Novel decision tree models predict the overall survival of patients with submandibular gland cancer.

BACKGROUND: While the accurate prediction of the overall survival (OS) in patients with submandibular gland cancer (SGC) is paramount for informed therapeutic planning, the development of reliable survival prediction models has been hindered by the rarity of SGC cases. The purpose of this study is to identify key prognostic factors for OS in SGC patients using a large database and construct decision tree models to aid the prediction of survival probabilities in 12, 24, 60 and 120 months. MATERIALS AND METHODS: We performed a retrospective cohort study using the Surveillance, Epidemiology and End Result (SEER) program. Demographic and peri-operative predictor variables were identified. The outcome variables overall survival at 12-, 24-, 60, and 120 months. The C5.0 algorithm was utilized to establish the dichotomous decision tree models, with the depth of tree limited within 4 layers. To evaluate the performances of the novel models, the receiver operator characteristic (ROC) curves were generated, and the metrics such as accuracy rate, and area under ROC curve (AUC) were calculated. RESULTS: A total of 1,705, 1,666, 1,543, and 1,413 SGC patients with a follow up of 12, 24, 60 and 120 months and exact survival status were identified from the SEER database. Predictor variables of age, sex, surgery, radiation, chemotherapy, tumor histology, summary stage, metastasis to distant lymph node, and marital status exerted substantial influence on overall survival. Decision tree models were then developed, incorporating these vital prognostic indicators. Favorable consistency was presented between the predicted and actual survival statuses. For the training dataset, the accuracy rates for the 12-, 24-, 60- and 120-month survival models were 0.866, 0.767, 0.737 and 0.797. Correspondingly, the AUC values were 0.841, 0.756, 0.725, and 0.774 for the same time points. CONCLUSIONS: Based on the most important predictor variables identified using the large, SEER database, decision tree models were established that predict OS of SGC patients. The models offer a more exhaustive evaluation of mortality risk and may lead to more personalized treatment strategies.

Organophosphate esters in human serum: a relatively simple and efficient liquid chromatography-mass spectrometry method.

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers, which are of growing concern due to their endocrine-disrupting effects, developmental toxicity, and potential carcinogenicity. However, data on human exposure to OPEs is still scarce. In this study, a relatively simple and efficient method with less serum consumption for the detection of OPEs in human serum was developed and validated. Nine OPEs in 200 µL of human serum were extracted by an acetonitrile-formic acid system and analyzed using ultra-high-performance liquid chromatography-quadrupole tandem time-of-flight high-resolution mass spectrometry. Several experiments were conducted to optimize the chromatographic and mass spectrometric conditions as well as sample preparation to obtain a more sensitive and efficient analytical protocol. The proposed method was examined in terms of its linearity, accuracy, precision, detection limit, and matrix effect. The matrix-spiked recoveries of the target OPEs ranged from 83.3% to 111.1%, with relative standard deviations between 2.7% and 16.6%. The detection limits were within (0.002 to 0.029) ng mL-1, while the quantification limits were within (0.007 to 0.098) ng mL-1. The internal standard-corrected matrix effects varied from 82.7% to 113.9%. Finally, the method was applied to detect OPEs in actual human serum samples. All nine OPEs were detected in 269 serum samples to varying degrees, with the average concentrations ranging from (0.08 to 1.77) ng mL-1. After validation, the method was found to be simple in pretreatment, high in sensitivity, good in practicality, and suitable for exposure evaluation of OPEs in populations.

Thyroid cancer prognostic biomarker ARL4A and its relationship with immune infiltration.

BACKGROUND: Thyroid cancer (THCA) is a prevalent form of cancer with high rates of morbidity and mortality. The small GTPase ADP-ribosylation factor-like 4A (ARL4A) is integral to various cellular processes, including cytoskeletal restructuring, vesicular transport, cell migration, and neuronal development. However, the role of ARL4A as a clinical predictor, particularly its relation to immune cell infiltration in THCA, remains unclear. METHODS: A combination of experimental studies and analysis of online databases was employed to investigate ARL4A expression in THCA. Clinical and pathological data from THCA patients were compiled for a comprehensive subgroup analysis. The Kaplan-Meier and Cox regression methods were utilized to evaluate the prognostic significance of ARL4A in THCA patients. Finally, the "Cancer Genome Atlas" was analyzed to explore the correlation between immune cell infiltration, ARL4A expression, and their joint impact on prognosis. RESULTS: ARL4A exhibited low expression in THCA. An elevated ARL4A was associated with poor prognosis. Moreover, the expression of ARL4A was correlated with the age, gender, and pathological stage of THCA patients. Finally, ARL4A expression was found to be negatively correlated with immune cell infiltration and influenced the prognosis of patients through changes in the immune environment. CONCLUSION: ARL4A may serve as a potential biomarker for the diagnosis and treatment of THCA, impacting the prognosis of patients through the modulation of the immune microenvironment.

Prognostic factors and novel prediction models for overall survival of patients with submandibular gland cancer: A population-based retrospective cohort study.

Background: Accurately predicting the survival rate of submandibular gland cancer (SGC) is of significant importance for guiding treatment decision-making and improving patient outcomes. This study was aimed to identify the independent prognostic factors of overall survival (OS) in SGC patients, and develop novel prediction models to aid clinicians in predicting the survival probability. Materials and methods: Patients diagnosed with primary SGC after the year 2010 were extracted from SEER database and then randomly allocated into training and test samples in a 7:3 ratio. Uni- and multi-variable COX analyses were employed using the training sample to ascertain independent prognostic factors for OS. Subsequently, graphic and online dynamic nomograms were established basing on the independent prognostic factors. We utilized C-index, calibration curve, receiver operating characteristic (ROC) curve, and area under ROC curve (AUC) value to evaluate the discrimination capacity and the consistency between predicted and actual survival. Results: A total of 527 SGC patients were included (369 assigned to training group and 158 assigned to test group). The multivariable COX analysis showed that age, sex, marital status, tumor histology, summary stage, metastases to bone, and tumor size were independently associated with OS. Novel graphical and online dynamic (URL: https://yangxg1209.shinyapps.io/overall_survival_submandibular_gland_tumor/) nomograms were established. The C-indices (training: 0.77, 95%CI 0.71-0.84; test: 0.77, 95%CI 0.68-0.85) indicate favorable discrimination ability of the model, and the calibration curves demonstrated favorable consistency between the predicted and actual survival rates. Conclusions: Our study identified the independent prognostic factors influencing OS in patients with SGC, and successfully established and validated novel nomograms, which provide accurate prediction of survival rates and allows for personalized risk assessment.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy.

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Concurrent chemoradiotherapy plus anlotinib vs. concurrent chemoradiotherapy alone in locally advanced nasopharyngeal carcinoma: An interim analysis of a multicenter randomized controlled trial.

Despite the use of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy (CCRT), the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is not satisfactory. EGFR and VEGFR are highly expressed in 60-80% of patients with LA-NPC and this is associated with a poor prognosis, which suggests the potential effectiveness of an inhibitor targeting tumor angiogenesis for treating LA-NPC. The present study aimed to assess the safety and effectiveness of CCRT combined with anlotinib in patients with LA-NPC. The study involved patients with LA-NPC (stage III-IVA) from four institutions in Guangxi, China. Patients were randomized to receive CCRT + anlotinib (n=36) or CCRT alone (n=37). Acute toxicity and short-term efficacy were evaluated. The most common grade 3 or 4 adverse events were leucopenia [10 (27.7%) vs. 8 (21.6%)], neutropenia [6 (16.7%) vs. 5 (13.5%)] and mucositis [13 (36.1%) vs. 11 (29.7%)] in the CCRT + anlotinib vs. CCRT cohort but there were no significant differences between the two cohorts (P=0.54, P=0.70 and P=0.56, respectively). Two patients (5.6%) displayed grade 1/2 hemorrhage in the CCRT + anlotinib cohort. No patient displayed grade 3/4 hemorrhages or adverse event-associated deaths in any cohort. Complete response rates in the CCRT + anlotinib arm at 1 week and 3 and 6 months post-radiotherapy were 60.0, 91.4, and 97.1%, respectively, compared with 40.5, 81.1 and 91.9% in the CCRT arm but there was no significant difference (P=0.10, P=0.35 and P=0.65, respectively). This interim analysis of the ongoing trial showed that administration of CCRT + anlotinib has acceptable toxicity profiles, good compliance and promising results in patients with LA-NPC. A larger study cohort and a longer follow-up period are needed to confirm therapeutic effectiveness and late toxicity.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Current understanding of cancer stem cells: Immune evasion and targeted immunotherapy in gastrointestinal malignancies.

As a relatively rare population of cancer cells existing in the tumor microenvironment, cancer stem cells (CSCs) possess properties of immune privilege to evade the attack of immune system, regulated by the microenvironment of CSCs, the so-called CSCs niche. The bidirectional interaction of CSCs with tumor microenvironment (TME) components favors an immunosuppressive shelter for CSCs' survival and maintenance. Gastrointestinal cancer stem cells (GCSCs) are broadly regarded to be intimately involved in tumor initiation, progression, metastasis and recurrence, with elevated tumor resistance to conventional therapies, which pose a major hindrance to the clinical efficacy for treated patients with gastrointestinal malignancies. Thus, a multitude of efforts have been made to combat and eradicate GCSCs within the tumor mass. Among diverse methods of targeting CSCs in gastrointestinal malignancies, immunotherapy represents a promising strategy. And the better understanding of GCSCs immunomodulation and immunoresistance mechanisms is beneficial to guide and design novel GCSCs-specific immunotherapies with enhanced immune response and clinical efficacy. In this review, we have gathered available and updated information to present an overview of the immunoevasion features harbored by cancer stem cells, and we focus on the description of immune escape strategies utilized by CSCs and microenvironmental regulations underlying CSCs immuno-suppression in the context of gastrointestinal malignancies. Importantly, this review offers deep insights into recent advances of CSC-targeting immunotherapeutic approaches in gastrointestinal cancers.

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

The applicability of the Second Revision of the International Staging System for patients with multiple myeloma receiving immunomodulatory drugs or proteasome inhibitor-based regimens as induction treatment: A real-world analysis.

The Second Revision of the International Staging System (R2-ISS) was recently introduced to improve risk stratification over that provided by the extensively applied standard revised International Staging System (R-ISS). In addition to the variables included in the R-ISS, the R2-ISS incorporates chromosome 1q gain/amplification and divides the patients into 4 groups with different survival outcomes, better stratifying patients within the R-ISS intermediate-risk. The new model was developed based on a great quantity of data from patients participating in uniform clinical trials and has not been validated in real-world clinical practice. Therefore, we retrospectively analyzed the prognostic value of the R2-ISS in 474 consecutive patients with multiple myeloma receiving immunomodulatory drugs or proteasome inhibitor-based regimens as their first-line treatment. According to the R2-ISS, 41 (8.6%), 76 (16%), 275 (58%), and 82 (17.3%) patients were identified as R2-ISS I, R2-ISS II, R2-ISS III, and R2-ISS IV, respectively. The median progression-free survival (PFS) was 48 (95% CI: 38-58), 35 (95% CI: 23-47), 24 (95% CI: 21-27), and 12 (95% CI: 7-17) months, and the estimated median overall survival (OS) was 110 (95% CI: 42-178), 88 (95% CI: 75-101), 50 (95% CI: 43-57), and 26 (95% CI: 19-33) months (p < 0.001) in the 4 groups, respectively. The R2-ISS could also classify groups with distinct survival among patients with renal impairment or classified as R-ISS II. Adjusted by age, sex, treatment approaches and transplantation status, the R2-ISS was an independent prognostic factor associated with OS with a hazard ratio of 7.055 (95% CI: 3.626-13.726) (p < 0.001) for R2-ISS IV versus R2-ISS I and 2.707 (95% CI: 1.436-5.103) (p = 0.002) for R2-ISS III versus R2-ISS I. In conclusion, our results suggest that the R2-ISS is a simple and robust risk stratification tool for patients with multiple myeloma treated with novel drugs and could be used in everyday clinical practice.

Maintenance therapy improves the survival outcomes of patients with metastatic nasopharyngeal carcinoma responding to first-line chemotherapy: a multicentre, randomized controlled clinical study.

PURPOSE: To explore the safety and role of tegafur/gimeracil/oteracil (S1) maintenance therapy (MT) in metastatic nasopharyngeal carcinoma (NPC) patients after response to first-line chemotherapy and to assess outcome-associated biomarkers. METHODS: This was a multicentre, open-label, randomized controlled study involving metastatic NPC patients recruited (from May 2015 to May 2019) at five hospitals in China. The participants were randomized to S1-MT (receiving S1 MT until disease progression or intolerance) or non-MT (followed up until disease progression) groups. The primary endpoint was the progression-free survival (PFS). The secondary endpoints were the overall survival (OS), the correlation between EBV-DNA, serum amyloid A (SAA) status, and outcomes after the first-line chemotherapy, and safety. RESULTS: The median follow-up was 24.3 months; 88 and 95 participants were evaluable in the S1-MT and non-MT groups, respectively. Compared with non-MT, S1-MT prolonged PFS (16.9 vs. 9.3 months, P < 0.001) and OS (33.6 vs. 20.6 months, P < 0.001). Regardless of their EBV-DNA status after first-line chemotherapy, participants were able to benefit from S1 MT, but EBV-DNA-positive participants benefited more significantly (PFS: HR = 0.600, 95% CI = 0.373-0.965, P = 0.035; OS: HR = 0.393, 95% CI = 0.227-0.681, P = 0.001). MT only improved PFS and OS in patients with an SAA decline after first-line chemotherapy (PFS: HR = 0.570, 95% CI = 0.350-0.919, P = 0.021; OS: HR = 0.404, 95% CI = 0.230-0.709, P = 0.002). The median S1 treatment was 23 cycles. Grade 1-2 skin pigmentation, oral mucositis, and hand and foot syndrome were the main adverse reactions. CONCLUSION: For metastatic NPC patients with first-line chemotherapy response, S1 MT can improve PFS and OS, with good tolerability. EBV-DNA and SAA can better help us identify patients who can benefit from MT after standard treatment. TRIAL REGISTRATION: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR-IOR-16007939).

A prospective, open-label, multicenter phase IV clinical trial on the safety and efficacy of lobaplatin-based chemotherapy in advanced breast cancer.

Background: Since lobaplatin (LBP) has been approved to treat metastatic breast cancer in China, this study aimed to evaluate the safety and efficacy of LBP-based chemotherapy in clinical practice. Methods: This trial was a prospective, open-label, multicenter phase IV clinical trial that enrolled patients with unresectable locally advanced or recurrent/metastatic breast cancer from 34 sites between July 2013 and March 2017. Patients were treated with LBP monotherapy or in combination for four to six cycles. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 1179 patients were analyzed; 59 (5.0%) were treated with LBP alone, 134 (11.4%) with LBP plus paclitaxel, 263 (22.3%) with LBP plus docetaxel, 237 (20.1%) with LBP plus gemcitabine, 403 (34.2%) with LBP plus vinorelbine, and 83 (7.0%) with other LBP-based regimens. The overall incidence of adverse events (AEs) was 95.2%, and 57.9% of patients had grade >3 AEs. The most common grade >3 AEs were neutropenia (43.9%), leukopenia (39.4%), anemia (17.8%), and thrombopenia (17.7%). LBP monotherapy showed the lowest incidence of grade >3 AEs (39.0%), followed by LBP plus docetaxel (52.9%), LBP plus paclitaxel (59.0%), LBP plus vinorelbine (62.5%), and LBP plus gemcitabine (62.9%). The ORR and DCR were 36.8 and 77.0%, respectively. The median PFS was 5.5 months (95% confidence interval: 5.2-5.9). Conclusion: LBP-based chemotherapy shows favorable efficacy in patients with advanced breast cancer, with manageable safety profile. Trial registration: This trial was registered with ChiCTR.org.cn, ChiCTR-ONC-13003471.

A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Downregulation of the enhancer of zeste homolog 1 transcriptional factor predicts poor prognosis of triple-negative breast cancer patients.

Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer and lacks effective biomarkers. This study seeks to unravel the expression status and the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC tissue samples. Moreover, another objective of this study is to reveal the prognostic molecular signatures for risk stratification in TNBC patients. Methods: To determine the expression status of EZH1/EZH2 in TNBC tissue samples, microarray analysis and immunohistochemistry were performed on in house breast cancer tissue samples. External mRNA expression matrices were used to verify its expression patterns. Furthermore, the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC were explored by performing differential expression analysis, co-expression analysis, and chromatin immunoprecipitation sequencing analysis. Kaplan-Meier survival analysis and univariate Cox regression analysis were utilized to detect the prognostic molecular signatures in TNBC patients. Nomogram and time-dependent receiver operating characteristic curves were plotted to predict the risk stratification ability of the prognostic-signatures-based Cox model. Results: In-house TMAs (66 TNBC vs. 106 non-TNBC) and external gene microarrays, as well as RNA-seq datasets (1,135 TNBC vs. 6,198 non-TNBC) results, confirmed the downregulation of EZH1 at both the protein and mRNA levels (SMD = -0.59 [-0.80, -0.37]), as is opposite to that of EZH2 (SMD = 0.74 [0.40, 1.08]). The upregulated transcriptional target genes of EZH1 were significantly aggregated in the cell cycle pathway, where CCNA2, CCNB1, MAD2L1, and PKMYT1 were determined as key transcriptional targets. Additionally, the downregulated transcriptional targets of EZH2 were enriched in response to the hormone, where ESR1 was identified as the hub gene. The six-signature-based prognostic model produced an impressive performance in this study, with a training AUC of 0.753, 0.981, and 0.977 at 3-, 5-, and 10-year survival probability, respectively. Conclusion: EZH1 downregulation may be a key modulator in the progression of TNBC through negative transcriptional regulation by targeting CCNA2, CCNB1, MAD2L1, and PKMYT1.

Case Report: Extracorporeal Membrane Oxygenation Followed by Intra-Aortic Balloon Counterpulsation Successfully Treated Cardiac Arrest Caused by Anomalous Origin of a Left Coronary Artery From the Right Coronary Sinus.

Background: Anomalous origin of a coronary artery (AOCA) is defined as the failure of the coronary artery to originate from the normal coronary sinus. The anomalous origin of the left coronary artery arising from the right coronary sinus is rare, dangerous and at risk of malignant arrhythmia, sudden death, and high mortality. Case Presentation: In this study, we present a 14-year-old adolescent male who went to a hospital with transient unconsciousness after exercise, who subsequently developed cardio arrest due to malignant arrhythmia. He was admitted to the intensive care unit, and who subsequently received successful veno-arterial extracorporeal membrane oxygenation (VA ECMO) assisted circulation followed by intra-aortic balloon counterpulsation (IABP). Echocardiography and cardiac CTA were also performed, further confirming that the abnormal left coronary artery originated from the right coronary sinus. The patient subsequently underwent heart surgery. Conclusion: The successful treatment of the patient in this report was attributed to the immediately VA ECMO, supplemented by IABP. Establishing clear diagnosis is a process of multidisciplinary joint diagnosis, which provides a reference for clinicians when encountering similar cases.

Identification of a TGF-ß signaling-related gene signature for prediction of immunotherapy and targeted therapy for lung adenocarcinoma.

BACKGROUND: Transforming growth factor (TGF)-ß signaling functions importantly in regulating tumor microenvironment (TME). This study developed a prognostic gene signature based on TGF-ß signaling-related genes for predicting clinical outcome of patients with lung adenocarcinoma (LUAD). METHODS: TGF-ß signaling-related genes came from The Molecular Signature Database (MSigDB). LUAD prognosis-related genes were screened from all the genes involved in TGF-ß signaling using least absolute shrinkage and selection operator (LASSO) Cox regression analysis and then used to establish a risk score model for LUAD. ESTIMATE and CIBERSORT analyzed infiltration of immune cells in TME. Immunotherapy response was analyzed by the TIDE algorithm. RESULTS: A LUAD prognostic 5-gene signature was developed based on 54 TGF-ß signaling-related genes. Prognosis of high-risk patients was significantly worse than low-risk patients. Both internal validation and external dataset validation confirmed a high precision of the risk model in predicting the clinical outcomes of LUAD patients. Multivariate Cox analysis demonstrated the model independence in OS prediction of LUAD. The risk model was significantly related to the infiltration of 9 kinds of immune cells, matrix, and immune components in TME. Low-risk patients tended to respond more actively to anti-PD-1 treatment, while high-risk patients were more sensitive to chemotherapy and targeted therapy. CONCLUSIONS: The 5-gene signature based on TGF-ß signaling-related genes showed potential for LUAD management.