Distinct clinical characteristics in stage III rectal cancer among different age groups and treatment outcomes after neoadjuvant chemoradiotherapy.

Background: There is a rapidly increasing incidence of early-onset colorectal cancer (EO-CRC) which threatens the survival of young people, while aging also represents a challenging clinical problem. Objectives: We aimed to investigate the differences in the clinical characteristics and prognosis in stage III rectal cancer (RC), to help optimize treatment strategies. Design and methods: This study included 757 patients with stage III RC, all of whom received neoadjuvant chemoradiotherapy and total mesorectal excision. The whole cohort was categorized as very early onset (VEO, ⩽30 years old), early onset (EO, >30 years old, ⩽50 years old), intermediate onset (IO, >50 years, ⩽70 years), or late onset (LO, >70 years old). Results: There were more female VEO patients than males, more mucinous adenocarcinoma, signet-ring cell carcinoma, pre-treatment cT4 stage, and higher pre-treatment serum carbohydrate antigen 19-9 compared with the other three groups. VEO patients had the worst survival with the highest RC-related mortality (34.5%), recurrence (13.8%), and metastasis (51.7%). LO patients had the highest non-RC-related mortality rate (16.6%). The Cox regression model showed VEO was a negative independent prognostic factor for disease-free survival [DFS, hazard ratio (HR): 2.830, 95% confidence interval (CI): 1.633-4.904, p < 0.001], distant metastasis-free survival (DMFS, HR: 2.969, 95% CI: 1.720-5.127, p < 0.001), overall survival (OS, HR: 2.164, 95% CI: 1.102-4.249, p = 0.025), and cancer-specific survival (CSS, HR: 2.321, 95% CI: 1.145-4.705, p = 0.020). LO was a negative independent factor on DFS (HR: 1.800, 95% CI: 1.113-2.911, p = 0.017), DMFS (HR: 1.903, 95% CI: 1.150-3.149, p = 0.012), OS (HR: 2.856, 95% CI: 1.745-4.583, p < 0.001), and CSS (HR: 2.248, 95% CI: 1.282-3.942, p = 0.005). VEO patients had better survival in the total neoadjuvant therapy-like (TNT-like) pattern on DFS (p = 0.039). IO patients receiving TNT-like patterns had better survival on DFS, OS, and CSS (p = 0.006, p = 0.018, p = 0.006, respectively). Conclusion: In stage III RC, VEO patients exhibited unique clinicopathological characteristics, with VEO a negative independent prognostic factor for DFS, DMFS, OS, and CSS. VEO and IO patients may benefit from a TNT-like treatment pattern.

Development of monoclonal antibodies targeting the conserved fragment of hexon protein to detect different serotypes of human adenovirus.

Human adenovirus (HAdV) infects the respiratory system, thus posing a threat to health. However, immunodiagnostic reagents for human adenovirus are limited. This study aimed to develop efficient diagnostic reagents based on monoclonal antibodies for diagnosing various human adenovirus infections. Evolutionary and homology analyses of various human adenoviral antigen genes revealed highly conserved antigenic fragments. The prokaryotic expression system was applied to recombinant penton, hexon, and IVa2 conserved fragments of adenovirus, which were injected into BALB/c mice to prepare human adenovirus-specific monoclonal antibodies. Enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IFA), and Western blotting were used to determine the immune specificity of the monoclonal antibodies. Indirect ELISA showed that monoclonal antibodies 1F10, 8D3, 4A1, and 9B2 were specifically bound to HAdV-3 and HAdV-55 and revealed high sensitivity and low detection limits for various human adenoviruses. Western blotting showed that 1F10 and 8D3 specifically recognized various human adenovirus types, including HAdV-1, HAdV-2, HAdV-3, HAdV-4, HAdV-5, HAdV-7, HAdV-21, and HAdV-55, and 4A1 specifically recognized HAdV-1, HAdV-2, HAdV-3, HAdV-5, HAdV-7, HAdV-21, and HAdV-55. IFAs showed that 1F10, 8D3, and 4A1 exhibited highly selective localization to A549 cells infected with HAdV-3 and HAdV-55. Finally, two antibody pairs that could detect hexon antigens HAdV-3 and HAdV-55 at low concentrations were developed. The monoclonal antibodies developed in this study show potential for detecting human adenoviruses. IMPORTANCE: In this study, we selected the three most conserved antigenic fragments of human adenovirus to prepare a murine monoclonal antibody for the first time, and human adenovirus antigenic fragments with heretofore unheard of degrees of conservatism were isolated. The three monoclonal antibodies with the ability to recognize human respiratory adenovirus over a broad spectrum were screened by hybridoma and monoclonal antibody preparation. Human adenovirus infections are serious; however, therapeutic drugs and diagnostic reagents are scarce. Thus, to reduce the serious consequences of human viral infections and adenovirus pneumonitis, early diagnosis of infection is required. The present study provides three monoclonal antibodies capable of recognizing a wide range of human adenoviruses, thereby offering guidance for subsequent research and development.

[Corrigendum] Azurocidin 1 inhibits the aberrant proliferation of triple­negative breast cancer through the regulation of pyroptosis.

Following the publication of the above article, the authors drew to our attention that they had made a couple of inadvertent errors in assembling Figs. 4 and 5; first, for the BT­549 cell line, the data shown for the Pro­caspase­1/Cleaved caspase­1 in Fig. 5 and the GSDMD­F/GSDMD­N data in Fig. 4B were identical, and had been derived from the same original source; secondly, in Fig. 4A, the data shown correctly for the GSDMD BT­549 cell line had also inadvertently been included in this figure to represent the MDA­MB­231 cell line. The revised and corrected versions of Figs. 4 and 5, showing the correct western blotting data for the GSDMD experiment in Fig. 4A and the Pro­caspase­1/Cleaved caspase­1 data for the BT­549 cell line in Fig. 5, are shown in the next two pages. The authors regret that these errors in the assembly of Figs. 4 and 5 went unnoticed before the article was published, and thank the Editor of Oncology Reports for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused.[Oncology Reports 50: 188, 2023; DOI: 10.3892/or.2023.8625].

Non-high-density lipoprotein cholesterol levels as a risk factor for short-term mortality in elderly Chinese: a large-scale, population-based cohort study.

OBJECTIVES: To explore the association between non-high-density lipoprotein (non-HDL) and mortality risk, both short-term and long-term, in Chinese people. DESIGN: A prospective cohort study. SETTING: The National Basic Public Health Service (BPHS) in China. PARTICIPANTS: Including 621 164 elderly individuals around Hunan Province who underwent healthcare management receiving check-ups in China BPHS from 2010 to 2020. EXCLUSION CRITERIA: (1) missing information on gender; (2) missing records of lipid screening; (3) missing information on key covariates; and (4) missing records of comorbidities (cardiovascular disease, hypertension, diabetes, cancer.) PRIMARY AND SECONDARY OUTCOME MEASURES: The study's primary endpoint was all-cause and cause-specific mortality, sourced from Hunan's CDC(Center for Disease Control and Prevention)-operated National Mortality Surveillance System, tracking participants until 24 February 2021. RESULTS: 26 758 (4.3%) deaths were recorded, with a median follow-up of 0.83 years. Association between non-HDL and mortality was non-linear after multivariable adjustment, with the optimum concentration (OC) being 3.29 and 4.85 mmol/L. Compared with OC, the risk increased by 1.12-fold for non-HDL <3.29 mmol/L (HR: 1.12 (1.09 to 1.15)) and 1.08-fold for non-HDL ≥4.85 mmol/L (HR: 1.08 (1.02 to 1.13)) for all-cause mortality. Furthermore, there is also an increased risk of cardiovascular mortality (HR for non-HDL <3.29: 1.10 (1.06 to 1.32) and HR for non-HDL ≥4.85: 1.07 (1.01 to 1.14)). However, cancer mortality risk was significantly increased only for non-HDL <3.29 mmol/L (HR: 1.11 (1.04 to 1.18)). Non-optimum concentration of non-HDL had significant effects on both the long-term and the short-term risk of mortality, especially for risks of mortality for all-cause (log HR:0 .086 (0.038 to 0.134)), cardiovascular (log HR:0 .082 (0.021 to 0.144)), and cancer (log HR:0 .187 (0.058 to 0.315)) within 3 months. A two-sided value of p <0.05 was considered to be statistically significant. CONCLUSIONS: Non-HDL was non-linearly associated with the risk of mortality, and non-optimal concentrations of non-HDL significantly increased short-term mortality in elderly Chinese, which needs more attention for cardiovascular disease prevention.

RAMP1 as a novel prognostic biomarker in pan-cancer and osteosarcoma.

Receptor activity modifying protein 1 (RAMP1) facilitates the localization of the calcitonin-like receptor (CLR) to the plasma membrane, but its role in osteosarcoma (OS) remains unclear. We evaluated the RAMP1 expression and prognostic value across different cancers, studying tumor immune infiltration. The prognostic value was analyzed using the GSE39058 and TARGET datasets. Differential gene expression was evaluated. a protein-protein interaction network was constructed, and gene set enrichment analysis was performed. The function of RAMP1 in the tumor microenvironment was analyzed, and its expression in OS cell lines was validated using quantitative real-time PCR. High RAMP1 expression correlated with poor prognosis relative to low RAMP1 expression (p < 0.05). Low RAMP1 expression correlated with an abundance of CD4+ memory-activated T cells. whereas a high expression level correlated with a high proportion of gamma-delta T cells (γδ T cells). Differentially expressed genes from TARGET was enriched in olfactory transduction pathways (normalized enrichment scores [NES] = 1.6998, p < 0.0001). RAMP1 expression negatively correlated with CD44 expression but positively correlated with TNFSF9 expression. The RAMP1 gene is substantially expressed in OS cells compared to the normal osteoblast cell line hFOB1.19. Thus, RAMP1 may be a prognostic biomarker and potential therapeutic target in OS.

Mesenchymal stem cell-derived exosomal miR-548x-3p inhibits pyroptosis of vascular endothelial cells through HMGB1 in heat stroke.

Heat stroke (HS) is an acute physical illness associated with a higher risk of organ dysfunction. This study is the first to explore exosomal miR-548x-3p derived from human bone marrow mesenchymal stem cells (BMSCs) in the pyroptosis of vascular endothelial cells (VECs) associated with HS. Human BMSCs-derived exosome alleviated the injury of the heart, liver, kidney and ileum tissues, the increase of IL-1ß, IL-18 and TNF-α levels, pyroptosis of endothelial cells and the increase of HGMB1, NLRP3, ASC, caspase1 and GSDMD-N protein expression in HS mice and HS-induced human umbilical vein endothelial cells (HUVECs). miR-548x-3p was down-expressed in HS patients, while up-expressed in BMSCs-derived exosome. BMSCs-ExomiR-548x-3p mimics to inhibit pyroptosis, inflammation and HGMB1/NLRP3 activation in HS-induced HUVECs and HS mice, which were blocked by overexpression of HMGB1. In conclusion, human BMSCs-derived exosomes carried miR-548x-3p mimics to inhibit pyroptosis of VECs through HMGB1 in HS mice.

Azurocidin 1 inhibits the aberrant proliferation of triple­negative breast cancer through the regulation of pyroptosis.

Azurocidin 1 (AZU1) is a heparin­binding protein which has been reported to be aberrantly expressed in various tumors, but its definite role in breast cancer (BC) has not been clarified. The aim of the present study was to explore the associations between AZU1 and BC. In the present study, bioinformatics and western blot analyses were applied to detect the expression level of AZU1 in BC tissues. The effect of AZU1 on cell proliferation and apoptosis was analyzed using Cell Counting Kit­8 assay, colony formation assay and flow cytometry. Based on bioinformatics analysis, AZU1 exhibited low expression in tissues and was negatively associated with the survival rate of patients with triple­negative BC (TNBC). Exogenous AZU1 stimuli significantly inhibited the proliferation and colony formation of TNBC cell lines. Furthermore, the data of flow cytometry revealed that exogenous AZU1 stimuli enhanced apoptosis in MDA­231 and BT­549 cells. As pyroptosis is a new type of cell death, the effects AZU1 played on the expression of gasdermin D (GSDMD), a specific biomarker of pyroptosis, were also investigated. The findings of the present study revealed that GSDMD, as well as its upstream regulators [NF­κB, NLR family pyrin domain containing 3 (NLRP3) and caspase­1], were significantly increased in TNBC cell lines when treated with exogenous AZU1, indicating that AZU1 contributed to the inhibition of pyroptosis of TNBC cell lines through the NF­κB/NLRP3/caspase­1 axis. Collectively, it was revealed for the first time, that AZU1 exposure promoted pyroptosis through the modulation of the pNF­κB/NLRP3/caspase­1/GSDMD axis in TNBC in vitro. The findings of the present study unveiled a novel mechanism of AZU1­induced pyroptosis in TNBC, which may aid in developing new strategies for therapeutic interventions in TNBC. breast cancer is the most commone form of cancer in women and is second only to lung cancer in terms of cancer­related mortality.

Metagenomic Analysis of Intratumoral Microbiome Linking to Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

PURPOSE: To assess taxonomic and functional characteristics of tumor-bearing microbiota and its association with response to neoadjuvant chemoradiation therapy (nCRT) in patients with locally advanced rectal cancer. METHODS AND MATERIALS: We performed metagenomic sequencing of biopsy tumoral tissues from 73 patients with locally advanced rectal cancer before nCRT. Patients were classified into poor responders (PR) and good responders (GR) according to response to nCRT. Subsequent investigation of network alteration, key community, microbial biomarkers, and function related to nCRT responses were carried out. RESULTS: The network-driven analysis systematically revealed 2 co-occurring bacteria modules that exhibited opposite relationship with rectal cancer radiosensitivity. In the 2 modules, prominent alteration of global graph properties and community structure was observed between networks of PR and GR group. By quantifying changes in between-group association patterns and abundances, a total of 115 discriminative biomarker species linked to nCRT response were found, and 35 microbial variables were selected to establish the optimal randomForest classifier for nCRT response prediction. It yielded an area under the curve value of 85.5% (95% CI, 73.3%-97.8%) in the training cohort and 88.4% (95% CI, 77.5%-99.4%) in the validation cohort. In a comprehensive consideration, 5 key bacteria showed high relevance with inducing resistance to nCRT, including Streptococcus equinus, Schaalia odontolytica, Clostridium hylemonae, Blautia producta, and Pseudomonas azotoformans. One key hub including several butyrate-formation bacteria involving with driving network alteration from GR to PR indicate that microbiota-derived butyrate may also be involved in reducing the antitumor effects of nCRT, especially Coprococcus. The functional analysis of metagenome linked the nitrate and sulfate-sulfur assimilation, histidine catabolic process, and resistance to cephamycin to the reduced therapeutic response. It also linked to leucine degradation, isoleucine biosynthesis, taurine, and hypotaurine metabolism to the improved response to nCRT. CONCLUSIONS: Our data offer novel potential microbial factors and shared metagenome function linked to resistance to nCRT.

Intraparotid lymph node metastasis affects distant metastasis in parotid adenoid cystic carcinoma.

To evaluate the relationship between factors of metastatic intraparotid lymph node (IPLN) and distant metastasis in parotid adenoid cystic carcinoma (ACC). Patients with surgically treated parotid ACC were retrospectively enrolled, and primary outcome variable was distant metastasis free survival (DMFS). The effect of factors of metastatic IPLN on DMFS was evaluated using Cox model. In total, 232 patients were included. Extranodal extension of IPLN and cervical lymph nodes did not impact the DMFS, and the 7th but not 8th AJCC N stage was associated with DMFS. Groups of 0 and 1 metastatic IPLN had comparable DMFS, but presence of 2+ positive IPLN was related to increased worse DMFS (p = 0.034, HR 2.09). A new N stage (0 vs 1-2 vs 3+) based on total positive lymph node number exhibited better C-index than traditional N stage. IPLN metastasis increased the risk of distant metastasis, and the impact was mainly determined by the number of metastatic IPLN. Our proposed N stage provided better DMFS prediction than the 8th AJCC N classification.

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

BACKGROUND: Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. METHODS: Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. DISCUSSION: The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Total neoadjuvant treatment and PD-1/PD-L1 checkpoint inhibitor in locally advanced rectal cancer.

For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.

Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study.

BACKGROUND: The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer. METHODS: This open-label, single-arm, phase 2 study was done at the Sun Yat-sen University Cancer Center, Guangzhou, China. Patients aged 18-75 years with mismatch-repair deficient or microsatellite instability-high locally advanced rectal cancer were enrolled and received neoadjuvant sintilimab monotherapy (200 mg by intravenous infusion) every 21 days. After an initial four cycles of treatment, patients and clinicians could choose one of the following options: total mesorectal excision surgery, followed by four cycles of adjuvant sintilimab with or without CapeOX chemotherapy (capecitabine 1000 mg/m2, orally administered twice daily on days 1-14; oxaliplatin 130 mg/m2, intravenously administered on day 1 every 3 weeks), determined by clinicians; or another four cycles of sintilimab followed by radical surgery or observation (only for patients with a clinical complete response; also known as the watch and wait strategy). The primary endpoint was the complete response rate, which included both a pathological complete response after surgery and a clinical complete response after completion of sintilimab treatment. Clinical response was evaluated by digital rectal examination, MRI, and endoscopy. Response was assessed in all patients who received treatment at least until the first tumour response assessment, after the first two cycles of sintilimab. Safety was analysed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04304209). FINDINGS: Between Oct 19, 2019, and June 18, 2022, 17 patients were enrolled and received at least one dose of sintilimab. The median age was 50 years (IQR 35-59) and 11 (65%) of 17 patients were male. One patient was excluded from efficacy analyses because they were lost to follow-up after the first sintilimab cycle. Of the remaining 16 patients, six underwent surgery, of whom three had a pathological complete response. Nine other patients had a clinical complete response and chose the watch and wait strategy. One patient had a serious adverse event and discontinued treatment; this patient did not have a complete clinical response and refused to undergo surgery. A complete response was thus noted for 12 (75%; 95% CI 47-92) of 16 patients. One of the three patients who underwent surgery but did not have a pathological complete response showed an increase in tumour volume after the initial four cycles of sintilimab (at which point they underwent surgery); this patient was deemed to have primary resistance to immune checkpoint inhibitors. After a median follow-up of 17·2 (IQR 8·2-28·5) months, all patients were alive and none had disease recurrence. Only one (6%) patient had a grade 3-4 adverse event, which was deemed a serious adverse event (grade 3 encephalitis). INTERPRETATION: The preliminary results of this study suggest that anti-PD-1 monotherapy is effective and tolerable for patients with mismatch-repair deficient locally advanced rectal cancer and could potentially spare some patients from radical surgery. Longer treatment courses might be needed to achieve maximum effects in some patients. Longer follow-up is also needed to observe the duration of response. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Science and Technology Program of Guangzhou, and Innovent Biologics.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

A nomogram for predicting 10-year cancer specific survival in patients with pathological T3N0M0 rectal cancer.

Background: The pathological T3N0M0 (pT3N0M0) rectal cancer is the earliest stage and has the best prognosis in the locally advanced rectal cancer, but the optimal treatment remains controversial. A reliable prognostic model is needed to discriminate the high-risk patients from the low-risk patients, and optimize adjuvant chemotherapy (ACT) treatment decisions by predicting the likelihood of ACT benefit for the target population. Patients and methods: We gathered and analyzed 276 patients in Sun Yat-sen University Cancer Center from March 2005 to December 2011. All patients underwent total mesorectal excision (TME), without preoperative therapy, and were pathologically proven pT3N0M0 rectal cancer with negative circumferential resection margin (CRM). LASSO regression model was used for variable selection and risk factor prediction. Multivariable cox regression was used to develop the predicting model. Optimum cut-off values were determined using X-Tile plot analysis. The 10-fold cross-validation was adopted to validate the model. The performance of the nomogram was evaluated with its calibration, discrimination and clinical usefulness. Results: A total of 188 patients (68.1%) had ACT and no patients had adjuvant radiotherapy. Age, monocyte percentage, carbohydrate antigen 19-9, lymph node dissection numbers and perineural invasion (PNI) were identified as significantly associated variables that could be combined for an accurate prediction risk of Cancer Specific Survival (CSS) for pT3N0M0 patients. The model adjusted for CSS showed good discrimination with a C-index of 0.723 (95% CI: 0.652-0.794). The calibration curves showed that the nomogram adjusted for CSS was able to predict 3-, 5-, and 10-year CSS accurately. The corresponding predicted probability was used to stratify high and low-risk patients (10-year CSS: 69.1% vs. 90.8%, HR = 3.815, 95%CI: 2.102-6.924, P < 0.0001). ACT improved overall survival (OS) in the low-risk patients (10-year OS: 91.9% vs. 83.3%, HR = 0.338, 95% CI: 0.135-0.848, P < 0.0001), while it did not exhibit a significant benefit in the high-risk patients. Conclusion: The present study showed that age, monocyte percentage, carbohydrate antigen 19-9, lymph node dissection numbers and PNI were independent prognostic factors for pT3N0M0 rectal cancer patients. A nomogram based on these prognostic factors effectively predicts CSS in patients, which can be conveniently used in clinical practice. ACT may improve overall survival in the low-risk patients. But the benefit of ACT was not seen in the high-risk patients.

Dengue virus is involved in insulin resistance via the downregulation of IRS-1 by inducing TNF-α secretion.

During the epidemic, the individuals with underlying diseases usually have a higher rate of mortality. Diabetes is highly prevalent worldwide, making it a frequent comorbidity in dengue fever patients. Therefore, understanding the relationship between dengue virus (DENV) infection and diabetes is important. We first demonstrated that DENV-3 infection down-regulated the expression of IRS-1. In vitro, treatment of HepG2 cells with TNF-α inhibitors and siRNA proved that after DENV-3 infection in HepG2 cells, cellular TNF-α secretion was increased, which negatively regulated IRS-1, thereby leading to an insulin-resistant state. In vivo, DENV-3 induced insulin resistance (IR) in hepatocytes by promoting the secretion of TNF-α and inhibiting the expression of IRS-1 was proved. In vivo approaches also showed that after DENV-3 infection, TNF-α levels in the serum of C57BL/6 mice with insulin resistance increased, and upon TNF-α antagonist III treatment, IRS-1 expression in the liver, reduced by infection, was upregulated. In addition, transcriptomic analysis revealed more negative regulatory events in the insulin receptor signaling pathway after DENV-3 infection. This is the first report of a link between DENV-3 infection and insulin resistance, and it lays a foundation for further research.

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Association of the collagen signature with pathological complete response in rectal cancer patients.

Collagen in the tumor microenvironment is recognized as a potential biomarker for predicting treatment response. This study investigated whether the collagen features are associated with pathological complete response (pCR) in locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (nCRT) and develop and validate a prediction model for individualized prediction of pCR. The prediction model was developed in a primary cohort (353 consecutive patients). In total, 142 collagen features were extracted from the multiphoton image of pretreatment biopsy, and the least absolute shrinkage and selection operator (Lasso) regression was applied for feature selection and collagen signature building. A nomogram was developed using multivariable analysis. The performance of the nomogram was assessed with respect to its discrimination, calibration, and clinical utility. An independent cohort (163 consecutive patients) was used to validate the model. The collagen signature comprised four collagen features significantly associated with pCR both in the primary and validation cohorts (p < 0.001). Predictors in the individualized prediction nomogram included the collagen signature and clinicopathological predictors. The nomogram showed good discrimination with area under the ROC curve (AUC) of 0.891 in the primary cohort and good calibration. Application of the nomogram in the validation cohort still gave good discrimination (AUC = 0.908) and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. In conclusion, the collagen signature in the tumor microenvironment of pretreatment biopsy is significantly associated with pCR. The nomogram based on the collagen signature and clinicopathological predictors could be used for individualized prediction of pCR in LARC patients before nCRT.

Early predictive value of platelet function for clinical outcome in sepsis.

OBJECTIVE: Sepsis is the leading course of morbidity and mortality in critically ill patients. This study aimed to evaluate the predictive value of the platelet aggregation for mortality in patients with sepsis. In addition, the relationship between impaired mitochondria and the platelet aggregation was explored. METHOD: This was a prospective, observational cohort study. The platelet aggregation rate in response to adenosine diphosphate (ADP) was assessed. The primary outcome was 28-day mortality. Platelet mitochondrial parameters, including adenosine triphosphate(ATP), mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening, were measured. Platelet mitochondrial ultrastructure was observed using transmission electron microscopy. RESULTS: 86 patients with 65 survivors and 21 non-survivors were enrolled. Platelets of non-survivors with sepsis were hyporesponsive to ADP, in terms of maximal aggregation rate (P < 0.001). Receiver operating characteristic curves analysis demonstrated that the AUC estimated 28-day mortality for platelet aggregation rate was 0.814. At the optimal cut-off value of 35.8% for platelet aggregation rate, the sensitivity was 86.2% and the specificity was 66.7%. Kaplan-Meier analysis showed that a platelet aggregation rate of less than 35.8% was associated closely with poor survival. After adjusting for lactate by Cox regression analysis, platelet aggregation rate was identified as an independent predictor for the probability of 28-day mortality. Compared with survivors, non-survivors showed a significant reduction in platelet ATP and MMP-index (both P < 0.001), and a remarkable increase in mPTP opening (P < 0.001). ATP and MMP-index were positively correlated with platelet aggregation rate (R square=0.75, R square=0.44, respectively). CONCLUSION: Platelet aggregation rate could be an early predictive biomarker for mortality in sepsis. Impaired platelet mitochondrial activity affects platelet aggregation and correlates with the severity of sepsis.

Long-term Survivals, Toxicities and the Role of Chemotherapy in Early-Stage Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Radiation Therapy: A Retrospective Study with 15-Year Follow-up.

PURPOSE: This study was aimed to investigate long-term survivals and toxicities of early-stage nasopharyngeal carcinoma (NPC) in endemic area, evaluating the role of chemotherapy in stage II patients. MATERIALS AND METHODS: Totally 187 patients with newly diagnosed NPC and restaged American Joint Committee on Cancer/International Union Against Cancer 8th T1-2N0-1M0 were retrospectively recruited. All received intensity-modulated radiotherapy (IMRT)±chemotherapy (CT) from 2001 to 2010. RESULTS: With 15.7-year median follow-up, 10-year locoregional recurrence-free survival, distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were 93.3%, 93.5%, 92.9% and 88.2%, respectively. Multivariable analyses showed cervical lymph nodes positive and pre-treatment prognostic nutritional index ≥ 52.0 could independently predict DMFS (p=0.036 and p=0.011), DSS (p=0.014 and p=0.026), and OS (p=0.002 and p < 0.001); Charlson comorbidity index < 3 points could predict DSS (p=0.011); age > 45 years (p=0.002) and pre-treatment lactate dehydrogenase ≥ 240 U/L (p < 0.001) predicted OS. No grade 4 late toxicity happened; grade 3 late toxicities included subcutaneous fibrosis (4.3%), deafness or otitis (4.8%), skin dystrophy (2.1%), and xerostomia (1.1%). No differences on survivals were shown between IMRT+CT vs. IMRT alone in stage II patients, even in T2N1M0 (p > 0.05). Unsurprising, patients in IMRT+CT had more acute gastrointestinal reaction, myelosuppression, mucositis, late ear toxicity, and cranial nerve injury (all p < 0.05) than IMRT alone group. CONCLUSION: Superior tumor control and satisfying long-term outcomes could be achieved with IMRT in early-stage NPC with mild late toxicities. As CT would bring more toxicities, it should be carefully performed to stage II patients.