Prognostic and incremental value of computed tomography-based radiomics from tumor and nodal regions in esophageal squamous cell carcinoma.

Objective: This study aimed to evaluate the prognostic value of preoperative radiomics and establish an integrated model for esophageal squamous cell cancer (ESCC). Methods: A total of 931 patients were retrospectively enrolled in this study (training cohort, n=624; validation cohort, n=307). Radiomics features were obtained by contrast-enhanced computed tomography (CT) before esophagectomy. A radiomics index was set based on features of tumor and reginal lymph nodes by using the least absolute shrinkage and selection operator (LASSO) Cox regression. Prognostic nomogram was built based on radiomics index and other independent risk factors. The prognostic value was assessed by using Harrell's concordance index, time-dependent receiver operating characteristics and Kaplan-Meier curves. Results: Twelve radiomic features from tumor and lymph node regions were identified to build a radiomics index, which was significantly associated with overall survival (OS) in both training cohort and validation cohort. The radiomics index was highly correlated with clinical tumor-node-metastasis (cTNM) and pathologic TNM (pTNM) stages, but it demonstrated a better prognostic value compared with cTNM stage and was almost comparable with pTNM stage. Multivariable Cox regression showed that the radiomics index was an independent prognostic factor. An integrated model was constructed based on gender, preoperative serum sodium concentration, pTNM and the radiomics index for clinical usefulness. The integrated model demonstrated discriminatory ability better compared with the traditional clinical-pathologic model and pTNM alone, indicating incremental value for prognosis. Conclusions: CT-based radiomics for primary tumor and reginal lymph nodes was sufficient in predicting OS for patients with ESCC. The integrated model demonstrated incremental value for prognosis and was robust for clinical applications.

Development and Validation of a Practical Prognostic Coagulation Index for Patients with Esophageal Squamous Cell Cancer.

BACKGROUND: This study aimed to establish an effective and practical prognostic index for esophageal squamous cell cancer (ESCC) based on the coagulation factors. METHODS: The training cohort of 965 patients with ESCC was retrospectively collected at Sichuan Cancer Hospital from 2012 to 2014, along with clinical characteristics and follow-up information. Risk factors of coagulation status, including 11 blood parameters (platelet [PLT], mean platelet volume [MPV], platelet distribution width [PDW], plateletocrit [PCT], thrombin time [TT], prothrombin time [PT], international normalized ratio [INR], activated partial thromboplastin time [APTT], fibrinogen, D-dimer, and fibrinogen degradation product [FDP]), were studied by least absolute shrinkage and selection operator (LASSO) Cox regression and the Coagulation Index was established. The index was validated in a cohort of 848 patients with ESCC at the same institution, from 2015 to 2016. RESULTS: Three variables of PLT, MPV, and fibrinogen were identified by selecting features with coefficients in the LASSO algorithm, and a Coagulation Index was established as follows: Coagulation Index = 0.0005 × PLT (109/L) - 0.0384 × MPV (fL) + 0.1148 × fibrinogen (g/L). A higher Coagulation Index score was significantly associated with higher pT stage and pN stage (p < 0.05). With this prognostic index, patients could be stratified into three risk groups. The 3-year overall survival (OS) rates of the low-, middle- and high-risk groups in the training cohort were 63.5%, 55.5% and 43.1%, respectively (log-rank p < 0.001). Similarly, in the validation set, the respective 3-year OS for each risk group was significantly different across the three risk groups. Multivariate analysis indicated that the Coagulation Index remained a significant factor for predicting OS, independently of pathological TNM stage. CONCLUSIONS: The Coagulation Index is an independent predictor of survival for patients with ESCC.

Spatiotemporal Changes in the Gene Expression Spectrum of the ß2 Adrenergic Receptor Signaling Pathway in the Lungs of Rhesus Monkeys.

OBJECTIVE: ß2 adrenergic receptor (ADRB2) agonists mainly participate in regulation of airway function through the ADRB2-G protein-adenylyl cyclase (AC) signaling pathway; however, the key genes associated with this pathway and the spatiotemporal changes in the expression spectrum of some of their subtypes remain unclear, resulting in an insufficient theoretical basis for formulating the dose and method of drug administration for neonates. METHODS: We performed sampling at different developmental time points in rhesus monkeys, including the embryo stage, neonatal stage, and adolescence. The MiSeq platform was used for sequencing of key genes and some of their subtypes in the ADRB2 signaling pathway in lung tissues, and target gene expression was normalized and calculated according to reads per kilobase million. RESULTS: At different lung-developmental stages, we observed expression of phenylethanolamine N-methyltransferase (PNMT), ADRB2, AC, AKAP and EPAC subtypes (except AC8, AKAP4/5), and various phosphodiesterase (PDE) subtypes (PDE3, PDE4, PDE7, and PDE8), with persistently high expression of AC6, PDE4B, and AKAP(1/2/8/9/12/13, and EZR) maintained throughout the lung-developmental process, PNMT, ADRB2, AC(4/6), PDE4B, and AKAP(1/2/8/9/12/13, EZR, and MAP2)were highly expressed at the neonatal stage. CONCLUSION: During normal lung development in rhesus monkeys, key genes associated with ADRB2-G protein-AC signaling and some of their subtypes are almost all expressed at the neonatal stage, suggesting that this signaling pathway plays a role in this developmental stage. Additionally, AC6, PDE4B, and AKAP(1/2/8/9/12/13, and EZR) showed persistently high expression during the entire lung-developmental process, which provides a reference for the development and utilization of key gene subtypes in this pathway.

Postoperative Chemotherapy for Thoracic Pathological T3N0M0 Esophageal Squamous Cell Carcinoma.

INTRODUCTION: The role of postoperative chemotherapy (POCT) in pathologic T3N0M0 thoracic esophageal squamous cell carcinoma (TESCC) has not been well addressed. The purpose of this study was to investigate the impact of postoperative adjuvant chemotherapy on survival, recurrence, and toxicities in pathologic T3N0M0 TESCC. METHODS: This study included 582 patients with pT3N0M0 TESCC who were treated at Sichuan Cancer Hospital from January 2009 to December 2017. The patients were divided into two groups: surgery plus postoperative chemotherapy group (S + POCT), and surgery group (S group). Propensity score matching was used to create patient groups that were balanced across several covariates (n = 236 in each group). Outcome measures included overall survival (OS) and disease-free survival (DFS). RESULTS: After PSM, both groups have balance factors. S + POCT have significantly improved the 5-year OS and DFS (OS, 70.8% vs. 52.8%, p <0.0001; DFS, 66.5% vs. 50.2%, p < 0.0001). Multivariate Cox analyses in the matched samples revealed that S + POCT were independently associated with longer OS (hazard ratio (HR) = 0.56, 95% confidence index (CI) 0.41-0.77, p < 0.0001) and longer DFS (HR = 0.60, 95% CI 0.45-0.82, p = 0.001) than surgery alone. Subgroup analyses showed that prognostic effect of POCT was significantly influenced by the number of resected lymph node (≤ 20) and pStage IIB but not influenced by the number of node > 20 and pStage IIA. CONCLUSIONS: Postoperative adjuvant chemotherapy is strongly associated with improved OS and DFS in patients with pT3N0M0 TESCC. A multicenter, randomized, phase III clinical trial is warranted to confirm these findings.

[Expression of B7 Family Co-inhibitory Molecules in the Establishment of Pulmonary Regional Immunity].

OBJECTIVE: To identify the temporal-spatial expression of B7 family co-inhibitory molecules during lung development, and to explore the roles of B7 family co-inhibitory molecules in the developmental process of pulmonary regional immunity. METHODS: The expression of B7 family co-inhibitory molecules (B7-1, B7-2, B7-H1, B7-DC) in different developmental stages of Rhesus monkey lungs were normalized and calculated by the reads per kilo-base of transcript per million mapped reads (RPKM) method. Immunohistochemical staining was performed to identify the localization and the protein of B7 family co-inhibitory molecules in different developmental phase (canalicular stage, cystic stage, alveolar stage) in mouse. RESULTS: The expression of B7 family co-inhibitory molecules in rhesus monkey were increased during the prenatal period (cystic stage, alveolar stage), the expressions of B7-2 and B7-H1 mRNA were significantly increased in alveolar stage (P<0.05). The results of immuno-histochemistry indicated that B7 family co-inhibitory molecules were mainly expressed in airway epithelial cells, and their protein levels were increased during the prenatal period. The expressions of B7-2, B7-H1 and B7-DC were significantly increased from canalicular stage (P<0.05). The protein of B7-2 was higher in airway than that in bronchus (P<0.05). CONCLUSIONS: B7 family co-inhibitory molecules are mainly expressed in airway epithelial cells, and the expressions are increased during the prenatal period, which suggests that B7 family co-inhibitory molecules are involved possibly in the development of pulmonary regional immunity.

Differential expression of LEF1/TCFs family members in colonic carcinogenesis.

Lef1/Tcfs family, which includes Lef1, Tcf1, Tcf3, and Tcf4, is required for the transcriptional activation induced by ß-catenin. However, whether all the members play the same role in colon carcinogenesis is not clear. We found that Lef1 and Tcf1, but not Tcf3 and Tcf4, were upregulated at both mRNA and protein level with the formation of colon tumor in AOM-DSS mouse model. The same profiles were seen in human specimens with the evolvement from adenoma to adenocarcinoma. Additionally, Lef1 and Tcf1 were correlated with a subgroup of Wnt target genes, including Lgr5, a key gene of intestinal stem cell. Further studies supported the role of Tcf1 on sphere formation and transcriptional regulation of Lgr5 in vitro. Interestingly, 3' UTR of each Lef1/Tcfs member were targeted by diverse miRNAs, which were negatively correlated with respective member in human colon cancer specimens. Furthermore, these miRNAs were verified to repress Tcf1 and Lef1 in vitro. Taken together, Lef1 and Tcf1 showed oncogenic effect in colonic carcinogenesis. Cellular context of miRNAs might play important roles in carcinogenesis by altering the expression pattern of Lef/Tcfs members. © 2017 Wiley Periodicals, Inc.

A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer.

BACKGROUND: The clinical benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) is controversial. This study aimed to explore novel gene signature to predict outcome benefit of postoperative 5-Fu-based therapy in stage II CRC. METHODS: Gene-expression profiles of stage II CRCs from two datasets with 5-Fu-based adjuvant chemotherapy (training dataset, n = 212; validation dataset, n = 85) were analyzed to identify the indicator. A systemic approach by integrating gene-expression and protein-protein interaction (PPI) network was implemented to develop the predictive signature. Kaplan-Meier curves and Cox proportional hazards model were used to determine the survival benefit of adjuvant chemotherapy. Experiments with shRNA knock-down were carried out to confirm the signature identified in this study. RESULTS: In the training dataset, we identified 44 PPI sub-modules, by which we separate patients into two clusters (1 and 2) having different chemotherapeutic benefit. A predictor of 11 PPI sub-modules (11-PPI-Mod) was established to discriminate the two sub-groups, with an overall accuracy of 90.1%. This signature was independently validated in an external validation dataset. Kaplan-Meier curves showed an improved outcome for patients who received adjuvant chemotherapy in Cluster 1 sub-group, but even worse survival for those in Cluster 2 sub-group. Similar results were found in both the training and the validation dataset. Multivariate Cox regression revealed an interaction effect between 11-PPI-Mod signature and adjuvant therapy treatment in the training dataset (RFS, p = 0.007; OS, p = 0.006) and the validation dataset (RFS, p = 0.002). From the signature, we found that PTGES gene was up-regulated in CRC cells which were more resistant to 5-Fu. Knock-down of PTGES indicated a growth inhibition and up-regulation of apoptotic markers induced by 5-Fu in CRC cells. CONCLUSIONS: Only a small proportion of stage II CRC patients could benefit from adjuvant therapy. The 11-PPI-Mod as a potential predictor could be helpful to distinguish this sub-group with favorable outcome.

Tumor-infiltrating immune cell score as an independent prognostic predictor for endometrial carcinoma: Insights from a comprehensive analysis of the immune landscape.

BACKGROUND: Immune cells are crucial components in the tumor microenvironment and have a significant impact on the outcomes of patients. AIMS: Here, we aimed to establish a prognostic score based on different types of tumor-infiltrating immune cells for Endometrial Carcinoma (EC). METHODS AND RESULTS: We enrolled and analyzed 516 EC patients from The Cancer Genome Atlas. The relative abundance of 22 immune cells were estimated by using the CIBERSORTx algorithm. Cox regression was performed to identify potential prognostic immune cells, which were used to develop a Tumor-infiltrating Immune Cell Score (TICS). The prognostic and incremental value of TICS for overall survival were compared with traditional prognostic factors using the C-index and decision curves. Clustering analysis using all immune cells identified three immune landscape subtypes, which had weak correlation with survival. A TICS was constructed using CD8T cells, resting memory CD4 T cells, activated NK and activated DCs, and classified patients as low-, moderate- and high-risk subgroups. The low-risk subgroup had higher tumor mutation burden and activation of IL2/STAT5, IL2/STAT3 and IFN-gamma response pathways. Conversely, the high-risk subgroup was associated with DNA copy number variation, hypoxia and EMT process. The TICS subgroups significantly predicted overall survival, which was independent of patient age, tumor stage, grade and molecular classification. Moreover, we developed a nomogram incorporating TICS and clinicopathologic factors, which significantly improved the predictive accuracy compared to the clinicopathologic model alone. CONCLUSION: The TICS is an effective and independent prognostic predictor for EC patients and may serve as a useful supplement to clinicopathological factors and molecular subtyping.

NAD+ Metabolism Reprogramming Mediates Irradiation-Induced Immunosuppressive Polarization of Macrophages.

PURPOSE: Radiation therapy stands as an important complementary treatment for head and neck squamous cell carcinoma (HNSCC), yet it does not invariably result in complete tumor regression. The infiltration of immunosuppressive macrophages is believed to mediate the radiation therapy resistance, whose mechanism remains largely unexplored. This study aimed to elucidate the role of immunosuppressive macrophages during radiation therapy and the associated underlying mechanisms. METHODS AND MATERIALS: Male C3H mice bearing syngeneic SCC-VII tumor received irradiation (2 × 8 Gy). The impact of irradiation on tumor-infiltrating macrophages was assessed. Bone marrow-derived macrophages were evaluated in differentiation, proliferation, migration, and inflammatory cytokines after treatment of irradiated tumor culture medium and irradiated tumor-derived extracellular vesicles (irTEVs). A comprehensive metabolomics profiling of the irTEVs was conducted using liquid chromatography-mass spectrometry, whereas key metabolites were investigated for their role in the mechanism of immunosuppression of macrophages in vitro and in vivo. RESULTS: Radiation therapy on SCC-VII syngeneic graft tumors increased polarization of both M1 and M2 macrophages in the tumor microenvironment and drove infiltrated macrophages toward an immunosuppressive phenotype. Irradiation-induced polarization and immunosuppression of macrophages were dependent on irTEVs which delivered an increased amount of niacinamide (NAM) to macrophages. NAM directly bound to the nuclear factor kappa-B transcriptional activity regulator USP7, through which NAM reduced translocation of nuclear factor kappa-B into the nucleus, thereby decreasing the release of cytokines interleukin 6 and interleukin 8. Increased enzyme activity of NAM phosphoribosyl transferase which is the rate-limiting enzyme of NAD+ metabolism, contributed to the irradiation-induced accumulation levels of NAM in irradiated HNSCC and irTEVs. Inhibition of NAM phosphoribosyl transferase decreased NAM levels in irTEVs and increased radiation therapy sensitivity by alleviating the immunosuppressive function of macrophages. CONCLUSIONS: Radiation therapy could induce NAD+ metabolic reprogramming of HNSCC cells, which regulate macrophages toward an immunosuppressive phenotype. Pharmacologic targeting of NAD+ metabolism might be a promising strategy for radiation therapy sensitization of HNSCC.

Dysregulation of peripheral and intratumoral KLRG1+ CD8+T cells is associated with immune evasion in patients with non-small-cell lung cancer.

OBJECTIVES: Killer cell lectin like receptor G1 (KLRG1) is identified as a co-inhibitory receptor for NK cells and antigen-experienced T cells. The role of KLRG1 in immune regulation in patients with non-small cell lung cancer (NSCLC) remains poorly understood. MATERIALS AND METHODS: We measured the proportion and immune function of KLRG1+CD8+T cells derived from peripheral blood in patients with NSCLC by flow cytometry. Besides, using data from the gene expression profiles and single-cell sequencing, we explored the expression and immune role of KLRG1 in tumor tissues of patients with NSCLC. We further determined the prognostic value of KLRG1 in terms of overall survival (OS) in NSCLC patients. RESULTS: We found that the proportion of KLRG1+CD8+T cells in peripheral blood significantly increased in patients with NSCLC as compared to those with benign pulmonary nodules and healthy donors. Peripheral KLRG1+CD8+T cell proportion was increased in elder subjects compared to that in younger ones, implying an immunosenescence phenotype. Moreover, the KLRG1+CD8+T cell levels were positively correlated with tumor size and TNM stage in the NSCLC cohort. In vitro stimulation experiments demonstrated that the KLRG1+CD8+T cells from peripheral blood expressed higher levels of Granzyme B and perforin than the KLRG1-CD8+ T cells. However, single-cell RNA sequencing data revealed that the KLRG1+CD8+ T cells were less infiltrated in tumor microenvironment and exhibited impaired cytotoxicity. The KLRG1 gene expression levels were significantly lower in tumor tissues than that in normal lung tissues, and were inversely correlated with CDH1 expression levels. Moreover, higher expression of CDH1 in tumor tissues predicted worse overall survival only in patients with KLRG1-high expression, but not in the KLRG1-low subset. CONCLUSION: This study demonstrates that KLRG1+CD8+T cells were associated with tumor immune evasion in NSCLC and suggests KLRG1 as a potential immunotherapy target.

Toripalimab plus chemotherapy and radiotherapy for treatment-naive advanced esophageal squamous cell carcinoma: a single-arm phase 2 trial.

This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.

Electronic Patient-Reported Outcome-Based Symptom Management Versus Usual Care After Lung Cancer Surgery: Long-Term Results of a Multicenter, Randomized, Controlled Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported superior symptom control of electronic patient-reported outcome (ePRO)-based symptom management after lung cancer surgery for up to 1 month postdischarge. Here, we present the long-term results (1-12 months) of this multicenter, randomized trial, where patients were assigned 1:1 to receive postoperative ePRO-based symptom management or usual care daily postsurgery, twice weekly postdischarge until 1 month, and at 3, 6, 9, and 12 months postdischarge. Long-term patient-reported outcomes were assessed with MD Anderson Symptom Inventory-Lung Cancer module. Per-protocol analyses were performed with 55 patients in the ePRO group and 57 in the usual care group. At 12 months postdischarge, the ePRO group reported significantly fewer symptom threshold events (any of the five target symptom scored ≥4; median [IQR], 0 [0-0] v 0 [0-1]; P = .040) than the usual care group. From 1 to 12 months postdischarge, the ePRO group consistently reported significantly lower composite scores for physical interference (estimate, -0.86 [95% CI, -1.32 to -0.39]) and affective interference (estimate, -0.70 [95% CI, -1.14 to -0.26]). Early intensive ePRO-based symptom management after lung cancer surgery reduced symptom burden and improved functional status for up to 1 year postdischarge, supporting its integration into standard care.

Genes involved in the transition from normal epithelium to intraepithelial neoplasia are associated with colorectal cancer patient survival.

Whether the heterogeneity in tumor cell morphology and behavior is the consequence of a progressive accumulation of genetic alterations or an intrinsic property of cancer-initiating cells established at initiation remains controversial. The hypothesis of biological predetermination in human cancer was proposed many years ago and states that the biological potency of cancer cells is predestinated in the precancerous stage. The present study aimed to investigate whether the aberrant molecular events occurring in initial cancer stages could eventually influence colorectal cancer (CRC) progression. We analyzed the mRNA and miRNA expression profiles of colorectal normal mucosa, low-grade intraepithelial neoplasia (LIN), high-grade intraepithelial neoplasia (HIN), and adenocarcinoma tissues. Compared with the transitions from LIN to HIN to invasive carcinoma, the transition from normal epithelium to LIN appeared to be associated with greater changes in the number and expression levels of mRNAs and miRNAs, with a differential expression of 2322 mRNAs and 71 miRNAs detected. Utilizing these early molecular changes, a miRNA-hub network analysis showed that 166 genes were identified as targets regulated by 30 miRNAs. Among these genes, a 55-gene signature regulated by 5 miRNAs was shown to be associated with overall survival or disease-free survival in three independent sample sets. Thus, the molecular changes in the transcriptome associated with the transition from normal to intraepithelial neoplasm may influence CRC progression.

[Analyzed the molecular interaction network of tumor suppressor gene 14-3-3 sigma in lung cancer cell based on stable isotope labeling by amino acids in cell culture technology].

OBJECTIVE: To analysis the molecular interaction network of 14-3-3 sigma in non small cell lung cancer (NSCLC) cells. METHODS: Established stable over-expressed 14-3-3 sigma protein PG cells, MTT assay was used to assess the growth rate of PG cells. Though stable isotope labeling by amino acids in cell culture (SILAC) and Mass spectrometry (MS) technology, to identify difference expressed proteins caused by over expressed 14-3-3 sigma. The protein expressed >2 or <0.5 times was termed as the differential protein. By searching Human protein reference database (HPRD) and Kyoto encyclopedia of genes and genomes (KEGG), established the molecular interaction network of tumor suppressor gene 14-3-3 sigma. RESULTS: The growth rate of over-expressed 14-3-3 sigma PG cell was obviously slower down compared to vector PG cells. A database including 147 differential protein was established. And a molecular interaction network of 14-3-3 sigma containing 26 protein was constructed.In this network, the expression of CSNK2A1 (casein kinase II subunit alpha), involved in numerous cellular processes, such as cell cycle progression, apoptosis and transcription, was the most significantly increased. A DNA repair protein, MEN1 (Menin) which functions as a transcriptional regulator was the most significantly decreased. CONCLUSION: After stable transfected with 14-3-3 sigma gene, growth rate of PG cells was inhibited, the proteins associated with cell cycle, DNA damage repair mechanisms were significantly changed, and constructed the molecular interaction network.

Prognostic significance and postoperative chemoradiotherapy guiding value of mean platelet volume for locally advanced esophageal squamous cell carcinoma patients.

Objective: To investigate the predicting prognosis and guiding postoperative chemoradiotherapy (POCRT) value of preoperative mean platelet volume (MPV) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: We proposed a blood biomarker, MPV, for predicting disease-free survival (DFS) and overall survival (OS) in LA-ESCC patients who underwent surgery (S) alone or S+POCRT. The median cut-off value of MPV was 11.4 fl. We further evaluated whether MPV could guide POCRT in the study and external validation groups. We used multivariable Cox proportional hazard regression analysis, Kaplan-Meier curves, and log-rank tests to ensure the robustness of our findings. Results: In the developed group, a total of 879 patients were included. MVP was associated with OS and DFS defined by clinicopathological variables and remained an independent prognostic factor in the multivariate analysis (P = 0.001 and P = 0.002, respectively). For patients with high MVP, 5-year OS and 0DFS were significantly improved compared to those with low MPV (P = 0.0011 and P = 0.0018, respectively). Subgroup analysis revealed that POCRT was associated with improved 5-year OS and DFS compared with S alone in the low-MVP group (P < 0.0001 and P = 0.0002, respectively). External validation group analysis (n = 118) showed that POCRT significantly increased 5-year OS and DFS (P = 0.0035 and P = 0.0062, respectively) in patients with low MPV. For patients with high MPV, POCRT group showed similar survival rates compared with S alone in the developed and validation groups. Conclusions: MPV as a novel biomarker may serve as an independent prognosis factor and contribute to identifying patients most likely to benefit from POCRT for LA-ESCC.

A retrospective comparative cohort study of SEER database analysis of the prognostic value of breast-conserving surgery and mastectomy in patients with multifocal multicenter breast cancer.

Background: The prognosis of multifocal multicentric breast cancer (MIBC) was related to many factors, and there are different recommendations for surgical approaches. We compare the effects of breast-conserving surgery (BCS) and mastectomy on the survival of multifocal multicenter breast cancer female patients. Methods: A total of 38,164 female patients with pathologically confirmed multifocal multicenter invasive breast cancer from 2000 to 2018 in the Surveillance, Epidemiology, and End Results (SEER) database were extracted, and the effects of different factors on the survival of these patients were retrospectively analyzed. The patients were divided into a BCS group and a mastectomy group, and the differences of breast cancer-specific survival (BCSS) and overall survival (OS) were compared between the 2 groups. Results: Of the 38,164 patients included in the analysis, 14,533 (38.08%) underwent BCS and 23,631 (61.92%) underwent mastectomy. Multivariate analysis showed that age, grading, staging, number of lesions, radiotherapy, and BCS would affect the independent factors of BCSS and OS in patients. The median follow-up time was 108 months [interquartile range (IQR): 64-162 months). Multifactorial Cox proportional model analysis of prognostic risk showed that BCS reduced BCSS in patients older than 70 years [hazard ratio (HR): 1.35; 95% confidence interval (CI): 1.2-1.53; P<0.001], stage I and II, positive hormone receptor (HR), all 2-3 lesions, no radiotherapy (HR: 1.46; 95% CI: 1.33-1.6; P<0.001) and no chemotherapy (HR: 1.42; 95% CI: 1.28-1.57; P<0.001); BCS also reduced OS in patients over 40 years of age, stages I, II, and IIIC, all molecular subtypes, all HR-positive or negative, 2-3 lesions, and no radiotherapy (HR: 1.38; 95% CI: 1.31-1.46; P<0.001) and no chemotherapy (HR: 1.36; 95% CI: 1.29-1.44; P<0.001) patients. Multivariate Cox regression showed that BCS is an adverse factor for BCSS [adjusted HR 1.2 (1.11-1.3), P<0.001] and OS [adjusted HR 1.24 (1.19-1.3), P<0.001]. Conclusions: In early, good prognosis, treatment-sensitive patients, there is no survival advantage for BCS and more BCSS and OS benefit for mastectomy patients.

90 K increased delivery efficiency of extracellular vesicles through mediating internalization.

Using mass spectrometry-based high-throughput proteomics, we identified a membrane protein on extracellular vesicles (EVs), 90 K, which predicts poor overall survival of patients with head and neck cancer. 90 K levels in serum EVs could serve as an independent factor for poor prognosis of patients with head and neck cancer. Pre-treatment of immune competent mice with tumor-derived EVs (TDEs) elicited an immune-suppressive microenvironment for tumor cells, which was regulated by 90 K. The immunosuppressive function of TDE-90 K depends on the presence of myeloid derived suppressor cells (MDSCs) rather than regulatory T cells. The immune regulatory role of TDEs on MDSCs depends on miR-21 which is encapsulated in TDEs. Moreover, 90 K is required for the internalization of TDE cargo though interacting with integrin-ß1 and anti-siglec-9 rather than directly affecting the immune function of MDSCs. 90 K modification of γδT cell-derived EVs (γδTEVs) could increase the delivery efficiency and therapeutic effect of PD-L1 siRNA by γδTEVs. We concluded that as a secreted protein modulating cell-cell and cell-matrix interactions, 90 K can be carried by TDEs to mediate the internalization and delivery of TDEs cargo by recipient cells. This function of 90 K could be utilized to improve the efficiency of EV-based drug delivery.

Engineered mesenchymal stem cell-derived extracellular vesicles constitute a versatile platform for targeted drug delivery.

Extracellular vesicles (EVs) are promising therapeutic carriers owing to their ideal size range and intrinsic biocompatibility. However, limited targeting ability has caused major setbacks in the clinical application of EV therapeutics. To overcome this, we genetically engineered natural free streptavidin (SA) on the cellular surface of bone marrow mesenchymal stem cells (BMSCs) and obtained typical EVs from these cells (BMSC-EVs). Biotin-coated gold nanoparticles confirmed the expression of SA on the membrane of EVs, which has a high affinity for biotinylated molecules. Using a squamous cell carcinoma model, we demonstrated that a pH-sensitive fusogenic peptide -modification of BMSC-EVs achieved targetability in the microenvironment of a hypoxic tumor to deliver anti-tumor drugs. Using EGFR+HER2- and EGFR-HER2+ breast cancer models, we demonstrated that anti-EGFR and anti-HER2 modifications of BMSC-EVs were able to specifically deliver drugs to EGFR+ and HER2+ tumors, respectively. Using a collagen-induced arthritis model, we confirmed that anti-IL12/IL23-modified BMSC-EVs specifically accumulated in the arthritic joint and alleviated inflammation. Administration of SA-overexpressing BMSC-EVs has limited immunogenicity and high safety in vivo, suggesting that BMSC-derived EVs are ideal drug delivery vehicle. These representative scenarios of targeting modification suggest that, using different biotinylated molecules, the SA-overexpressing BMSC-EVs could be endowed with different targetabilities, which allows BMSC-EVs to serve as a versatile platform for targeted drug delivery under various situations.

The prognostic value of positron emission tomography/computed tomography-based parameters in locally advanced esophageal squamous cell carcinoma treated with chemoradiation therapy.

OBJECTIVES: To assess the prognostic value of PET/computed tomography-based parameters in patients with locally advanced esophageal squamous cell carcinoma (ESSC). METHODS: Sixty-seven patients with ESSC undergoing definitive chemoradiotherapy (dCRT) were retrospectively enrolled. PET/CT parameters (maximum standardized uptake value (SUVmax) metabolic tumor volume (MTV), and total glycolysis (TLG) were obtained from 18F-fluorodeoxyglucose (18F-FDG) PET/CT studies. The correlation between overall survival and PET/CT parameters was analyzed using a Cox proportional hazards model. RESULTS: There were no differences in TLG, MTV, and SUVmax values across age, sex, tumor location, and lymph node status. However, for patients with cT3-4 disease, TLG and SUVmax were significantly higher (P = 0.019 and P = 0.018, respectively), and MTV showed an increasing trend (P = 0.068). There were significant correlations among TLG, MTV and SUVmax. According to the receiver-operating curve, the cutoff values of TLG, MTV and SUVmax dichotomized by survival status at 2 years were 64.00 g, 9.63 ml and 9.97 g/ml, respectively. In univariate analysis, increased TLG, MTV and SUVmax were significant negative prognostic factors for OS. However, in multivariate analysis, only SUVmax was an independent prognostic factor for overall survival (hazard ratios = 2.857, 95% confidence intervals: 1.837-4.442; P = 0.017). CONCLUSIONS: PET/CT is a useful tool for predicting the prognoses in patients with locally advanced ESSC treated with dCRT. Future prospective studies with a large number of samples should be conducted to confirm these results.