.3%–73.8%, I2 = 0).ConclusionsThe flare of patients with cancer and preexisting psoriasis treated with ICI therapy is frequent, but the incidence of de novo irAEs and the efficacy of ICI therapy are comparable to those of the general population. Most AEs are mild and manageable with conventional therapy, which required discontinuation of ICI therapy in 18.5%.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022320646

Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of patients with NSCLC needs to be clarified. In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Synthesis database (Gene Expression Omnibus, GEO) were used to build a model of ferroptosis-related differentially expressed genes (DEGs). A total of 101 ferroptosis-related DEGs were screened using R language, and a 12-gene signature was finally established through univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. According to the risk scores, the patients were divided into a high-risk or a low-risk group, with patients in the low-risk group showing better prognosis. AURKA, one of the genes in the 12-gene signature, was found to be highly expressed in tumors. In addition, further study verified AURKA to be a negative regulator of ferroptosis in NSCLC cells. Ophiopogonin B (OP-B) had been reported to induce apoptosis, mitotic catastrophe, and autophagy in NSCLC cells. Herein, proteomic sequencing analysis and OP-B administration revealed the upregulation of AURKA and the downregulation of PHKG2 and SLC7A5 in the 12-gene signature, indicating that OP-B induced ferroptosis in NSCLC. Determination of the concentrations of malondialdehyde (MDA), glutathione (GSH), and intracellular iron and the mitochondrial membrane potential (MMP) confirmed the induction of ferroptosis by OP-B in vitro. Furthermore, transmission electron microscopy (TEM) examination of lung cancer xenotransplantation in nude mice confirmed that OP-B induced ferroptosis in vivo. Further study of the molecular mechanism showed that the ferroptosis effect caused by OP-B can be partially reversed by the overexpression of AURKA. Overall, our study established a new ferroptosis-related risk prediction model for the prognosis of patients with NSCLC, revealed the enrichment pathways of ferroptosis in NSCLC, and discovered the negative regulation of AURKA in ferroptosis. On this basis, we demonstrated that OP-B can induce ferroptosis in NSCLC and clarified the specific molecular mechanism of OP-B inducing ferroptosis by regulating the expression of AURKA.

BackgroundsFunctional liver imaging can identify functional liver distribution heterogeneity and integrate it into radiotherapy planning. The feasibility and clinical benefit of functional liver-sparing radiotherapy planning are currently unknown.MethodsA comprehensive search of several primary databases was performed to identify studies that met the inclusion criteria. The primary objective of this study was to evaluate the dosimetric and clinical benefits of functional liver-sparing planning radiotherapy. Secondary objectives were to assess the ability of functional imaging to predict the risk of radiation-induced liver toxicity (RILT), and the dose-response relationship after radiotherapy.ResultsA total of 20 publications were enrolled in descriptive tables and meta-analysis. The meta-analysis found that mean functional liver dose (f-MLD) was reduced by 1.0 Gy [95%CI: (-0.13, 2.13)], standard mean differences (SMD) of functional liver volume receiving ≥20 Gy (fV20) decreased by 0.25 [95%CI: (-0.14, 0.65)] when planning was optimized to sparing functional liver (P >0.05). Seven clinical prospective studies reported functional liver-sparing planning-guided radiotherapy leads to a low incidence of RILD, and the single rate meta-analysis showed that the RILD (defined as CTP score increase ≥2) incidence was 0.04 [95%CI: (0.00, 0.11), P

AimTo summarize the features of splenic tuberculosis and splenic lymphoma by contrast-enhanced ultrasound (CEUS) and examine the application of CEUS in differentiating splenic tuberculosis from splenic lymphoma.MethodsThe ultrasound and CEUS manifestations of 30 cases of splenic tuberculosis and 19 cases of splenic lymphoma were retrospectively analyzed, and the number of lesions, degree of splenomegaly, internal echogenicity, color blood flow signal, and CEUS manifestations of the two diseases were statistically determined.ResultsA significant difference was noted in the internal echogenicity between splenic tuberculosis and splenic lymphoma lesions, particularly the strip-shaped hyperechoic areas of the lesions. The ultrasound features of perisplenic, retroperitoneal, and superficial lymph node enlargement were found to overlap (p < 0.05). Splenic tuberculosis showed heterogeneous enhancement and non-enhancement, whereas lymphoma showed low enhancement and high enhancement, and CEUS findings were statistically significant in distinguishing both, p < 0.05.ConclusionSplenic tuberculosis is characterized by a lack of blood supply, mostly heterogeneous enhancement, and non-enhancement noted in CEUS. Splenic lymphoma lesions are often characterized by a rich blood supply and homogeneous enhancement on CEUS. CEUS can help identify the microcirculation of lesions in both patients with splenic lymphoma and patients with splenic tuberculosis. Thus, CEUS has great application value.

Recent studies have revealed that long non-coding RNAs (IncRNAs) involve in the progression of oral squamous cell carcinoma (OSCC). These IncRNAs have emerged as biomarkers or therapeutic targets for OSCC. We here aimed to investigate the role of IncRNA LINC01315 in OSCC and the related mechanisms. LINC01315 and DLG3 were determined to be poorly expressed while microRNA-211 (miR-211) was highly expressed in OSCC tissues and cells using RT-qPCR and western blot analysis. Based on the results obtained from dual-luciferase reporter gene, RIP, and FISH assays, LINC01315 was found to upregulate DLG3 expression by competitively binding ETRAC to miR-211. Upon altering the expression of LINC01315, and/or miR-211 in OSCC cells with shRNA, mimic, or an inhibitor, we assessed their effects on OSCC cell proliferation, migration, invasion, and apoptosis. LINC01315 knockdown enhanced OSCC cell proliferation, migration and invasion, but dampened their apoptosis, all of which could be reversed by miR-211 inhibition. Elevation of DLG3, a target gene of miR- 211, activated the Hippo signaling pathway, whereby suppressing OSCC progression in vitro. Finally, their roles in tumor growth were validated in vivo. These findings suggest that LINC01315 elevates DLG3 expression by competitively binding to miR-211, thereby suppressing OSCC progression. [ABSTRACT FROM AUTHOR]

ObjectiveThe aim of this study is to identify the risk factors associated with orocutaneous fistula (OCF) formation after free flap reconstruction for oral squamous cell carcinoma (SCC).MethodsPatients undergoing free flap reconstruction for oral SCC were retrospectively enrolled. The relationship between clinicopathologic variables and OCF formation was analyzed by univariate and multivariate analyses.ResultsA total of 87 OCFs occurred in 856 patients. Univariate analysis revealed cachexia, tumor at the tongue/floor of the mouth (TFOM), T4 stage, preoperative hemoglobin level, pull-through procedure, preoperative albumin level, and surgical site infection were associated with the formation of OCF. Multivariate analysis confirmed the independence of cachexia, TFOM, T4 stage, and surgical site infection in predicting OCF development. Conventional wound care could achieve successful fistula closure in 82.4% of the patients with a median time of 28 days.ConclusionsOCF formation was common after free flap reconstruction. The presence of cachexia, TFOM tumor site, T4 stage, and surgical site infection significantly increased the risk of OCF formation. Although it required a long period, conventional wound care can obtain satisfactory outcomes in OCF management.

Intrahepatic cholangiocarcinoma (ICC) is a highly lethal hepatobiliary neoplasm, which originates from the bile ducts proximal to the second-order division. ICC can be anatomically divided into two subtypes: the large duct type (mucin-production ICC, muc-ICC) and the small duct type (mixed-ICC) origins from hepatic progenitor cells (HPCs). The immunoreactivity of S100P and neural cell adhesion molecule (NCAM) are useful biomarkers to distinguish the two subtypes. In this study, we report a difficult-to-diagnose case of metastatic retroperitoneal tumor of occult hepatolithiasis-associated ICC. Besides, this case was both positive for S100P and NCAM, considered as a rare muc-ICC with the HPCs features. Tumor whole exome sequencing detection results by Genetron (China) revealed that there were 41 gene mutations in this patient. The SMAD4-p.His530ThrfsTer47 and KRAS-p.Gly12Val mutation might promote the occurrence and distant metastasis of the tumor.

BackgroundIt remains undetermined whether neuroticism affects the risk of lung cancer. Therefore, we performed complementary observational and Mendelian randomization (MR) analyses to investigate the association between neuroticism and lung cancer risk.MethodsWe included 364,451 UK Biobank participants free of cancer at baseline. Neuroticism was ascertained using the 12-item of Eysenck Personality Inventory Neuroticism Scale. Multivariable Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Two-sample MR analysis was carried out with summary genetic data from UK Biobank (374,323 individuals) and International Lung Cancer Consortium (29,266 lung cancer cases and 56,450 controls). Furthermore, we calculated a polygenic risk score of lung cancer, and examined the joint-effect and interaction between neuroticism and genetic susceptibility on lung cancer risk.ResultsDuring a median follow-up of 7.13 years, 1573 lung cancer cases were documented. After adjusting for smoking and other confounders, higher neuroticism was associated with an increased risk of lung cancer (HR per 1 SD=1.07, 95% CI: 1.02-1.12). Consistently, MR analysis suggested a causal effect of neuroticism on lung cancer risk (OR IVW=1.10, 95% CI: 1.03-1.17). Compared to individuals with low neuroticism and low PRS, those with both high neuroticism and high PRS had the greatest risk of lung cancer (HR=1.82, 95%CI: 1.51-2.20). Furthermore, there was a positive additive but no multiplicative interaction between neuroticism and genetic risk.ConclusionsOur findings suggest that neuroticism is associated with an elevated risk of incident lung cancer, which is strengthened by the genetic susceptibility to lung cancer. Further studies are necessary to elucidate underlying mechanisms.

BackgroundRenal cell carcinoma (RCC) is one of the most common and lethal human urological malignancies around the world. Although many advancements in diagnostic and therapeutic strategies have been acquired, the prognosis of patients with metastatic RCC was poor. Thus, there is an urgent need to understand the molecular mechanism of RCC.MethodsThe quantitative real-time PCR (qRT-PCR) was used to detect the RNA expression of MOF in human RCC tissues and cell lines. The protein expression of MOF was analyzed with immunohistochemistry (IHC) and Western blot. To understand the regulatory mechanism of MOF in liver cancer, ChIP-qPCR assay and dual-luciferase assay were performed. Moreover, a series of in vivo and in vitro experiments were conducted to evaluate the effect of MOF on renal cell carcinoma progression.ResultsIn the present study, we found that Males absent on the first (MOF), a histone acetyltransferase involved in transcription activation, was significantly decreased in both RCC tissues and RCC cells compared to normal tissues and non-cancer cells. Moreover, MOF downregulation was associated with advanced histological grade, pathologic stage and distant metastasis of RCC patients. Ectopic expression of MOF could significantly attenuate cell proliferation and promote cell apoptosis. Besides, MOF overexpression also suppressed migration of RCC cells through inhibiting epithelial-mesenchymal transition (EMT). Importantly, the inhibition of tumor growth by MOF was further confirmed by in vivo studies. Mechanism dissection revealed that MOF could transcriptionally upregulate the expression of SIRT1, leading to attenuated STAT3 signaling, which was involved in cell proliferation and migration. Moreover, SIRT1 knockdown could restore the biological function induced by MOF overexpression.ConclusionsOur findings indicated that MOF serves as a tumor suppressor via regulation of SIRT1 in the development and progression of RCC, and MOF might be a potent biomarker for diagnosis and prognosis prediction of RCC patients.

ObjectivesTo compare the oncologic outcomes in patients with cT1N0 tongue squamous cell carcinoma (SCC) who underwent different neck management strategies stratified by sonographic depth of invasion (DOI).MethodsThe included patients were retrospectively enrolled, and divided into two groups: observation (OBS) and elective neck dissection (END). The regional control (RC) and disease-specific survival (DSS) rates were compared and stratified by sonographic DOI.ResultsThe mean sonographic and pathologic DOIs were 3.8 and 3.7 mm, respectively; the two DOIs were significantly correlated (Spearman correlation coefficient 0.974. p

ObjectivesWe compared the outcomes of transperitoneal robotic partial nephrectomy (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN) for complete upper pole renal masses (1 point for the “L” component of the RENAL scoring system).Material and MethodsWe retrospectively reviewed patients who underwent either TRPN or RRPN from 2013 to 2016. Baseline demographics and perioperative, functional, and oncological results were compared. Multivariable analysis was performed to identify factors related to pentafecta achievement (ischemia time ≤25 min, negative margin, perioperative complication free, glomerular filtration rate (eGFR) preservation >90%, and no chronic kidney disease upstaging).ResultsNo significant differences between TRPN vs. RRPN were noted for operating time (110 vs. 114 min, p = 0.870), renal artery clamping time (19 vs. 18 min, p = 0.248), rate of positive margins (0.0% vs. 3.3%, p = 0.502), postoperative complication rates (25.0% vs. 13.3%, p = 0.140). TRPN was associated with a more estimated blood loss (50 vs. 40 ml, p = 0.004). There were no significant differences in pathologic variables, rate of eGFR decline for postoperative 12-month (9.0% vs. 7.1%, p = 0.449) functional follow-up. Multivariate analysis identified that only RENAL score (odd ratio: 0.641; 95% confidence interval: 0.455–0.904; p = 0.011) was independently associated with the pentafecta achievement.ConclusionsFor completely upper pole renal masses, both TRPN and RRPN have good and comparable results. Both surgical approaches remain viable options in the treatment of these cases.

BackgroundsCD146 is highly expressed in various malignant tumors and associated with the poor prognosis. However, the role of CD146 in clear cell renal cell carcinoma (ccRCC) is still unknown. This study aimed to identify the role of CD146 in ccRCC by integrated bioinformatics analysis.MethodsCD146 mRNA expression and methylation data in ccRCC was examined using the TIMER, UALCAN, and MethSurv databases. CD146 expression in paraffin-embedded tissues (140 cancer samples and 140 paracancer tissues) from our cohort were examined by immunohistochemistry assay. The LinkedOmics database was used to study the signaling pathways related to CD146 expression. TIMER and TISIDB were used to analyze the correlations among CD146, CD146-coexpressed genes, tumor-infiltrating immune cells, and immunomodulators. The relationship between CD146 and drug response in renal cancer cell lines was analyzed by the CTRP and CCLE databases.ResultsThe mRNA and protein levels of CD146 were elevated in ccRCC tissues than that in paracancer tissues. The DNA methylation of CD146 in ccRCC tissues were lower than that in normal tissues. Importantly, high CD146 expression was associated with poor prognosis in patients with ccRCC. Furthermore, multivariate Cox regression analysis showed that CD146 was an independent prognostic factor in ccRCC. GO and KEGG pathway analyses indicated the co-expressed genes of CD146 were mainly related to a variety of immune-related pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, and leukocyte transendothelial migration. Our data demonstrated that the expression and methylation status of CD146 were strongly correlated with immune infiltration levels, immunomodulators, and chemokines. Further, the sensitivity and resistance of renal cancer cell lines to some drugs were related to CD146 expression.ConclusionsOur study highlights the clinical significance of CD146 in ccRCC and provides novel insights into the immune function of CD146 in the tumor microenvironment.

Clear cell renal cell carcinoma (ccRCC), which is the most prevalent renal cell carcinoma subtype, has a poor prognosis. Emerging strategies for enhancing the immune response in ccRCC therapy are currently being investigated. Fibrinogen-like Protein 1(FGL1) is a novel mechanism that tumors may use to evade the immune system by binding LAG-3 and negatively regulating T cells. In this study, we aimed at investigating the underlying mechanism of FGL1 in ccRCC, and its expression and prognostic value. We found that FGL1 was upregulated in tumor tissues and plasma specimens of ccRCC patients. High FGL1 expression predicted a poor prognosis for ccRCC patients. We also discovered that overexpression of FGL1 enhances RCC cell migration, invasion, and metastasis by activating the epithelial-to-mesenchymal transition (EMT). Consistent with these results, we identified a significant positive correlation between expression of FGL1 and EMT-related genes through tissue microarray analysis. Gene-expression analysis revealed that FGL1-deficient ccRCC cell lines had altered transcriptional output in inflammatory response, cell-cell signaling, negative regulation of T cell activation, and intracellular signal transduction. Depletion of FGL1 significantly inhibited tumor growth and lung metastasis in orthotopic xenograft mouse model. Infiltration of myeloid-derived CD11b+ and Ly6G+ immune cells in tumor microenvironment (TME) was strikingly decreased when FGL1 expression reduced. Therefore, increased FGL1 expression in ccRCC is positively correlated with poor prognosis. Mechanistically, FGL1 facilitates the EMT process and modulates TME, which promotes ccRCC progression and metastasis. Consequently, targeting FGL1 can potentially improve clinical outcome of ccRCC patients.

Recent studies showed that molecule interacting with CasL2 (MICAL2) could be a novel tumor growth factor, and it is closely associated with tumor growth and invasion. However, the role it plays in glioblastoma (GBM) and its potential mechanisms are currently unknown. Our study is designed to identify the effect of MICAL2 on GBM cells and the potential mechanisms behind it. Here, we found that MICAL2 interacts with TGF receptor-type I (TGFRI) and promotes the proliferation and migration of glioblastoma through the TGF-β/p-Smad2/EMT-like signaling pathway. MICAL2-knockdown inhibited the proliferation of glioblastoma cells, which was related to cell cycle arrest and downregulation of DNA replication. The invasion abilities of U87 and U251 cells were reduced after the knockdown of MICAL2. MICAL2 promoted the growth of GBM in nude mice. High MICAL2 predicts poor outcome of GBM patients. MICAL2 could be identified as a novel promising therapeutic target for human GBM.

AimWe aimed to evaluate the ability of contrast-enhanced ultrasonography (CEUS) to perform differential diagnosis of cervical tuberculous lymphadenitis and lymph node metastasis from papillary thyroid cancer (PTC).MethodsWe analyzed 102 enlarged cervical lymph nodes as diagnosed by conventional ultrasound (US) and CEUS. The US and CEUS enhancement pattern and the time intensity curve (TIC) of the metastatic lymph nodes or tuberculous lymph nodes were compared following standard pathological protocols. The TIC included peak time (TTP), peak intensity (PI), and area under the gamma curve (AUC).ResultsPathological results demonstrated that 48 out of the 102 enlarged lymph nodes were lymph node metastasis from PTC, while 54 were tuberculous lymphadenitis. There was statistically significant differences in hyperechoic islands, pulse-like enhancement, and asynchronous enhancement between tuberculous lymphadenitis and lymph node metastasis (P 0.05). Similarly, quantitative parameters such as PI, TTP, and AUC did not yield significant differences between the groups.ConclusionTaken together, the present results demonstrate that CEUS can provide valuable information on lymph node blood flow, which can be used to identify tuberculous lymphadenitis and lymph node metastasis of PTC.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase (FH) gene; it manifests as cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. Here, we describe aggressive HLRCC in a 26-year-old man who presented with RCC that exhibited a novel heterozygous germline insertion mutation in exon 2 of the FH gene (c.191dupA: p.N64fs). Systemic lymph node metastasis had already occurred. The patient underwent robot-assisted laparoscopic resection of the right kidney, but new metastases appeared within 5 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1). The patient was treated with anti-PD-1 antibody as first-line therapy. After 2 years of immune checkpoint inhibitor (ICI) treatment, all lesions had disappeared; this response was maintained at 51 months. To our knowledge, this is the first successful treatment of HLRCC-RCC with single-agent immunotherapy. Our approach might be effective for patients with advanced HLRCC-RCC.

BackgroundMounting randomized clinical trials have proved that immune checkpoint inhibitors (ICIs) achieved better overall survival (OS) and progression-free survival (PFS) than chemotherapy drugs for advanced non-small cell lung cancer (NSCLC) patients. However, some literatures have indicated that different sexes might not have equal immune response. Also, no agreement reached on the issue whether therapeutic benefit of ICIs is related to sex.ObjectivesTo explore the association between efficacy of ICIs for NSCLC patients and their sexes and summarize overall treatment-related adverse events (TRAEs) in an exploratory manner.MethodsWe performed this systematic review and meta-analysis of all potentially relevant studies retrieved from PubMed, EMBASE, and the Cochrane Library until June 2021, for eligible randomized controlled trials (RCTs) comparing immunotherapy with chemotherapy in advanced NSCLC patients. Literature screening, summary data extraction was performed independently and in duplicate. The pooled hazard ratio (HR) and 95% confidence interval (CI) of OS, PFS and TRAEs were calculated, applying STATA software and random-effects models. This study was registered in international prospective register of systematic reviews (PROSPERO), number CRD42020210797.ResultsTwenty-one trials involving 12,675 NSCLC patients were included. For patients with advanced NSCLC, ICIs significantly prolonged the OS (males: HR 0.73, 95%CI 0.67-0.79; females: HR 0.73, 95%CI 0.61-0.85) and PFS (males: HR 0.62, 95%CI 0.55-0.70; females: HR 0.68, 95%CI 0.55-0.81) versus chemotherapy. Overall, there was no statistical difference between their sexes (OS: P = 0.97; PFS: P = 0.43), respectively. Owing to insufficient TRAEs data of different sexes, we only found immunotherapy for NSCLC patients had more all-grades (RR 0.88; 95%CI 0.82-0.95) and 3-5 grades (RR 0.60; 95%CI 0.47-0.75) AEs compared with chemotherapy.ConclusionOur findings indicated that the interaction between immunotherapy efficacy and different sexes was equally evident. Overall, patients with NSCLC could obtain more benefits from ICIs than chemotherapy regimen regardless of their sexes.Systematic Review RegistrationPROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020210797.

ObjectivePD-L1 is one of the predictors of immunotherapy efficacy. Our goal was to analyze its expression and prognostic significance in high-grade salivary gland carcinoma (SGC).MethodsPD-L1 expression was evaluated using paraffin-embedded specimens from patients with surgically treated high-grade SGC, and it was scored by the tumor proportion score (TPS), combined positive score (CPS), and immune cell (IC) score. Associations between clinicopathological variables, disease-free survival (DFS), overall survival (OS) and PD-L1 expression were assessed.ResultsTPS≥1% occurred in 47 patients with an incidence of 43.1%, and it was significantly related to an advanced tumor stage. In patients with TPS

Immune-related genes are important factors in tumor progression. The main aim of this study was to identify the immune-related genes in kidney papillary cell carcinoma (pRCC) patients. We downloaded RNAseq data and clinical information of pRCC patients from the TCGA database and retrieved the immune-related genes list from Immport. From the data, we mined out 2,468 differential expression genes (DEGs) and 183 immune-related DEGs. Four hub DEGs (NTS, BIRC5, ELN, and CHGA) were identified after conducting Cox analysis and LASSO analysis. Moreover, the prognostic value of the signature based on four hub DEGs was verified using Kaplan–Meier analysis (P = 0.0041 in the training set and p = 0.021 in the test set) and ROC analysis (AUC: 0.957 in 1 year, 0.965 in 2 years, and 0.901 in 3 years in the training set, and 0.963 in 1 year, 0.898 in 2 years, and 0.742 in 3 years in the test set). Furthermore, we found that the high-risk score group had a higher percentage of B cells in the immune component, a higher expression of immune-related genes (CTLA4, LAG3, PDCD1LG2, and TIGIT), and a better immunotherapy response.

BackgroundPulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of lung cancer with less than 700 cases being reported in the literature, and no specialized treatment guidelines have been established. The prognostic significance of metabolic parameters on 18F-FDG PET in pulmonary LELC still remains unknown.MethodsFrom July 2011 to September 2020, 76 pulmonary LELC patients undergoing pre-treatment 18F-FDG PET imaging were enrolled, and PET parameters including maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. In addition, whole-body tumor burdens were categorized into primary tumor lesion (PRL), thoracic lymph-node lesion (TRLN), and distant metastasis (DM) for respective metabolic parameters acquisition. ROC curves were generated to evaluate the predictive performance of the PET parameters, and correlations between tumor burdens of the different regional lesions were analyzed using linear correlation analysis. The prognostic significance for progression-free survival (PFS) and overall survival (OS) was assessed using univariate and multivariate survival analyses.ResultsTumor stage, pre-/post-treatment serum EBV-DNA copies, SUVmax (cutoff 17.5), MTV, and TLG were significantly associated with PFS and OS in univariate analysis. MTV and TLG (AUC = 0.862 and 0.857, respectively) showed significantly higher predictive value than SUVmax (AUC = 0.754) and remained independent prognostic indicators for PFS in multivariate analysis (P = 0.026 and 0.019, respectively). Besides, non-colinearity was detected between metabolic burdens of the different regional lesions. MTV-PRL, MTV-DM, TLG-PRL, and TLG-DM were identified to be independent prognostic factors for PFS and OS, whereas MTV-TRLN and TLG-TRLN were not.ConclusionThe study demonstrated that MTV and TLG had independent prognostic significance for pulmonary LELC, which supported the incorporation of 18F-FDG PET imaging into clinical treatment protocols for pulmonary LELC and implied multi-disciplinary cooperation for primary and distant metastatic lesions to further improve prognosis.

BackgroundClear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with a poor clinical outcome. Although several studies have examined the genomic features of ccRCC, the genetic profile of VTT along with its matched primary tumor has not been fully elucidated.Materials and methodsSamples of VTT tissues and matched primary tumor tissues from ccRCC patients (n = 25), as well as primary tumor tissues from patients without VTT (n = 25) were collected and analyzed using whole-exome sequencing. Four additional ccRCC patients who were unfit for surgery were treated with an anti-programmed death receptor-1 (PD-1) monoclonal antibody (Toripalimab, 240 mg, Q3W, IV).ResultsBy comparing the primary kidney tumors from ccRCC patients with or without VTT, a relatively higher prevalence of BAP1 and KDM5C alterations were found in ccRCC patients with VTT, and these alterations were associated with worse overall survival in the kidney renal clear cell carcinoma (KIRC) database. Based on subclone analysis, VTT was predicted to primarily originate directly from the primary renal mass. A significantly higher prevalence of CELSR2 and TET2 alterations were identified in the VTTs compared with the matched primary tumors. An increased prevalence of DNA damage repair genes, especially those involved in homologous recombination repair and non-homologous end joining, was found in ccRCC patients with VTT. Notably, VTT was characterized by the increase incidence of copy number loss in the whole exome (p < 0.05), particularly in the chromosome 9 and 14 regions. Deletion of chromosome 9 and 14 was associated with worse survival, unfavorable clinical features, and the presence of an immunosuppressive microenvironment, which was characterized by higher infiltration of regulatory T cells, follicular helper T cells, and resting mast cells, but lower counts of resting CD4 memory T cells and CD8 positive T cells. A significantly lower count of CD4+ and CD8+ tumor-infiltrated lymphocytes was identified in the VTT samples comparing with matched primary tumor. Of note, three out of the four ccRCC patients with VTT in our cohort who were treated with the anti-PD-1 therapy exhibited remarkable remission in the renal mass but no notable shrinkage in the VTT mass.ConclusionOur study revealed the genetic profile of Chinese ccRCC patients with VTT, and identified multiple features associated with known poor outcomes, including gene alterations and copy number loss. The deletions in chromosomes 9 and 14, and the associated immunosuppressive microenvironment may indicate limited sensitivity to anti-PD-1/PD-L1 monotherapy in VTT.

ObjectiveOur goal was to analyze the demographic and pathologic characteristics as well as prognosis in nonsmoking and nondrinking (NSND) oral squamous cell carcinoma (SCC) patients compared with typical oral SCC patients.Patients and MethodsA total of 353 patients were retrospectively enrolled and divided into two groups: the NSND group and the current smoking/current drinking (CSCD) group. Demographic, pathologic, and molecular data were compared between the two groups. The main research endpoints were locoregional control (LRC) and disease-specific survival (DSS).ResultsIn the NSND group, 16.3%, 41.9%, and 53.5% of patients were aged no more than 40 years, were female, and had an educational background of high school or above compared to 3.7%, 6.0%, and 38.2% of patients in the CSCD group, respectively. A total of 15.1% of the NSND patients had SCC of the lower gingiva and floor of the mouth, which was lower than the 35.6% of patients in the CSCD group. CSCD patients were likely to have an advanced disease stage (48.7% vs 32.5%, p=0.042) and poorly differentiated cancer (26.6% vs 16.3%, p=0.042). The NSND patients had a mean Ki-67 index of 24.5%, which was lower than the mean of 35.7% in the CSCD patients. The two groups had no HPV infection and similar p16 expression (4.7% vs 10.1%, p=0.132), but there was higher expression of p53 (38.6% vs 17.4%, p

PurposeBurkitt lymphoma (BL) is an invasive lymphoma subtype with FDG avid at 18F-FDG PET/CT, but there is currently no validated criterion in treatment evaluation and prognosis prediction. The aim of this study was to analyze the clinical accuracy of 18F-FDG PET/CT in Burkitt lymphoma in end of therapy PET/CT (EOT-PET) to assess the treatment response in BL and conduct a survival analysis with different Deauville 5-point score (DS) cutoff values.Materials and MethodsA total of 189 patients were retrospectively included: 97 underwent baseline PET/CT and all underwent EOT-PET. Survival curves were plotted according to the Kaplan-Meier method. Different DS cutoff values in EOT-PET were evaluated for risk stratification in Burkitt lymphoma.ResultsThe median progression free survival (PFS) and overall survival (OS) were 52 and 53 months, respectively. Applying the conventional DS 4 to 5, there was significant difference in outcome between EOT-PET negative and positive patients. However, the positive predictive value (PPV) (28.3% for PFS and 26.4% for OS) is low despite a high negative predictive value (NPV) (94.1% for OS and 94.9% for OS). When we moved the cutoff point to DS 5, the PPV was improved evidently (88.2% for PFS and 82.3% for OS) with the satisfactory NPV simultaneously (95.3% for PFS and 95.9% for OS).ConclusionsEOT-PET results using DS significantly related with PFS and OS. DS of 5 may be a better cutoff point at the end of treatment to determine whether patients have a significant risk of recurrence or progress.

Extensive research has revealed that the score derived from the Gleason grading system plays a pivotal role in predicting prostate cancer (PCa) progression. However, the underlying involvement of Gleason-related genes in PCa requires further investigation. This study aimed to identify Gleason-related genes with the potential to guide PCa therapy and future research. Differentially expressed genes (DEGs) were identified by comparing PCa tissues with high or low Gleason scores using the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. R v3.6.1, SPSS v23, and ImageJ software were used for all analyses. An effective recurrence-free survival (RFS) predictive model based on seven Gleason-related genes was established and validated (TCGA, AUC = 0.803; five years, AUC = 0.740; three years, AUC = 0.722; one year, AUC = 0.711; GSE46602, AUC = 0.766; five years, AUC = 0.808; three years, AUC = 0.723; one year, AUC = 0.656; GSE116918, AUC = 0.788; five years, AUC = 0.704; three years, AUC = 0.693; one year, AUC = 0.996). Calibration and nomogram plots were conducted. Weighted correlation network analysis (WGCNA) was used, and COL5A2 was selected for further analysis. The results from in vitro experiments demonstrated that COL5A2 was upregulated in PCa with high Gleason scores. The knockdown of COL5A2 inhibited cell proliferation and invasion in PC-3 and LNCaP cell lines. Meanwhile, COL5A2 displayed a strong association with immune infiltration, which might be an underlying immunotherapy target for PCa. We successfully established a robust RFS predictive model. The findings from this study indicated that COL5A2 could promote cell proliferation and invasion in PCa.

Gastric cancer is a malignant tumor characterized by high morbidity and invasion. Surgery combined with chemo-radiotherapy is the most common treatment for gastric cancer, while multiple drug resistance always results in treatment failure. Once the anti-tumor drugs enter the tumor foci, tumor cells as well as those found in the microenvironment are affected. However, the effects of drugs on tumor microenvironment (TME) are easily overlooked. In this study, we investigated the effects of the anti-cancer drug 3,3’-diindolylmethane (DIM) on gastric cancer-derived mesenchymal stem cells (GC-MSCs) and their subsequent impact on cancer progression. Surprisingly, we found that the therapeutic concentration of DIM upregulated the expression level of tumor-related factors such as CCL-2, IL-6, and IL-8 in GC-MSCs. The conditioned medium of DIM-treated GC-MSCs promoted the proliferation, invasion, and migration of gastric cancer cells in vitro and tumor growth in vivo. Mechanistically, DIM enhanced the expression of β-TrCP, an E3 ubiquitin ligase leading to IκBα degradation and NF-κB activation in GC-MSCs. The β-TrCP knockdown partially eliminated positive results caused by DIM. Our results showed that the therapeutic dosage of DIM induced cell death in cancer cells, while enhancing MSC paracrine functions in the stroma to offset the original DIM effect on cancer cells. These findings provide a new mechanism of anti-cancer drug resistance and remind us to adjust the chemotherapeutic scheme by combining the anti-cancer drug with an appropriate signaling pathway inhibitor to block the side effects of drug on targeted TME cells.

Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination.

BackgroundConventional clinical detection methods such as CT, urine cytology, and ureteroscopy display low sensitivity and/or are invasive in the diagnosis of upper tract urinary carcinoma (UTUC), a factor precluding their use. Previous studies on urine biopsy have not shown satisfactory sensitivity and specificity in the application of both gene mutation or gene methylation panels. Therefore, these unfavorable factors call for an urgent need for a sensitive and non-invasive method for the diagnosis of UTUC.MethodsIn this study, a total of 161 hematuria patients were enrolled with (n = 69) or without (n = 92) UTUC. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel. Further, a logistic regression prediction model that contained several significant features was used to evaluate the risk of UTUC in these patients.ResultsIn total, 86 UTUC− and 64 UTUC+ case samples were enrolled for the analysis. A logistic regression analysis of significant features including age, the mutation status of TERT promoter, and ONECUT2 methylation level resulted in an optimal model with a sensitivity of 94.0%, a specificity of 93.1%, the positive predictive value of 92.2% and a negative predictive value of 94.7%. Notably, the area under the curve (AUC) was 0.957 in the training dataset while internal validation produced an AUC of 0.962. It is worth noting that during follow-up, a patient diagnosed with ureteral inflammation at the time of diagnosis exhibiting both positive mutation and methylation test results was diagnosed with ureteral carcinoma 17 months after his enrollment.ConclusionThis work utilized the epigenetic biomarker ONECUT2 for the first time in the detection of UTUC and discovered its superior performance. To improve its sensitivity, we combined the biomarker with high-throughput sequencing of 17 genes test. It was found that the selected logistic regression model diagnosed with ureteral cancer can evaluate upper tract urinary carcinoma risk of patients with hematuria and outperform other existing panels in providing clinical recommendations for the diagnosis of UTUC. Moreover, its high negative predictive value is conducive to rule to exclude patients without UTUC.

Glioblastoma multiforme (GBM) is a devastating disease yet no effective drug treatment has been established to date. Glioblastoma stem-like cells (GSCs) are insensitive to treatment and may be one of the reasons for the relapse of GBM. Maternal embryonic leucine zipper kinase gene (MELK) plays an important role in the malignant proliferation and the maintenance of GSC stemness properties of GBM. However, the therapeutic effect of targeted inhibition of MELK on GBM remains unclear. This study analyzed the effect of a MELK oral inhibitor, OTSSP167, on GBM proliferation and the maintenance of GSC stemness. OTSSP167 significantly inhibited cell proliferation, colony formation, invasion, and migration of GBM. OTSSP167 treatment reduced the expression of cell cycle G2/M phase-related proteins, Cyclin B1 and Cdc2, while up-regulation the expression of p21 and subsequently induced cell cycle arrest at the G2/M phase. OTSSP167 effectively prolonged the survival of tumor-bearing mice and inhibited tumor cell growth in in vivo mouse models. It also reduced protein kinase B (AKT) phosphorylation levels by OTSSP167 treatment, thereby disrupting the proliferation and invasion of GBM cells. Furthermore, OTSSP167 inhibited the proliferation, neurosphere formation and self-renewal capacity of GSCs by reducing forkhead box M1 (FOXM1) phosphorylation and transcriptional activity. Interestingly, the inhibitory effect of OTSSP167 on the proliferation of GSCs was 4-fold more effective than GBM cells. In conclusion, MELK inhibition suppresses the growth of GBM and GSCs by double-blocking AKT and FOXM1 signals. Targeted inhibition of MELK may thus be potentially used as a novel treatment for GBM.

BackgroundTo evaluate the efficacy and safety of everolimus, a mTOR inhibitor, on invasive malignant renal epithelioid angiomyolipoma (EAML).Materials and MethodsFrom Oct 2014 to May 2019, we collected data from seven patients with a definite (clinical and pathological) diagnosis of EAML received everolimus in our hospital. Targeted sequence capture array technique with next-generation of high throughput sequencing (NGS) were performed to detect mutations of TSC1/2 genes. All patients had received surgery and everolimus. The clinical efficacy and safety of the therapy were evaluated.ResultsMutations of TSC1 and TSC2 were detected in two and three patients though targeted sequence capture array technique with NGS, respectively. Among seven patients, three had missense mutations, one had nonsense mutation, and one had the large fragment deletion mutation. Five patients accompanied with tuberous sclerosis complex (TSC) were identified. All patients were administered 10mg everolimus once daily, the treatment duration lasted for 3 to 28 months. The objective response was assessed 3 months later, five partial response, two stable disease (SD), the mean greatest tumor diameter of all patients decreased from 9.6 to 5.2cm. Six patients stayed SD and one patient died during follow up. Patients accompanying with TSC had better responses to everolimus compared with non-TSC.ConclusionThe mTOR inhibitor can be an effective treatment for patients with invasive malignant renal EAML. Patients with TSC may benefit more from the therapy.

ObjectivesOur goal was to analyze the possibility of using metabolic tumor volume (MTV) to predict occult cervical metastasis and survival in cT1-2N0 squamous cell carcinoma (SCC) of the tongue.MethodsData on the primary tumor MTV and cervical node status as determined by the maximum standardized uptake value were retrieved. The sensitivity and specificity in predicting occult metastasis were calculated with a fourfold table. Associations between occult metastasis and clinicopathological variables were evaluated by univariate and multivariate analyses. The main study endpoints were locoregional control (LRC) and disease-specific survival (DSS).ResultsA total of 24 (20.3%) of 118 patients had occult metastasis. An MTV cutoff value of 4.3 cm3 showed a sensitivity of 50.0% and a specificity of 76.6% in predicting occult metastasis. The sensitivity and specificity of PET-CT in predicting occult metastasis in cT1 tumors were 66.6 and 89.8%, respectively, with values of 83.3 and 67.3%, respectively, when combined with the MTV. The sensitivity and specificity of PET-CT in predicting occult metastasis in cT2 tumors were 72.2 and 82.2%, respectively, with values of 88.9 and 57.8%, respectively, when combined with the MTV. Patients with MTV ≥4.3 cm3 had a higher occult metastasis rate than patients with MTV

Meningiomas are the most common primary tumors of the central nervous system. Given the fact that the majority of meningiomas are benign, the preoperative risk stratification and treatment strategy decision-making highly rely on the conventional subjective radiologic evaluation. However, this traditional diagnostic and treatment modality may not be effective in patients with aggressive-growing tumors or symptomatic patients with potential risk of recurrence after surgical resection or radiotherapy, as this passive “wait and see” strategy could miss the optimal opportunity of intervention. Radiomics, a new rising discipline, translates high-dimensional image information into abundant mathematical data by multiple computational algorithms. It provides an objective and quantitative approach to interpret the imaging data, rather than the subjective and qualitative interpretation from relatively limited human visual observation. In fact, the enormous amount of information generated by radiomics analyses provides radiological to histopathological tumor information, which are visually imperceptible, and offers technological basis to its applications amid diagnosis, treatment, and prognosis. Here, we review the latest advancements of radiomics and its applications in the prediction of the pathological grade, pathological subtype, recurrence possibility, and differential diagnosis of meningiomas, and the potential and challenges in general clinical applications. In this review, we highlight the generalization of shared radiomic features among different studies and compare different performances of popular algorithms. At last, we discuss several possible aspects of challenges and future directions in the development of radiomic applications in meningiomas.