BMC Cancer

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Online ISSN: 1471-2407
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Abbreviations PCa: Prostate cancer; RT: radiotherapy; IG: Intervention Group; CG: Control Group; RC: randomized controlled trial; IMRT: Intensity-Modulated RT; QoL: quality of life; ECOG PS: Eastern Cooperative Oncology Group Performance Status Scale; BMI: body mass index; MUST: Malnutrition Universal Screening Tool; hs-CRP: C-reactive protein; IL-6: Interleukin-6; LH: Luteinizing hormone; RTOG: Radiation Therapy Oncology Group; EORTC : European Organization for Research and Treatment of Cancer; WCRF: World Cancer Research Fund.
Background Prostate cancer (PCa) is the second most common cancer in men worldwide. The standard non-surgical approach for localized PCa is radiotherapy (RT), but one of the limitations of high-dose RT is the potential increase in gastrointestinal and genitourinary toxicities. We present the protocol of the Microstyle study, a multicentre randomized two-arm crossover clinical trial. The primary outcome will be assessed at the end of 6-month intervention, by measuring the change in adherence to a healthy lifestyle score. The hypothesis is that modifying lifestyle we change microbiome and improve quality of life and decrease side effects of RT. Methods Study participants will be recruited among men undergoing RT in two Italian centers (Milan and Naples). We foresee to randomize 300 patients in two intervention arms: Intervention Group (IG) and Control Group (CG). Participants allocated to the IG will meet a dietitian and a physiotherapist before RT to receive personalized diet and exercise recommendations, according to their health status, to improve overall lifestyle and reduce side effects (bowel and/or urinary problems). Dietitian and physiotherapist will work together to set individualized goals to reduce or eliminate side effects and pain according to their health status. All participants (IG) will be given a pedometer device (steps counter) in order to monitor and to spur participants to increase physical activity and reduce sedentary behavior. Participants included in the CG will receive baseline general advice and materials available for patients undergoing RT. According to the cross-over design, the CG will cross to the intervention approach after 6-month, to actively enhance compliance towards suggested lifestyle recommendations for all patients. Discussion This trial is innovative in its design because we propose a lifestyle intervention during RT, that includes both dietary and physical activity counselling, as well as monitoring changes in microbiome and serum biomarkers. The promotion of healthy behaviour will be initiated before initiation of standard care, to achieve long lasting effects, controlling side effects, coping with feelings of anxiety and depression and improve efficacy of RT. Trial registration registration number: NCT05155618 . Retrospectively registered on December 13, 2021. The first patient was enrolled on October 22, 2021.
Background The high rate of aseptic loosening of cemented stems has led to their frequent use in endoprosthetic reconstruction. However, problems, such as stem breakage and stress shielding at the insertion site, remain. The Japanese Musculoskeletal Oncology Group (JMOG) has developed Kyocera Modular Limb Salvage System (KMLS) cementless stems with a unique tapered press-fit and short fixation design. This study aimed to clarify the short-term postoperative outcomes of this prosthesis and validate the stem design. Methods One hundred cases of KMLS cementless stems (51 male patients; median age, 49 years; mean follow-up period, 35 months), with a minimum follow-up of 2 years, for the proximal femur (PF), distal femur (DF), and proximal tibia were prospectively registered for use. Prosthesis survival, complication rates, postoperative functional, and radiographical evaluation were analyzed. Complications or failures after insertion of the KMLS endoprostheses were classified into five types and functional results were analyzed according to the MSTS scoring system at postoperative 1 year. The diaphyseal interface and anchorage were graded by the ISOLS system at postoperative 2 years. Results The overall prosthesis survival rates at 2 and 4 years were 88.2 and 79.6%, respectively. The prosthesis-specific survival rate excluding infection and tumor recurrence was 90.2 and 87.9%, respectively. Younger age ( p = 0.045) and primary tumor ( p = 0.057) were associated with poor prognosis of prosthesis-specific survival excluding infection and tumor recurrence. Complications were observed in 31 patients, 13 patients underwent revision surgery. The mean MSTS functional score at 1 year postoperatively was 68%. Early implant loosening was significantly more common in the DF ( p = 0.006) and PF/DF straight stem ( p = 0.038). The ISOLS radiographic evaluation at 2 years after surgery revealed good bone remodeling and anchorage in most cases (bone remodeling: 90% / excellent and good, anchorage: 97% / excellent and good). Conclusions Tumor endoprosthesis long-term fixation to the diaphysis of the lower extremity remains challenging. The KMLS cementless stem with a unique tapered press fit design showed good short-term results in maintaining bone stock. To prevent early loosening, a curved stem should be used in PF and DF, but long-term follow-up is necessary.
Change over time in PCS and MCS scores
Within-group changes in SF-36 domain and composite summary scores over time using per protocol analysis a
Background The residual effects of cancer and its treatment can profoundly affect women’s quality of life. This paper presents results from a multisite randomized controlled trial that evaluated the clinical benefits of an e-health enabled health promotion intervention (the Women’s Wellness after Cancer Program or WWACP) on the health-related quality of life of women recovering from cancer treatment. Methods Overall, 351 women previously treated for breast, blood or gynaecological cancers were randomly allocated to the intervention (WWACP) or usual care arms. The WWACP comprised a structured 12-week program that included online coaching and an interactive iBook that targeted physical activity, healthy diet, stress and menopause management, sexual wellbeing, smoking cessation, alcohol intake and sleep hygiene. Data were collected via a self-completed electronic survey at baseline (t 0 ), 12 weeks (post-intervention, t 1 ) and 24 weeks (to assess sustained behaviour change, t 2 ). The primary outcome, health-related quality of life (HRQoL), was measured using the Short Form Health Survey (SF-36). Results Following the 12-week lifestyle program, intervention group participants reported statistically significant improvements in general health, bodily pain, vitality, and global physical and mental health scores. Improvements were also noted in the control group across several HRQoL domains, though the magnitude of change was less. Conclusions The WWACP was associated with improved HRQoL in women previously treated for blood, breast, and gynaecological cancers. Given how the synergy of different lifestyle factors influence health behaviour, interventions accounting for the reciprocity of multiple health behaviours like the WWACP, have real potential for immediate and sustainable change. Trial registration The protocol for this randomised controlled trial was submitted to the Australian and New Zealand Clinical Trials Registry on 15/07/2014 and approved on 28/07/2014 ( ACTRN12614000800628 ).
Three fractionation regimens and the required clinical goals for MDRT using SBRT in the ADOPT trial
Background More than 60% of oligo-recurrent prostate cancer (PCa) patients treated with metastasis-directed radiotherapy (MDRT) develop biochemical recurrence within 2 years. This recurrence rate emphasises the need for improved treatment and patient selection. In line with the treatment of primary PCa, the efficacy of MDRT may be enhanced when combined with androgen-deprivation therapy (ADT). Furthermore, the availability of PSMA PET/CT offers an excellent tool for optimal patient selection for MDRT. This phase III randomised controlled trial will investigate the role of the addition of ADT to MDRT in oligo-recurrent PCa patients selected with PSMA PET/CT to enhance oncological outcome. Methods Two hundred and eighty patients will be randomised in a 1:1 ratio to the standard treatment arm (MDRT alone) or the experimental arm (MDRT + 6 months ADT). Patients with biochemical recurrence after primary treatment of PCa presenting with ≤ 4 metastases will be included. The primary endpoint is the 2.5-year metastases progression-free survival (MPFS). Secondary endpoints are acute and late toxicity, quality of life, biochemical progression-free survival, overall survival, and the sensitivity of the PSMA PET/CT for detecting oligometastases at low PSA-levels. So far, between March 2020 and December 2021, one hundred patients have been included. Discussion This phase III randomised controlled trial will assess the possible benefit of the addition of 6 months ADT to MDRT on metastases progression-free survival, toxicity, QoL and survival in PCa patients with 1–4 recurrent oligometastatic lesions. Trial registration, NCT04302454 . Registered 10 March 2020.
Introduction Colorectal cancer(CRC) patients are among the incurable groups who need comprehensive palliative care covering all aspects including physical, mental, social, and spiritual . The purpose of this study is to develop, implement, and evaluate a holistic palliative care program for CRC patients in order to improve quality of life of CRC patients. Methods This study is an exploratory mixed methods study which will be conducted using a sequential qualitative-quantitative design (QUAL quan) consists of four sequential steps using the approach proposed by Ewles & Sminett to develop the program. In the first phase, a qualitative study (semi-structured interview) will be conducted to discover the needs of CRC patients from the perspective of patients, family members and care providers. In the second phase, the literature review will be performed with the aim of confirming and completing the discovering new needs. In the third phase, in order to prioritize the identified needs and prepare a initial draft of the palliative care program will be done a panel of experts. In the fourth phase, the part of the developed program according to the opinions of the panel of experts, will be implemented as quasi-experimental intervention and the effect of intervention on quality of life will be evaluated. Discussion This results of this study are expected to meet the needs of CRC patients and their families through providing a holistic care and improve their quality of life in the socio-cultural context of Iran. This program can be useful in providing care, education, policy making and for future research.
Flowchart of selecting the eligible studies
Pooled objective response rate (A) and disease control rate (B) in the analysis
Background The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma. Methods PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities. Results Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31–58) for objective response and 66% (55–77) for disease control. Grade 3–4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3–16), 7% (3–11), and 8% (5–10) of chemotherapeutic cycles, respectively. 18% (7–32) and 6% (2–11) of patients suffered grade 3–4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment. Conclusion Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results.
Background Although targeting of the cholesterol pathway by statins prevents breast cancer development in mouse models, efficacy is not absolute. Therefore, the goal of this study is to investigate if the upregulation in the cholesterol biosynthesis pathway genes associates with response to statin chemoprevention and may potentially be used as response biomarkers. Methods Expression of cholesterol biosynthesis pathway genes was initially derived from the RNA sequencing of MCF10A cell line- based breast cancer progression model system and subsequently validated by quantitative PCR assay. Response to fluvastatin was assessed in vitro using the MCF10A cell line model system, including a statin resistant cell line that was generated (MCF10.AT1-R), and measured using colony forming assays. In vivo efficacy of statin for chemoprevention was assessed in the SV40C3 TAg mouse model. Mammary tumors were identified by histologic analysis of the mammary glands. Mammary glands without histologic evidence of high-grade lesions (in situ and/or invasive carcinoma) were considered responsive to statin treatment. Results We found more than 70% of a published multi-gene fluvastatin resistance signature to be significantly upregulated during breast cancer progression and inversely correlated with statin inhibition of cellular growth and proliferation. This inherent statin resistance gene signature was also largely shared with the signature of acquired resistance to fluvastatin in MCF10.AT1-R cell line model of acquired statin resistance. These inherent resistance genes and genes exclusive to acquired statin resistance map to steroid-, and terpenoid backbone- biosynthesis pathway. We found upregulation of ~ 80% of cholesterol biosynthesis pathway genes in the tumor bearing mammary glands of SV40 C3TAg transgenic mouse model of TNBC, suggesting the involvement of cholesterol biosynthesis pathway in resistance to statin chemoprevention in vivo. A panel of 13-genes from the pathway significantly associated with response to statin treatment, as did the expression level of HMGCR alone in a mouse model of breast cancer suggesting their utility to predict the efficacy of statin chemoprevention. Conclusions High basal level, or restorative upregulation, in the cholesterol biosynthesis pathway genes appear to be strongly associated with resistance to statin chemoprevention for breast cancer and may serve as a biomarker to tailor statin treatment to individuals who are most likely to benefit.
Bioinformatics analysis in websites of Metabolic gEne RApid Visualize and Kaplan Meier plotter. a Boxplot showed expression levels of ITGAM and CLU in lung adenocarcinoma tissues and adjacent tissues. The horizontal line represented the median expression level of proteins. The top and bottom of the vertical line represented the upper quartile (75%) and lower quartile (25%). These dots in the box plot are representing samples whose protein expression levels were more than the upper quartile (75%). b The survival curve of ITGAM showed that the expression level of ITGAM in lung tissues was related to a poor prognosis, while CLU with a favorable prognosis. c Heatmap displayed expression levels of ITGAM and CLU in lung adenocarcinoma tissues and adjacent tissues
Background Among the most aggressive and rapidly lethal types of lung cancer, lung adenocarcinoma is the most common type. Exosomes, as a hot area, play an influential role in cancer. By using proteomics analysis, we aimed to identify potential markers of lung adenocarcinoma in serum. Methods In our study, we used the ultracentrifugation method to isolate serum exosomes. The Liquid chromatography-mass spectrometry (LC–MS) and bioinformatics analysis were used to identify potential serum exosomal proteins with altered expression among patients with advanced lung adenocarcinoma, early lung adenocarcinoma, and healthy controls. A western blot (WB) was performed to confirm the above differential expression levels in a separate serum sample-isolated exosome, and immunohistochemistry (IHC) staining was conducted to detect expression levels of the above differential proteins of serum exosomes in lung adenocarcinoma tissues and adjacent tissues. Furthermore, we compared different expression models of the above differential proteins in serum and exosomes. Result According to the ITGAM (Integrin alpha M chain) and CLU (Clusterin) were differentially expressed in serum exosomes among different groups as well as tumor tissues and adjacent tissues. ITGAM was significantly and specifically enriched in exosomes. As compared to serum, CLU did not appear to be significantly enriched in exosomes. ITGAM and CLU were identified as serum exosomal protein markers of lung adenocarcinoma. Conclusions This study can provide novel ideas and a research basis for targeting lung adenocarcinoma treatment as a preliminary study.
Flow diagram of patient selection criteria
The thresholds for age and tumor sizes were established by X-tile analysis. (A, B): The thresholds for age were 27 and 38 years; (C, D): The cutoff values for sizes of tumor were 130 mm and 175 mm
The nomograms of 1-, 3-, and 5-year overall survival (OS)
Calibration curve of nomogram in external validation cohort. A 1-year overall survival (OS); (B) 3-year OS; (C) 5-year OS
C-statistic and Breir score of nomograms
Background Malignant ovarian germ cell tumors (MOGCTs) are rare gynecologic neoplasms. The use of nomograms that are based on various clinical indicators to predict the prognosis of MOGCTs are currently lacking. Methods Clinical and demographic information of patients with MOGCT recorded between 2004 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database, and Cox regression analysis was performed to screen for important independent prognostic factors. Prognostic factors were used to construct predictive calculational charts for 1-year, 3-year, and 5-year overall survival (OS). The externally validated case cohort included a total of 121 MOGCT patients whose data were recorded from 2008 to 2019 from the database of the Shengjing Hospital of China Medical University. Results A total of 1401 patients with MOGCT were recruited for the study. A nomogram was used to forecast the 1-year, 3-year, and 5-year OS using data pertaining to age, International Federation of Gynecology and Obstetrics (FIGO) staging, histological subtype and grade, and surgical type. Nomograms have a more accurate predictive ability and clinical utility than FIGO staging alone. Internal and external validation also demonstrated satisfactory consistency between projected and actual OS. Conclusions A nomogram constructed using multiple clinical indicators provided a more accurate prognosis than FIGO staging alone. This nomogram may assist clinicians in identifying patients who are at increased risk, thus implementing individualized treatment regimens.
  • Aqiao XuAqiao Xu
  • Xiufeng ChuXiufeng Chu
  • Shengjian ZhangShengjian Zhang
  • [...]
  • Xiaobo WengXiaobo Weng
Background The determination of HER2 expression status contributes significantly to HER2-targeted therapy in breast carcinoma. However, an economical, efficient, and non-invasive assessment of HER2 is lacking. We aimed to develop a clinicoradiomic nomogram based on radiomics scores extracted from multiparametric MRI (mpMRI, including ADC-map, T2W1, DCE-T1WI) and clinical risk factors to assess HER2 status. Methods We retrospectively collected 214 patients with pathologically confirmed invasive ductal carcinoma between January 2018 to March 2021 from Fudan University Shanghai Cancer Center, and randomly divided this cohort into training set ( n = 128, 42 HER2-positive and 86 HER2-negative cases) and validation set ( n = 86, 28 HER2-positive and 58 HER2-negative cases) at a ratio of 6:4. The original and transformed pretherapy mpMRI images were treated by semi-automated segmentation and manual modification on the DeepWise scientific research platform v1.6 ( ), then radiomics feature extraction was implemented with PyRadiomics library. Recursive feature elimination (RFE) based on logistic regression (LR) and LASSO regression were adpoted to identify optimal features before modeling. LR, Linear Discriminant Analysis (LDA), support vector machine (SVM), random forest (RF), naive Bayesian (NB) and XGBoost (XGB) algorithms were used to construct the radiomics signatures. Independent clinical predictors were identified through univariate logistic analysis (age, tumor location, ki-67 index, histological grade, and lymph node metastasis). Then, the radiomics signature with the best diagnostic performance (Rad score) was further combined with significant clinical risk factors to develop a clinicoradiomic model (nomogram) using multivariate logistic regression. The discriminative power of the constructed models were evaluated by AUC, DeLong test, calibration curve, and decision curve analysis (DCA). Results 70 (32.71%) of the enrolled 214 cases were HER2-positive, while 144 (67.29%) were HER2-negative. Eleven best radiomics features were retained to develop 6 radiomcis classifiers in which RF classifier showed the highest AUC of 0.887 (95%CI: 0.827–0.947) in the training set and acheived the AUC of 0.840 (95%CI: 0.758–0.922) in the validation set. A nomogram that incorporated the Rad score with two selected clinical factors (Ki-67 index and histological grade) was constructed and yielded better discrimination compared with Rad score ( p = 0.374, Delong test), with an AUC of 0.945 (95%CI: 0.904–0.987) in the training set and 0.868 (95%CI: 0.789–0.948; p = 0.123) in the validation set. Moreover, calibration with the p -value of 0.732 using Hosmer–Lemeshow test demonstrated good agreement, and the DCA verified the benefits of the nomogram. Conclusion Post largescale validation, the clinicoradiomic nomogram may have the potential to be used as a non-invasive tool for determination of HER2 expression status in clinical HER2-targeted therapy prediction.
  • Zonglin JiaoZonglin Jiao
  • Xiao FengXiao Feng
  • Yuqing CuiYuqing Cui
  • [...]
  • Qingwei MengQingwei Meng
Background EphrinA (EFNA) are Eph receptor ligands that regulate various disease processes. Nonetheless, the expression characteristics of EFNAs in pan-cancer, their relationship with tumor immune microenvironment, and prognostic value landscape remain unknown. Methods A comprehensive landscape of EFNAs was created using various statistical data extracted from 33 cancers. Subsequently, we identified differential expression, genetic variations, potential function enrichment, tumor immune-related analysis, and drug sensitivity. Further, we investigated the clinical features and diagnostic prognostic value of EFNAs. RT-qPCR, western blot and immunohistochemistry (IHC) were used to validate the expression level and significant clinical value of EFNA5 in lung adenocarcinoma cell lines and tissues. Results EFNAs were highly mutated in various cancers. Genomic and epigenetic alterations of EFNAs were observed in various tumors, where an oncogenic mutation in specific cancer types potentially affected EFNA expression. Moreover, tumor-derived EFNAs were significantly related to the tumor immune microenvironment, suggesting that they are promising therapeutic targets. The majority of EFNA family genes were significantly linked to patient prognosis. Eventually, EFNA5 was an independent prognostic factor in lung adenocarcinoma. Conclusion In summary, EFNAs are crucial in tumor immune regulation, and EFNA5 is a prognostic marker in lung adenocarcinoma. Our findings provide new insights into EFNAs from a bioinformatics standpoint and highlight the significance of EFNAs in cancer diagnosis and treatment.
  • Xiao LiuXiao Liu
  • Meng JiangMeng Jiang
  • Chenggang PangChenggang Pang
  • [...]
  • Lijuan HuLijuan Hu
Background Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study. Methods ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo. Results Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo. Conclusion These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.
Flow diagram of the FORTUNE protocol. A total of 41 to 45 patients will be enrolled; it is expected that the number of patients in Group A, B, C, and D will be approximately 10, 15, 15, and 5, respectively. Group A includes patients with advanced solid tumors harboring FGFR1-3 fusion. Group B includes patients with advanced solid tumors harboring FGFR1-3 mutation suggesting that the efficacy of E7090 is promising by MANO method. Group C includes patients with advanced solid tumors harboring FGFR1-3 mutation other than what is included Group B and/or FGFR1, 2 amplification. Group D includes patients with cholangiocarcinoma harboring FGFR2 gene fusion who received prior selective FGFR inhibitors other than E7090. E7090 is administered once daily as an oral single agent in 28-day cycles
  • Yohei ChibaYohei Chiba
  • Kazuki SudoKazuki Sudo
  • Yuki KojimaYuki Kojima
  • [...]
  • Masamichi TakahashiMasamichi Takahashi
Background Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). Methods/Design This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. Discussion A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. Trial registration Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) NCT04962867 (registered July 15, 2021).
Sera levels of several proteins in response and resistant to nCRT groups of rectal cancer. A-C PRM traces for the quantification of PZP, GELS and HEP2. D Scatter plots of sera PZP concentration obtained from pCR and non-pCR patients using the PRM. E Receiver operating characteristic (ROC) curve for nCRT response by the baseline PZP, GELS, HEP2 and CEA. ROC curves generated using the response information and levels of the baseline PZP, GELS, HEP2 and CEA are able to discriminate between pCR patients and non-pCR. PZP has the strongest predictive value (area under the curve [AUC] = 0.7993) to discriminate those patients. F ROC analysis for the training set using Random Forest. G ROC analysis for the testing set using Random Forest
Kaplan–Meier analysis of the correlation between the candidate proteins’ level and prognosis in rectal cancer patients. A-B Kaplan–Meier analysis of the correlation among HEP2 and GELS baseline levels and OS in rectal cancer patients. C-E PRM traces for the quantification of S10A8 in baseline and its correlation with OS and DFS. F-I PRM traces for the quantification of APOA1 and PEDF in post-nCRT level and its correlation with DFS
Kaplan–Meier estimates of OS of CRC patients according to several proteins level from TCGA CRC dataset. A The correlation between HEP2 and OS in CRC. B The correlation between HEP2 and OS in colon cancer. C The correlation between APOA1 and OS in rectal cancer. D The correlation between S10A8 and OS in CRC
  • Hanyang WangHanyang Wang
  • Dengbo JiDengbo Ji
  • Huifang TianHuifang Tian
  • [...]
  • Jin GuJin Gu
Background Preoperative neoadjuvant chemoradiation (nCRT) has been the standard treatment for locally advanced rectal cancer. Serum biomarkers to stratify patients with respect to prognosis and response to nCRT are needed due to the diverse response to the therapy. Methods Thirteen paired pre- and post-nCRT sera from rectal cancer patients were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Twenty-five proteins were selected for validation by parallel reaction monitoring (PRM) in ninety-one patients. Results Totally, 310 proteins were identified and quantified in sera samples. Reactome pathway analysis showed that the immune activation-related pathways were enriched in response to nCRT. Twenty-five proteins were selected for further validation. PRM result showed that the level of PZP was higher in pathological complete response (pCR) patients than non-pCR patients. The Random Forest algorithm identified a prediction model composed of 10 protein markers, which allowed discrimination between pCR patients and non-pCR patients (area under the curve (AUC) = 0.886 on testing set). Higher HEP2 and GELS or lower S10A8 in baseline sera were associated with better prognosis. Higher APOA1 in post nCRT sera was associated with better disease-free survival (DFS). Conclusions We identified and confirmed a 10-protein panel for nCRT response prediction and four potential biomarkers HEP2, GELS, S10A8 and APOA1 for prognosis of rectal cancer based on iTRAQ-based comparative proteomics screening and PRM-based targeted proteomic validation.
  • Bo ChenBo Chen
  • Zhan YangZhan Yang
  • Zhichao LangZhichao Lang
  • [...]
  • Suhui YuSuhui Yu
LncRNA N6-methylandenosine (m6A) modification has been shown to be associated with the constitution of the tumor microenvironment (TME) and tumorigenesis. It’s essential to understand the mechanisms of lncRNA m6A modification in hepatocellular carcinoma (HCC) and identify relative prognostic predictors to guide therapy and explore potential therapeutic targets. Pearson correlation analysis was performed to identify m6A-related lncRNAs in 374 patients with HCC. Unsupervised cluster analysis of the potential m6A-related lncRNA-based HCC subtypes was conducted, followed by the concurrent analysis of their relationship with TME characteristics, immune checkpoints, immune features, and prognosis through single sample gene set enrichment analysis and ESTIMATE algorithm. Cox regression analyses were performed to screen prognostic m6A-related lncRNA, construct an m6A-related lncRNA signature (m6A-RLRS), and establish an integrated nomogram for the prognosis of patients with HCC. We identified 61 m6A-related lncRNAs and two HCC subtypes defined by consensus cluster of m6A-related lncRNAs with distinct clinical features. Progression-free survival (PFS), three TME-related scores, 15 immune-associated gene sets, and two immune checkpoints expression were found to be significantly different among the two subtypes. Twenty-five prognostic m6A-related lncRNAs were determined, four of which were included to establish an m6A-RLRS with favorable discrimination, and the signature was validated in the validation set and an independent FAHWMU cohort ( n = 60). Furthermore, a novel nomogram combining signature and clinical predictors was generated with a C-index of 0.703, and an original ceRNA regulatory network consisting of 9 lncRNAs, 28 miRNAs, and 75 target mRNAs was constructed. Finally, the differential expression of four m6A-related lncRNA was verified by qRT-PCR. In conclusion, m6A-related lncRNA prognostic signature and molecular subtype contributes to accurately predict the prognosis of HCC and provide potential novel therapeutic targets.
The CONSORT flow diagram for this trial
Recurrence-free survival (RFS) (a), locoregional recurrence-free survival (LRFS) (c), and overall survival (OS) (e) of the whole cohort; and RFS (b), LRFS (d), and OS (f) of node-positive patients
  • Tao MaTao Ma
  • Xueli BaiXueli Bai
  • Qichun WeiQichun Wei
  • [...]
  • Tingbo LiangTingbo Liang
Background The role of adjuvant radiation in pancreatic adenocarcinoma (PDAC) remains unclear. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II PDAC. Methods In this single-center randomized controlled trial, patients with stage II PDAC that underwent margin-negative resection were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. Results Forty patients were randomly assigned to treatment between Sep 1, 2015 and Mar 31, 2018. Of these, 38 were included in the intention-to-treat analysis (20 in gemcitabine arm and 18 in gemcitabine plus SBRT arm). The median RFS and OS were 9.70, 28.0 months in the gemcitabine arm and 5.30, 15.0 months in the gemcitabine plus SBRT arm (RFS, P = 0.53; OS, P = 0.20), respectively. The median LRFS in both arms was unreached ( P = 0.81). Grade 3 or 4 adverse events were all comparable between the two arms. Evaluation of data from the enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence-free survival. Conclusions Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II PDAC. Trial registration, NCT02461836 . Registered 03/06/2015
  • Xinshu WangXinshu Wang
  • Zhiyuan HuangZhiyuan Huang
  • Lei LiLei Li
  • [...]
  • Yunhui LiYunhui Li
Background Lung squamous cell carcinoma (LUSC) is prone to metastasis and likely to develop resistance to chemotherapeutic drugs. DNA repair has been reported to be involved in the progression and chemoresistance of LUSC. However, the relationship between LUSC patient prognosis and DNA damage repair genes is still unclear. Methods The clinical information of LUSC patients and tumour gene expression level data were downloaded from the TCGA database. Unsupervised clustering and Cox regression were performed to obtain molecular subtypes and prognosis-related significant genes based on a list including 150 DNA damage repair genes downloaded from the GSEA database. The coefficients determined by the multivariate Cox regression analysis and the expression level of prognosis-related DNA damage repair genes were employed to calculate the risk score, which divided LUSC patients into two groups: the high-risk group and the low-risk group. Immune viability, overall survival, and anticarcinogen sensitivity analyses of the two groups of LUSC patients were performed by Kaplan–Meier analysis with the log rank test, ssGSEA and the pRRophetic package in R software. A time-dependent ROC curve was applied to compare the survival prediction ability of the risk score, which was used to construct a survival prediction model by multivariate Cox regression. The prediction model was used to build a nomogram, the discriminative ability of which was confirmed by C-index assessment, and its calibration was validated by calibration curve analysis. Differentially expressed DNA damage repair genes in LUSC patient tissues were retrieved by the Wilcoxon test and validated by qRT–PCR and IHC. Result LUSC patients were separated into two clusters based on molecular subtypes, of which Cluster 2 was associated with worse overall survival. A prognostic prediction model for LUSC patients was constructed and validated, and a risk score calculated based on the expression levels of ten DNA damage repair genes was employed. The clinical utility was evaluated by drug sensitivity and immune filtration analyses. Thirteen-one genes were upregulated in LUSC patient samples, and we selected the top four genes that were validated by RT–PCR and IHC. Conclusion We established a novel prognostic model based on DNA damage repair gene expression that can be used to predict therapeutic efficacy in LUSC patients.
Background IFN-γ has been traditionally recognized as an inflammatory cytokine that involves in inflammation and autoimmune diseases. Previously we have shown that sustained IFN-γ induced malignant transformation of bovine mammary epithelial cells (BMECs) via arginine depletion. However, the molecular mechanism underlying this is still unknown. Methods In this study, the amino acids contents in BMECs were quantified by a targeted metabolomics method. The acquisition of differentially expressed genes was mined from RNA-seq dataset and analyzed bioinformatically. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry (IHC) assay were performed to detect gene mRNA and protein expression levels. CCK-8 and would healing assays were used to detect cell proliferation and migration abilities, respectively. Cell cycle phase alternations were analyzed by flow cytometry. Results The targeted metabolomics analysis specifically discovered IFN-γ induced arginine depletion through accelerating arginine catabolism and inhibiting arginine anabolism in BMECs. Transcriptome analysis identified leucine aminopeptidase 3 (LAP3), which was regulated by p38 and ERK MAPKs, to downregulate arginine level through interfering with argininosuccinate synthetase (ASS1) as IFN-γ stimulated. Moreover, LAP3 also contributed to IFN-γ-induced malignant transformation of BMECs by upregulation of HDAC2 (histone deacetylase 2) expression and promotion of cell cycle proteins cyclin A1 and D1 expressions. Arginine supplementation did not affect LAP3 and HDAC2 expressions, but slowed down cell cycle process of malignant BMECs. In clinical samples of patients with breast cancer, LAP3 was confirmed to be upregulated, while ASS1 was downregulated compared with healthy control. Conclusions These results demonstrated that LAP3 mediated IFN-γ-induced arginine depletion to malignant transformation of BMECs. Our findings provide a potential therapeutic target for breast cancer both in humans and dairy cows.
Statistically significant Kaplan–Meier survival curves of the adjuvant chemotherapy and no adjuvant chemotherapy groups according to the grades and molecular subtypes of T1bN0M0 breast cancer patients treated at the Northern Jiangsu People’s Hospital. A T1b Grade II; B: T1b Grade III; C T1b HoR + HER2 + ; D T1b HoR- HER2 + ; E T1b HoR- HER2-. Abbreviations: HoR, hormone receptor; HER2, human epidermal growth factor receptor 2
Statistically significant Kaplan–Meier survival curves of the adjuvant chemotherapy and no adjuvant chemotherapy groups according to the grades and molecular subtypes of T1cN0M0 breast cancer patients treated at the Northern Jiangsu People’s Hospital. A T1c Grade II; B T1c Grade III; C T1c HoR + HER2-; D T1c HoR + HER2 + ; E T1c HoR- HER2 + ; F T1c HoR- HER2-. Abbreviations: HoR, hormone receptor; HER2, human epidermal growth factor receptor 2
Background There is no clear consensus on the benefits of adjuvant chemotherapy for tumor-node-metastasis (TNM) stage T1 (T1N0M0) breast cancer (BC). Our study investigated the effects of adjuvant chemotherapy on T1N0M0 BC patients. Methods Seventy-five thousand one hundred thirty-nine patients diagnosed with T1N0M0 BC were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate Cox analyses were performed to investigate the effects of adjuvant chemotherapy on T1a, T1b, and T1cN0M0 BC, including various tumor grades, and four molecular subtypes. Propensity score matching (PSM) was used to eliminate confounding factors and further compare the results between adjuvant chemotherapy and no adjuvant chemotherapy. Additionally, 545 T1N0M0 BC patients treated at the Northern Jiangsu People’s Hospital were included as an independent external validation cohort. Univariate and multivariate Cox analyses were used to confirm the effects of adjuvant chemotherapy in T1a, T1b, and T1cN0M0 BC. Survival curves for the different tumor grades and molecular subtypes were plotted using the Kaplan–Meier method. Results Adjuvant chemotherapy demonstrated a statistically significant improvement in overall survival (OS) in T1b and T1c BC, but not in T1a BC. Within T1b BC, adjuvant chemotherapy was found to have effects on grade III, and hormone receptor + (HoR +)/human epidermal growth factor receptor 2 + (HER2 +), HoR-/HER2 + , and HoR-/HER2- molecular subtypes, respectively. Adjuvant chemotherapy was beneficial to OS for grade II/III and T1c BC. Identical results were obtained after PSM. We also obtained similar results with external validation cohort, except that adjuvant chemotherapy made a difference in grade II and T1b BC of the external validation dataset. Conclusions Partial T1N0M0 BC patients with grade III T1bN0M0, patients with tumor grade II and III T1cN0M0, and excluding those with HoR + /HER2- subtype tumors, could obtain OS benefits from adjuvant chemotherapy.
Patients enrolled the study
Survival of the cohort
Survival of the measurable patients by traditional risk factors
Survival of the measurable patients by treatment respond
Background: The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70-75% of infants, 5-6% of children and 10-15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. Methods: A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. Results: The 48 enrolled patients included 28 males and 20 females; 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 109/L was detected in 7 (14.58%) patients; testicular leukemia (TL) or central nervous system involvement was found in 5 (10.41%) or 3 (6.25%) patients, respectively. Statistical differences were not found in the age groups of sex or initial WBC count, whereas TL was more common in the infant group (P < 0.05). 11q23 was detected in 18 patients; KMT2Ar was detected in 46 (95.83%) or 45 (93.75%) patients by FISH or multiplex RT-PCR technology, respectively; RNA-seq data were obtained for 18 patients, and 3 patients with uncommon KMT2Ar were identified. KMT2A-AFF1, KMT2A-MLLT3 and KMT2A-MLLT1 were the most common transcripts. Statistical differences were not found in treatment response by age groups, including dexamethasone induction, bone marrow (BM) smear status and minimal residual disease (MRD) level at different time points (TP), treatment-related mortality (TRM), or complete remission (CR) rate (P > 0.05); MRD levels monitored by FCM or PCR were unequal at the same TP. Four patients died of treatment, and TRM was 8.33%; 40 patients achieved CR, and the CR rate for the cohort was 83.33%. Seven patients quit, 15 patients relapsed, and the 5 yr cumulative relapse rate was 59.16 ± 9.16%; the 5 yr prospective EFS (pEFS) for patients who were included or excluded from the TRM group was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively. Multivariate analysis for prognosis and hazard ratio was performed for 37 patients without TRM and revealed that an initial WBC count of > 300 × 109/L and a positive level of FCM-MRD were strongly related to a poor outcome for B-ALL patients with KMT2Ar (P < 0.05).
PRISMA flow chart
Quality assessment of studies using the Quality Assessment of Diagnostic Accuracy Studies 2 score system
Background Cervical cancer is a preventable disease, but it is a major public health problem despite having a good prognosis when diagnosed early. Although the Pap smear has led to huge drops in rates of cervical cancer and death from the disease, it has some limitations, making new approaches necessary for early diagnosis and biomarkers discovery. MiRNAs have been considered a new class of non-invasive biomarkers and may have great clinical value for screening early-stage cervical intraepithelial neoplasia. Well-designed studies have emerged as a necessary strategy for the identification of miRNAs that could be used safely and reliably for a differential diagnosis. This review aims to provide an up-to-date perspective on the assessment of circulating miRNA expression from precursor lesions to cervical cancer, identifying circulating miRNAs or specific miRNA signatures that can be used as potential biomarkers of different stages of cervical carcinogenesis. Methods A systematic review was performed and searches were conducted in the PubMed, LILACS, and Scopus electronic databases. Results Most studies involved Chinese ethnic women and searched for circulating miRNAs in serum samples. Thirty three microRNAs were evaluated in the eligible studies and 17 (miR-196a, miR-16-2, miR-497, miR-1290, miR-425-5p, hsa-miR- 92a, miR-1266, miR-9, miR-192, miR-205, miR-21, miR-152, miR-15b, miR-34a, miR-218, miR-199a-5p and miR-155-5p) showed up-regulation in women with precursor lesion and cervical cancer and 16 microRNAs showed decreased expression in these same groups of women compared to healthy controls (miR-195, miR-2861, miR-145, miR-214, miR-34a, miR-200a, let-7d-3p, miR-30d-5p, miR-638, miR-203a-3p, miR-1914-5p, miR-521, miR-125b, miR-370, miR-218 and miR-100). Conclusion Therefore, defining promising circulating miRNAs or specific miRNA signatures of biological fluid samples can be useful for the screening, diagnosis, prognosis and clinical monitoring of women undergoing cervical carcinogenesis, but greater standardization of studies seems to be necessary for greater consolidation of information.
Distribution of breast cancer survivors in the FACIT-Fatigue clusters throughout the study (n = 38). Clusters developed from the 5% MCID between T0T1, T1T2, T0T2 and T0T1T2: The same, Patients who maintained the FACIT-Fatigue score between T0T1, T1T2, T0T2 or who maintained the score at all three times (T0T1T2); Better, Patients who improved the FACIT-Fatigue score between T0T1, T1T2, T0T2 or who improved at T1 and again at T2 (T0T1T2); Worse, Patients who worsened the FACIT-Fatigue score between T0T1, T1T2, T0T2 or who worsened at T1 and again at T2 (T0T1T2); V, Patients who worsened the FACIT-Fatigue score at T1 and improved at T2 (T0T1T2); Inverted V, Patients who improved the FACIT-Fatigue score at T1 and worsened at T2 (T0T1T2). Chi-square Independence Test showed that there was no association between time points of study and clusters, considering T0T1 and T1T2 [X2(2) = 4.452; p = 0.108]
Background The adjuvant treatment with Aromatase Inhibitor (AI) is considered standard of care for postmenopausal breast cancer (BC) women with hormone receptor-positive (HR +), however, it often causes adverse effects such as cancer-related fatigue (CRF). The high prevalence of vitamin D deficiency in postmenopausal women who start adjuvant AI supports the hypothesis that hypovitaminosis D would be one of the biological explanations for toxicity of AI. This study aimed to identify the relationship between 25-hydroxyvitamin D [25(OH)D] and CRF, and to analyze their associations and effects on depression, anxiety, functional disability, muscle/joint aches and HRQL. Methods This prospective study included 89 postmenopausal women diagnosed with HR + early BC in adjuvant endocrine therapy with AI. Anthropometric and body composition assessments were performed, as well as dietary assessments by application of 24-h dietary recall, at three time points, totaling 24 months of follow-up. The women completed the Cervantes Scale (CS), Hospital Anxiety and Depression Scale (HADS) and Health Assessment Questionnaire (HAQ). The CRF was determined from the Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F). The serum 25(OH)D was determined by electrochemiluminescence, with cut-off point above 75 nmol/L adopted as sufficiency. Generalized Linear Model (GLzM) and Generalized Mixed Model (GMM) analysis were used. Results At baseline, 36% ( n = 32) of the women presented CRF and 39.3% ( n = 35) had 25(OH)D below 75 nmol/L. None of the women reached the Estimated Average Requirements (EAR) of vitamin D. The causality between 25(OH)D and CRF was not significant. Longitudinally, lower levels of 25(OH)D had a negative effect on anxiety ( p = 0.020), Menopause and Health ( p = 0.033) and Vasomotor scores ( p = 0.007). Also, the CRF had a negative effect on anxiety ( p = 0.028); depression ( p = 0.027); functional disability ( p = 0.022); HRQL ( p = 0.007); Menopause and Health ( p = 0.042), Psychological ( p = 0.008) and Couple Relations ( p = 0.008) domains; and on Health ( p = 0.019) and Aging ( p = 0.036) subdomains. Vasomotor subdomain (β = -2.279, p = 0.045) and muscle/joint aches (β = -0.779, p = 0.013) were significant with CRF only at baseline. Conclusions This study found negative effect of body adiposity on CRF. Still, the clinical relevance of 25(OH)D and CRF is highlighted, especially that of CRF, considering the consistent impact on several adverse effects reported by BC survivors during adjuvant endocrine therapy.
Representative histopathological image of lymphatic or venous invasion (hematoxylin and eosin staining, × 200)
Representative histopathological image of tumor budding, isolated single cells, or clusters of up to four cells (hematoxylin and eosin staining, × 200)
The prevalence of lymph node (LN) metastasis is associated with the number of tumor budding
Akaike information criterion (AIC) in logistic regression models adjusted for histological type and lymphatic or venous invasion
Proportion of lymph node (LN) metastasis according to the total composite score. Total composite score: 2 × histological type [favorable differentiation, 0; unfavorable differentiation, 1] + 2 × lymphatic or venous invasion [negative, 0; positive, 1] + 1 × tumor budding [< 5/HPF, 0; ≥ 5/HPF, 1]
Background Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC. Methods In total, 395 patients with histologically confirmed T1N0–2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors. Results The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio [OR], 8.16; 95% confidence interval [CI], 1.80–36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91–11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21–7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and ≥ 3, respectively. Conclusions For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis.
X-tile analysis of survival data of NPC patients. a The optimal cut-off value for the SII was 655.54 (chi square = 18.922, p < 0.001); b The optimal cut-off value for the SIRI was 1.12 (chi square = 23.425, p < 0.001)
Kaplan–Meier curves for PFS and OS between different groups in training cohort. a Low SII group and high SII group for PFS; b Low SII group and high SII group for OS; c Low SIRI group and high SIRI group for PFS; d Low SIRI group and high SIRI group for O
Kaplan–Meier curves for PFS and OS between different groups in validation cohort. a Low SII group and high SII group for PFS; b Low SII group and high SII group for OS; c Low SIRI group and high SIRI group for PFS; d Low SIRI group and high SIRI group for OS
ROC curves analysis for comparing the prognostic potential of independent prognostic factors. a Prediction of PFS in training cohort; b Prediction of OS in training cohort; c Prediction of PFS in validation cohort; d Prediction of OS in validation cohort
Background Inflammatory parameters and Epstein–Barr virus (EBV) DNA status have been confirmed to be associated with prognosis in nasopharyngeal carcinoma (NPC) patients. However, there are few in-depth studies on the prognosis of NPC patients with negative EBV DNA. Our study aimed to look for inflammatory biomarkers that can identify disease progression in NPC patients with negative EBV DNA. Methods A total of 795 NPC patients were recruited, and ultimately 325 NPC patients with negative EBV DNA were included in this study (170 in training cohort and 155 in validation cohort). Kaplan–Meier method and log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). The multivariate analysis of Cox proportional hazards regression model was used to determine the independent prognostic factors. Receiver operating characteristic (ROC) curves were used to assess prognostic value. The logistic regression was used to evaluate the relationship between EBV DNA status and inflammatory parameters. The correlation between clinical characteristics was analyzed by the chi-squared test or the Fisher’s exact test. Results The optimal cutoff point for the SIRI was 1.12. The EBV DNA-negative NPC patients with high SIRI level had worse PFS and OS (all p < 0.001). In multivariate Cox proportional hazard models analysis, SIRI was an independent prognostic factor for PFS and OS (all p < 0.05), and had higher prognostic value than other indicators. Above results were found in the training cohort and confirmed in the validation cohort. In addition, EBV DNA status was not associated with any inflammatory parameters. Conclusions The SIRI can provide more accurate risk stratification and better prognostic prediction for NPC patients with negative EBV DNA.
Identification of dysregulated circRNAs between non-cirrhotic and cirrhotic HCC tissues. A Hierarchical clustering indicates differences in circRNA expression profiling between the two groups. B The volcano plot was showed the expression profiling between the two groups
Validation of dysregulated circRNAs. A Heat map of the six most prominent dysregulated circRNAs between non-cirrhotic and cirrhotic cases. B Agarose gel electrophoresis of PCR products as amplified by divergent and convergent primers of dysregulated circRNAs in cDNA and gDNA with GAPDH used as a reference gene. C and D Expressions of top three prominent up/down-regulated circRNAs in non-cirrhotic HCC samples as validated using qRT-PCR in 20 HCC samples from patients with or without liver cirrhosis. E and F Expressions of top three prominent up/down-regulated circRNAs in non-cirrhotic HCC in 20 HCC samples and paired non-cirrhotic tissues. c, cDNA; g, gDNA
Enrichment analyses of dysregulated circRNAs host genes. A GO and KEGG analyses of host genes of up-regulated circRNAs. B GO and KEGG analyses of host genes of down-regulated circRNAs
Construction of the circRNA-miRNA-mRNA regulatory network. A Interaction network consisting of four circRNAs (three up-regulated and one down-regulated), 20 miRNAs and 214 mRNAs as generated using Cytoscape software (V.3.2.1). B-C GO and KEGG analysis were performed to predict the biological function of target mRNAs
Biological functions of four most prominent dysregulated circRNAs were verified by in vitro experiments. A-D Knockdown effect of special siRNAs for these circRNAs was verified by qRT-PCR. E-H CCK-8 assay results showed that knockdown of these circRNAs significantly affects the proliferation of HCC cells. I Colony formation assay showed the influence of these circRNAs on the survival of HCC cells. J Wound healing assay was used to evaluate the biological function of these circRNAs in migration of HCC cells. **P < 0.01, ***P < 0.001. Similar results were obtained in 3 independent experiments
Background Liver cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC). However, some HCC cases can also originate from non-cirrhotic livers. The aim of this study was to identify key circular RNAs (circRNAs) associated with the tumorigenesis of non-cirrhotic liver disease. Methods The differently expressed circRNAs between non-cirrhotic and cirrhotic HCCs were assessed with use of high-throughput circRNAs sequencing and validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Potential biological functions of these dysregulated circRNAs were predicted with use of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA-miRNA-mRNA regulation network was constructed as achieved with use of miRanda software and visualized using Cytoscape software. Biological functions of the four most prominent dysregulated circRNAs identified were confirmed by in vitro experiments. Moreover, possible translations of these dysregulated circRNAs were also predicted. Results A total of 393 dysregulated circRNAs were identified between non-cirrhotic and cirrhotic HCC, including 213 that were significantly up-regulated and 180 significantly down-regulated circRNAs. Expression levels of the six most prominent dysregulated circRNAs were further validated using qRT-PCR. Many tumor related miRNAs were involved in the circRNA-miRNA-mRNA networks, including miR-182-5p, miR-561-3p, miR-125a-5p, miR-145, miR-23b-3p and miR-30e-3p, and downstream mRNAs of dysregulated circRNAs were significantly related with biological processes involved in the progression of tumors, including proliferation, migration, differentiation, and focal adhesion. Results from the in vitro experiments demonstrated that the most prominent dysregulated circRNAs exerted notable effects upon the proliferation and migration of HCC cells. Finally, we also identified 19 dysregulated circRNAs having potential for the coding of functional peptides. Conclusion The results of this present study indicate that circRNAs may play important roles in tumorigenesis of non-cirrhotic HCC. Such findings provide some novel insights and pave the way for the development of future studies directed at investigating the initiation and treatment of HCC.
Flowchart of the patient selection procedure
Representative images showing the appearance of CVs on CECT. We defined CVs as blood vessels of any diameter, with a definite connection between the tumor and the perirenal region. The yellow arrows indicate the CVs. CV, collateral vessel; CECT, contrast-enhanced computed tomography
Representative images showing the appearance of AI and OBS on CECT. A The AI in the parenchymal phase was defined as an angle of 90° or less (black lines). (B) A contact length ≥ 3 mm of the bulging portion of the renal tumor onto the renal surface was indicative of a positive OBS (black arrows). AI, angular interface; OBS, overflowing beer sign; CECT, contrast-enhanced computed tomography
CVs in five patients with RCC and recurrence. A–E The white arrows indicate CVs detected in the five patients with RCC and recurrence. CV, collateral vessel; RCC, renal cell carcinoma
Kaplan–Meier curves depicting the 5-year RFS in patients with small RCC after surgical resection. A The 5-year RFS after surgical resection of all patients with small RCCs was 96.8%. B Patients with CV had a significantly worse 5-year RFS than those with CV (p = 0.005). The 5-year RFS of patients with and without CV was 92.5 and 100%, respectively. RFS, recurrence-free survival; RCC, renal cell carcinoma; CV, collateral vessel
Background Active surveillance (AS) is one of the treatment methods for patients with small renal masses (SRMs; < 4 cm), including renal cell carcinomas (RCCs). However, some small RCCs may exhibit aggressive neoplastic behaviors and metastasize. Little is known about imaging biomarkers capable of identifying potentially aggressive small RCCs. Contrast-enhanced computed tomography (CECT) often detects collateral vessels arising from neoplastic angiogenesis in RCCs. Therefore, this study aimed to evaluate the association between SRM differential diagnoses and prognoses, and the detection of collateral vessels using CECT. Methods A total of 130 consecutive patients with pathologically confirmed non-metastatic SRMs (fat-poor angiomyolipomas [fpAMLs; n = 7] and RCCs [ n = 123]) were retrospectively enrolled. Between 2011 and 2019, SRM diagnoses in these patients were confirmed after biopsy or surgical resection. All RCCs were surgically resected. Regardless of diameter, a collateral vessel (CV) was defined as any blood vessel connecting the tumor from around the kidney using CECT. First, we analyzed the role of CV-detection in differentiating between fpAML and RCC. Then, we evaluated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of RCC diagnosis based on CV-detection using CECT. We also assessed the prognostic value of CV-detection using the Fisher exact test, and Kaplan-Meier method and the log-rank test. Results The sensitivity, specificity, PPV, NPV, and accuracy of CV-detection for the diagnosis of small RCCs was 48.5, 45.5, 100, 100, and 9.5% respectively. Five of 123 (4.1%) patients with RCC experienced recurrence. CV-detection using CECT was the only significant factor associated with recurrence ( p = 0.0177). Recurrence-free survival (RFS) was significantly lower in patients with CV compared with in those without CV (5-year RFS 92.4% versus 100%, respectively; p = 0.005). In addition, critical review of the CT images revealed the CVs to be continuous with the venous vessels around the kidney. Conclusions The detection of CVs using CECT is useful for differentiating between small fpAMLs and RCCs. CV-detection may also be applied as a predictive parameter for small RCCs prone to recurrence after surgical resection. Moreover, AS could be suitable for small RCCs without CVs.
Background Colorectal cancer (CRC) is the third most common cancer worldwide. However, limited effective biomarkers are associated with the tumorigenesis and prognosis of CRC. Methods The present study identified potential signatures from The Cancer Genome Atlas (TCGA) database and further validated the identified biomarkers in CRC tissues by immunohistochemistry (IHC). Results The expression of insulin-like growth factor 1 receptor ( IGF-1R ) and Livin gene was significantly upregulated in CRC samples compared to the adjacent normal samples in the TCGA dataset. IHC indicated that IGF-1R and Livin protein levels are increased in CRC and adenoma tissues compared to normal tissues. Notably, the IGF-1R protein levels differed significantly between adenoma and CRC. The elevated IGF-1R and Livin expression was associated with CRC clinicopathological features, including age, gender, histological subtype, individual cancer stages, nodal metastasis, and TP53-mutant in TCGA. Additionally, the IGF-1R promoter methylation level was closely related to CRC. Consistent with the TCGA study, IHC indicated that overexpressed IGF-1R and Livin proteins were independent risk factors for stage and metastasis. A marked correlation was established between IGF-1R and Livin expression in CRC, while the survival map showed no significant correlation with CRC. Kaplan–Meier survival curves showed that CRC patients with high IGF-1R or Livin expression had a prolonged overall disease-free survival than those with low expression in TCGA. Conclusion IGF-1R and Livin are associated with CRC tumorigenesis and might be valuable for novel biomarker identification and targeted therapeutic strategy development.
Background: Persistent high-risk (hr) human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Cervical cancer is a major public health problem in Sub-Saharan Africa including South Africa. This study investigated the prevalence of and factors associated with hr-HPV infection among women attending a tertiary hospital in Gauteng Province, South Africa. Methods: Cervical samples were collected from 526 participants aged ≥ 18 years using a Cervex Brush® Combi and tested for hr-HPV types on the Abbott m2000 analyzer using the Abbott RealTime HR HPV assay. Samples that tested hr-HPV deoxyribonucleic acid (DNA)-positive were further tested for hr-HPV E6/E7 messenger ribonucleic acid (mRNA) using the APTIMA® HPV assay on the Panther system (Hologic, Inc.). Sociodemographic data were collected using a self-administered questionnaire. Binomial regression analysis was used to assess factors associated with hr-HPV infection. Results: Overall hr-HPV DNA prevalence was 48.1% (95%CI: 43.8-52.4%). Of the hr-HPV DNA-positives, 24.5% (95%CI: 19.3-30.1) had HPV-16; 12.3% (95%CI: 8.5-16.9) had HPV-18 and 87.4% (95%CI: 82.6-91.2) had other 12 h-HPVs. Of the samples positive for hr-HPV DNA, 84.2% (95%CI: 79.1-88.5) (213/253) were positive for hr-HPV E6/E7 mRNA. Advanced age was an important factor linked to hr-HPV E6/E7 mRNA positivity. Based on multivariate binomial regression analysis, unemployment (PR: 1.50; 95%CI: 1.23-1.83) and being married (PR: 0.61; 95%CI: 0.47-0.81) were identified as statistically significant (p < 0.0001) predictive and protective factors, respectively, for hr-HPV infection. Conclusions: The prevalence of hr-HPV infection was high. Furthermore, hr-HPV DNA-positive samples had a high hr-HPV E6/E7 mRNA prevalence. The presence of hr-HPV E6/E7mRNA indicates active infection and thus a greater risk of developing the cervical disease. Therefore, HPV mRNA testing could be a better test to monitor women who are positive with Pap smear before colposcopy is performed to reduce the burden of referrals.
Extracellular acidosis increases PD-L1 expression in MDA-MB-231 cells. A–C The pH of the medium was adjusted by HCl or NaOH, and MDA-MB-231 cells were incubated for 18 h. Protein levels were analyzed by western blotting (A), the culture medium pH was measured using a pH meter (B), and mRNA levels were analyzed by qPCR (C). D–F MDA-MB-231 cells were incubated under acidic conditions for the indicated periods. Protein levels were analyzed by western blotting (D), culture medium pH was measured using a pH meter (E), and mRNA levels were analyzed by qPCR (F)
Tumor-derived lactic acidosis increases PD-L1 expression in MDA-MB-231 cells. A Schematic diagram of the glycolysis pathway in cancer cells. B Summary of the process through which various conditioned media were prepared (CON, control; fresh medium), (NCM, normoxic conditioned medium), (HCM, hypoxic conditioned medium). C–E MDA-MB-231 cells were treated with various conditioned media with/without NaOH for 18 h. Protein levels were analyzed by western blotting (C), mRNA levels were analyzed by qPCR (D), and the culture medium pH was measured using a pH meter (E).F–H MDA-MB-231 cells were treated with lactic acid or sodium lactate, with/without, NaOH for 24 h. Protein levels were analyzed by western blotting (F), mRNA levels were analyzed by qPCR (G), and the culture medium pH was measured using a pH meter (H)
Acidosis-induced PD-L1 expression is attenuated by targeting the acidic pH of MDA-MB-231 cells. A–C MDA-MB-231 cells were incubated with HCl-treated acidic medium for 18 h; the acidic culture medium was replaced with fresh medium, or NaHCO3 was added for 24 h. Protein levels were analyzed by western blotting (A), mRNA levels were analyzed by qPCR (B), and the culture medium pH was measured using a pH meter (C). D–F MDA-MB-231 cells were incubated with lactic acid-treated acidic medium for 24 h; the acidic culture medium was replaced with fresh medium or NaHCO3 was added for 24 h. Protein levels were analyzed by western blotting (D), mRNA levels were analyzed by qPCR (E), and the culture medium pH was measured using a pH meter (F)
Increased PD-L1 expression is correlated with activation of STAT3 under acidic conditions in MDA-MB-231 cells. A–C Gene set enrichment analysis (GSEA) results according to high and low expression of PD-L1 in breast cancer patients. D The pH of the medium was adjusted with HCl or NaOH, and MDA-MB-231 cells were treated for 18 h. Protein levels were analyzed by western blotting. E MDA-MB-231 cells were incubated under acidic conditions for the indicated periods, and protein levels were analyzed by western blotting. F, G MDA-MB-231 cells were incubated with HCl or lactic acid-treated acidic medium for 18 or 24 h; the acidic culture medium was replaced with new medium or NaHCO3 was added for 24 h. Protein levels were analyzed by western blotting. H MDA-MB-231 cells were transfected with si-NTC (negative control) or si-STAT3 for 24 h followed by treatment with HCl-treated acidic medium for 18 h. Protein levels were analyzed by western blotting. I MDA-MB-231 cells were transfected with mock-GFP or WT-STAT3-GFP for 48 h. Protein levels were analyzed by western blotting
Clinical relevance of PD-L1 expression in human breast cancer patients. A Immunohistochemical analysis of normal and tumor breast tissues. Scale bars: 50 μm. B, C mRNA expression of PD-L1 (B) and LDH-A (C) in normal and tumor breast tissues from GEO databases. N, normal tissue; T, tumor tissue. D Graphical summary adapted from “Cancer cell” by and retrieved from
Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.
The study flowchart of matched nested case-control cohort based on nationwide sampled database
Background Breast cancer is an umbrella term referring to a group of biologically and molecularly heterogeneous diseases originating from the breast. Globally, incidences of breast cancer has been increasing dramatically over the past decades. Analyses of multiple clinical “big data” can aid us in clarifying the means of preventing the disease. In addition, predisposing risk factors will be the most important issues if we can confirm their relevance. This study aims to provide an overview of the predisposing factors that contribute to a higher possibility of developing breast cancer and emphasize the signs that we ought to pay more attention to. Methods This is a matched nested case-control study. The cohort focused on identifying the eligible risk factors in breast cancer development by data screening (2000-2013) from the Taiwan National Health Insurance Research Database (NHIRD) under approved protocol. A total of 486,069 females were enrolled from a nationwide sampled database, and 3281 females was elligible as breast cancer cohort, 478,574 females who had never diagnosed with breast cancer from 2000 to 2013 were eligible as non-breast cancer controls, and matched to breast cancer cases according to age using a 1:6 ratio. Results We analyzed 3281 breast cancer cases and 19,686 non-breast cancer controls after an age-matched procedure. The significant predisposing factors associated with breast cancer development including obesity, hyperlipidemia, thyroid cancer and liver cancer. As for patients under the age of 55, gastric cancer does seem to have an impact on the development of breast cancer; compared with their counterparts over the age of 55, endometrial cancer appears to exhibit an evocative effect. Conclusions In this nationwide matched nested case-control study, we identified obesity, hyperlipidemia, previous cancers of the thyroid, stomach and liver as risk factors associated with breast cancer. However, the retrospective nature and limited case numbers of certain cancers still difficult to provide robust evidence. Further prospective studies are necessitated to corroborate this finding in order to nip the disease in the bud. Trial registration The studies involving human participants were reviewed and approved by the China Medical University Hospital [CMUH104-REC2-115(AR-4)].
Flow chart of study participants. Hs-CRP, high sensitivity C-reactive protein; MetS, metabolic syndrome
Subgroup analysis of the association between concurrence of MetS and high hs-CRP levels and PLC risk. Note: Adjusted models were adjusted for age (every 10 years), sex, family income, educational background, marital status, HBV infection, cirrhosis, fatty liver, BMI, TC, ALT, SUA, smoking status, drinking status, physical activity, sedentary lifestyle, tea consumption, salt intake, high-fat diet, family history of cancer
Background and aims High-sensitivity C-reactive protein (hs-CRP) levels and metabolic syndrome (MetS) are known to be associated with an increased incidence of different cancers. We aimed to evaluate the effect of MetS combined with high hs-CRP levels on the risk of primary liver cancer (PLC). Methods Participants were recruited from the Kailuan cohort study and were classified into four groups according to the presence or absence of MetS and inflammation (hs-CRP ≥ 3 or < 3 mg/L). The associations of MetS and inflammation with the risk of PLC were assessed using Cox proportional hazards models. Results This study included 92,770 participants. The mean age was 51.4 years old. Over a median follow-up of 13.02 years, 395 participants were diagnosed as PLC. Compared to the control participants without inflammation (hs-CRP < 3 mg/L) and MetS ( n = 69,413), participants with high hs-CRP levels combined with MetS ( n = 2,269) had a higher risk of PLC [hazard ratios (HR) 2.91; 95% confidence interval (CI), 1.77–4.81], and participants with high hs-CRP levels and without MetS ( n = 14,576) had the same trend (HR, 1.36; 95%CI, 1.05–1.75). However, participants with low hs-CRP levels and MetS ( n = 6,512) had no significant association with an elevated risk of PLC (HR, 1.18; 95%CI, 0.76–1.82). After excluding participants who had cancer during the first year of follow-up, sensitivity analysis showed the same trend. In addition, co-occurrence of MetS and high hs-CRP levels had significant interactive effects on the risk of PLC between the sexes ( P < 0.001) and the patients with HBV infection ( P = 0.012). Conclusions Participants with co-occurrence of MetS and high hs-CRP levels have an elevated risk of PLC. Trial registration Kailuan study, ChiCTR–TNRC–11001489. Registered 24 August, 2011-Retrospectively registered,
Flow diagram outlining how many cases were excluded from the study following the exclusion criteria
Reductions in emergency admission rates from Pre-COVID to During COVID period, by age and gender
Background: The pandemic disrupted society and health services through lockdowns and resource reallocation to care for COVID-19 patients. Reductions in numbers of cancer patients having surgery, being diagnosed pathologically or via 2-week wait, and screening programs pauses have been described. The effect on emergency presentation, which represents an acute episode with poor outcomes, has not been investigated. This study explored the pandemic's impact on emergency hospital admissions for cancer patients in a UK region. Methods: Hospital discharge data for cancer patients in Northern Ireland, which included route to admission, were analysed for the pandemic era in 2020 compared to averages for March to December 2017-2019, focusing on volume and route of emergency admissions by demography and tumour site. Findings: Compared with the pre-pandemic era, the number of cancer emergency admissions fell by 12·3% in 2020. Emergency admissions for cancer were significantly reduced when COVID-19 levels were highest (- 18·5% in April and - 16.8% in October). Females (- 15·8%), urban residents (- 13·2%), and age groups 0 to 49 and 65-74 years old (- 17%) experienced the largest decreases as did those with haematological (- 14·7%), brain and CNS (- 27·9%), and lung cancers(- 14·3%). Significant reductions in referrals from outpatient departments (- 51%) and primary care (- 43%) (p < 0·001) were counterbalanced by admissions from other routes including confirmed or suspected COVID-19 infection (increase 83·6%). Interpretation: Reductions in emergency admissions, and pathologically diagnosed cancers, as reported by the Northern Ireland Cancer Registry (NICR), indicate undiagnosed patients in the community which has implications for future workloads and survival. Data suggest undiagnosed cases may be higher for haematological, brain and CNS, and lung cancers and among females. Efforts should be made to encourage people with symptoms to present for diagnosis or reassurance. Funding: The NICR is funded by the Public Health Agency of Northern Ireland. This work was supported by Macmillan Cancer Support and uses data collected by health services as part of their care and support functions.
Study Schedule. Blood draw for PBMCs will be performed at screening, week 3, week 9 (prior to surgery), and first evaluation (week 12) and at moment of relapse. Tumor biopsies will be taken at screening, prior to first nivolumab administration and at moment of relapse in all patients for translational research purposes. Biopsies will be preserved and stored as fresh frozen and formalin-fixed paraffin-embedded material at all indicated time points. *The first dose of T-VEC is a seroconversion dose. CT, computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; PET, Positron Emission Tomography; PFU, plaque-forming units; QoL, quality of life questionnaires; RECIST, Response evaluation criteria in solid tumors; T-VEC, Talimogene laherparepvec; ULN, upper limit of normal; WHO PS, World Health Organization performance status
Schedule of enrollment, interventions and assessments
Background Trials investigating neoadjuvant treatment with immune checkpoint inhibitors (ICI) in patients with melanoma have shown high clinical and pathologic response rates. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1 (HSV-1), is approved for patients with unresectable stage IIIB-IVM1a melanoma and has the potential to make tumors more susceptible for ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neoadjuvant setting. Methods This single center, single arm, phase II study aims to show an improved major pathologic complete response (pCR) rate, either pCR or near-pCR, up to 45% in 24 patients with resectable stage IIIB-IVM1a melanoma upon neoadjuvant combination treatment with intralesional T-VEC and systemic nivolumab (anti-PD-1 antibody). Patients will receive four courses of T-VEC up to 4 mL (first dose as seroconversion dose) and three doses of nivolumab (240 mg flatdose) every 2 weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate. Secondary endpoints are safety, the rate of delay of surgery and event-free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed. Discussion Intralesional T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma in combination with ICI. However, the potential clinical benefit of T-VEC plus ICI in the neoadjuvant setting remains unknown. This is the first trial investigating the efficacy and safety of neoadjuvant treatment of T-VEC and nivolumab followed by surgical resection in patients with stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity. Trial registration This trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT- number: 2019–001911-22 ) and the Central Committee on Research Involving Human Subjects (NL71866.000.19) on 4th June 2020. Secondary identifying number: NCT04330430 .
Cancer survival by presence of cardiovascular disease prior to diagnosis: All cancers (ex NMSC) diagnosed 2011-2014
Cancer survival by presence of cardiovascular disease prior to diagnosis by cancer type. (a) Colorectal cancer diagnosed 2011-2014. (b) Lung cancer diagnosed 2011-2014. (c) Female breast cancer diagnosed 2011-2014. (d) Prostate cancer diagnosed 2011-2014
Background While cancer outcomes have improved over time, in Northern Ireland they continue to lag behind those of many other developed economies. The role of comorbid conditions has been suggested as a potential contributory factor in this but issues of data comparability across jurisdictions has inhibited efforts to explore relationships. We use data from a single jurisdiction of the UK using data from - the Northern Ireland Cancer Registry (NICR), to examine the association between mortality (all-cause and cancer specific) and pre-existing cardiovascular diseases among patients with cancer. Materials and Methods All patients diagnosed with cancer (excluding non-melanoma skin cancer) between 2011 and 2014 were identified from Registry records. Those with a pre-existing diagnosis of cardiovascular diseases were identified by record linkage with patient hospital discharge data using ICD10 codes. Survival following diagnosis was examined using descriptive statistics and Cox proportional hazards regression analyses. Analyses examined all-cause mortality and cancer specific mortality for lung, colorectal, breast and prostate cancer. As well as cardiovascular diseases, regression models controlled for age, gender (where appropriate), deprivation (as quintiles), stage at diagnosis and other comorbidities. Results Almost 35,000 incident cancer cases were diagnosed during the study period of which approximately 23% had a prior heart condition. The pan-cancer hazard ratio for death in the presence of pre-existing cardiovascular diseases was 1.28 (95% CI: 1.18-1.40). All-cause and cancer specific mortality was higher for patients with cardiovascular diseases across lung, female breast, prostate and colorectal cancer groups after controlling for age, gender (where appropriate), deprivation (as quintiles), stage at diagnosis and other comorbidities. Conclusion Pre-existing morbidity may restrict the treatment of cancer for many patients. In this cohort, cancer patients with pre-existing cardiovascular diseases had poorer outcomes than those without cardiovascular diseases. A high prevalence of cardiovascular diseases may contribute to poorer cancer outcomes at a national level.
Hematoxylin & Eosin with PD1 immunohistochemical staining images of Mantle cell lymphoma (× 400): A& B: expression of PD1 in a PD1 negative case, C&D: a PD1 positive case with 40% imunoreactivity in tumor cells
Hematoxylin & Eosin with PDL1 immunohistochemical staining images of Mantle cell lymphoma (× 400): A& B: a PDL1 negative case (< 5%), C&D: a PDL1 positive case with 60% imunoreactivity in tumor cells
Background Mantle cell lymphoma (MCL) has remained incurable in most patients. The expression of PD-L1 as a prognostic and predictive marker has not been fully evaluated in MCL. The current study aimed to determine PD-1/PD-L1 expression in MCL specimens and its significance as an immune check point inhibitor. Methods This retrospective study was conducted on the formalin-fixed paraffin-embedded blocks of 79 confirmed MCL patients based on immunohistochemistry (IHC). The IHC method was used to stain patient samples for PD1 and PDL1. Positive PD-1/PD-L1 expression was defined as moderate to strong or memberanous or memberanous/cytoplasmic staining in at least 5% of tumor and/or 20% of associated immune cells. Tumor aggressiveness was determined based on Ki67 and variant. Results The mean age of the patients was 60.08 ± 10.78 years old. Majority of the patients were male. The prevalence of aggressive tumor was 25%. Positive PD1 and PDL1 expression were identified in 12 (15.0%) and 3 (3.8%) of tumor cells, respectively. PD1 and PDL1 were positive in zero (0%) and 7 (8.9%) of background cells, respectively. There was no significant difference in terms of study parameters between positive and negative groups for both PD1 and PDL1 proteins. PD1 tumor cell percentage was negatively correlated with age ( r = -0.254, p = 0.046). Conclusion Our results suggest that neither PD-1 nor its ligands represent relevant targets for MCL treatment. Age may impact the efficiency of immune checkpoint inhibitors and could be related to the increased incidence of MCL with age.
Flow chart of patient selection
Background Whether hypokalemia can affect the short-term outcomes of CRC patients after radical surgery remains unclear. The purpose of this study was to investigate the impact of preoperative hypokalemia on the short-term outcomes for colorectal cancer (CRC) patients who underwent radical CRC surgery using propensity score matching (PSM). Methods We retrospectively enrolled consecutive CRC patients from Jan 2011 to Dec 2021 in a single-center hospital. Hypokalemia was defined as a serum potassium concentration < 3.5 mmol/L. The short-term outcomes were compared between the hypokalemia group and the normal blood potassium group. In addition, univariate and multivariate logistic regression analyses were conducted to identify independent risk factors for overall complications. Results A total of 6183 CRC patients who underwent radical surgery were included in this study, of whom 390 (6.3%) patients were diagnosed with hypokalemia before surgery. After 1:1 ratio PSM, there were 390 patients in the hypokalemia group and in the normal potassium group. No significant difference was found between the two groups after PSM in terms of baseline information ( p > 0.05). Regarding short-term outcomes, the hypokalemia group had a longer hospital stay ( p = 0.028), a higher proportion of overall complications ( p = 0.048) and a higher incidence of postoperative pneumonia ( p = 0.008) after PSM. Moreover, hypokalemia ( p = 0.036, OR = 1.291, 95% CI = 1.017–1.639) was an independent risk factor for overall complications. Conclusion Preoperative hypokalemia could increase complications after CRC surgery and prolong the hospital stay. Moreover, preoperative hypokalemia was an independent risk factor for overall complications.
Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research.
Background Although immune-checkpoint inhibitors (ICI) are overall promissory for cancer treatment, they entail, in some cases, an undesired side-effect called hyperprogressive-cancer disease (HPD) associated with acceleration of tumor growth and shortened survival. Methods To understand the mechanisms of HPD we assayed the ICI therapy on two murine tumors widely different regarding immunogenicity and, subsequently, on models of local recurrences and metastases of these tumors. To potentiate the immune response (IR), we combined ICI with meta-tyrosine—that counteracts immune-suppressive signals—and a selective inhibitor of p38 pathway that proved to counteract the phenomenon of tumor-immunostimulation. Results ICI were therapeutically effective against both tumor models (proportionally to their immunogenicity) but only when they faced incipient tumors. In contrast, ICI produced acceleration of large and residual tumors. The combined treatment strongly inhibited the growth of large tumors and it managed to cure 80% of mice with local recurrences and 60% of mice bearing residual metastases. Conclusions Tumor enhancement was paradoxically correlated to a weak increase of the antitumor IR suggesting that a weak IR – different from a strong tumor-inhibitory one—may produce stimulation of tumor growth, mimicking the HPD observed in some clinical settings.
The estimated frequencies (the proportion of successes) versus the true frequencies (the success probability) for both binomial (blue) and 0.05-truncated binomial (red) random variables
A. Three beta distributions, with α and β parameters as shown in the legend, representing alternative mutant allele frequency spectra for subclonal mutations. B. Relative error in the estimated TMB contribution from subclonal mutations derived from the three distributions in A
Illustration of how uncertainty in mutation frequency estimates can lead to over-estimation of the number of mutations above the frequency threshold, even if the estimated frequencies are unbiased. The red and blue shaded areas correspond to mutations for which sampling error could cause them to cross the frequency threshold (i.e. the estimated frequencies of mutations with true frequencies in the red shaded area may be below the threshold due to sampling error, while the estimated frequencies of mutations in the blue shared area may be above the threshold). Because the blue shaded area is much larger than the red area, the number of mutations that pass the threshold from left to right is likely to be much larger than the number of mutations that pass the threshold in the other direction, leading to over-estimation of the number of mutations above the threshold
Each TCGA data was downsampled to 50 percent. The plot shows the TMB in each downsampled data with respect to its corresponding original full data
Background Tumour mutation burden (TMB), defined as the number of somatic mutations per megabase within the sequenced region in the tumour sample, has been used as a biomarker for predicting response to immune therapy. Several studies have been conducted to assess the utility of TMB for various cancer types; however, methods to measure TMB have not been adequately evaluated. In this study, we identified two sources of bias in current methods to calculate TMB. Methods We used simulated data to quantify the two sources of bias and their effect on TMB calculation, we down-sampled sequencing reads from exome sequencing datasets from TCGA to evaluate the consistency in TMB estimation across different sequencing depths. We analyzed data from ten cancer cohorts to investigate the relationship between inferred TMB and sequencing depth. Results We found that TMB, estimated by counting the number of somatic mutations above a threshold frequency (typically 0.05), is not robust to sequencing depth. Furthermore, we show that, because only mutations with an observed frequency greater than the threshold are considered, the observed mutant allele frequency provides a biased estimate of the true frequency. This can result in substantial over-estimation of the TMB, when the cancer sample includes a large number of somatic mutations at low frequencies, and exacerbates the lack of robustness of TMB to variation in sequencing depth and tumour purity. Conclusion Our results demonstrate that care needs to be taken in the estimation of TMB to ensure that results are unbiased and consistent across studies and we suggest that accurate and robust estimation of TMB could be achieved using statistical models that estimate the full mutant allele frequency spectrum.
Flow chart of patient selection
Cumulative incidence curves of rebleeding in patients with head and neck cancer
Cumulative incidence curves of rebleeding in patients with head and neck cancer stratified by BMI
Kaplan–Meier survival curves of patients with head and neck cancer bleeding
Background Acute, catastrophic bleeding in patients with head and neck cancer (HNC) is challenging and also a burden for their families and frontline physicians. This study analyzed the risk factors for rebleeding and long-term outcomes in these patients with HNC. Methods Patients who presented to the emergency department (ED) with HNC bleeding were enrolled in this study (N = 231). Variables of patients with or without rebleeding were compared, and associated factors were investigated using Cox’s proportional hazard model. Results Of the 231 patients enrolled, 112 (48.5%) experienced a recurrent bleeding event. The cumulative rebleeding incidence rate was 23% at 30 days, 49% at 180 days, and 56% at 1 year. Multivariate Cox regression analyses demonstrated that overweight-to-obesity (HR = 0.52, 95% CI 0.28–0.98, p = 0.043), laryngeal cancer (hazard ratio [HR] = 2.13, 95% confidence interval [CI] 1.07–4.23, p = 0.031), chemoradiation (HR = 1.49, 95% CI 1.001–2.94, p = 0.049), and second primary cancer (HR = 1.75, 95% CI 1.13–2.70, p = 0.012) are significant independent predictors of rebleeding, and the prognostic factors for overall survival included underweight (HR = 1.89, 95% CI 1.22–2.93, p = 0.004), heart rate > 110 beats/min (HR = 1.58, 95% CI 1.04–2.39, p = 0.032), chemoradiation (HR = 2.31, 95% CI 1.18–4.52, p = 0.015), and local recurrence (HR = 1.74, 95% CI 1.14–2.67, p = 0.011). Conclusions Overweight-to-obesity is a protective factor, while laryngeal cancer, chemoradiation and a second primary cancer are risk factors for rebleeding in patients with HNC. Our results may assist physicians in risk stratification of patients with HNC bleeding.
The distribution of various types of variants in the exons of BRCA1 (A) and BRCA2 (B) exons. Grey boxes represent untranslated regions and green boxes represent coding exons. The positions on the gene map indicate the locations of the mutations and the changes in base (red circle: pathogenic variant; pink circle: likely pathogenic variant; blue circle: variant of uncertain significance)
Recurrent variants in BRCA1 and BRCA2 genes in Hakka population. Interpretation of BRCA1 (A) and BRCA2 (B) variant carrier number of breast cancer and ovarian cancer patients. The number of different variants for the number of variant carriers of breast cancer patients (inner ring) and the number of variant carriers of ovarian cancer patients (outer ring) (C). The top 25 variant types of BRCA1 (D) and BRCA2 (E) in descending order in the Hakka population
Distribution of pathogenic and nonpathogenic variants in the BRCA1 and BRCA2 genes. The number of pathogenic and nonpathogenic variants (likely pathogenic variants + VUS) in each exon and intron of the BRCA1 and BRCA2 genes, respectively, among all patients (A), breast cancer patients (B), and ovarian cancer patients (C). The number of different variants in BRCA1 (inner ring) and BRCA2 (outer ring) (D)
Objective To investigate the prevalence and spectrum of BRCA1 and BRCA2 mutations in Chinese Hakka patients with breast and ovarian cancer. Methods A total of 1,664 breast or ovarian cancer patients were enrolled for genetic testing at our hospital. Germline mutations of the BRCA gene were analysed by next-generation sequencing, including the coding regions and exon intron boundary regions. Results The 1,664 patients included 1,415 (85.04%) breast cancer patients and 245 (14.72%) ovarian cancer patients, while four (0.24%) patients had both the breast and ovarian cancers. A total of 151 variants, including 71 BRCA1 variants and 80 BRCA2 variants, were detected in the 234 (14.06%) patients. The 151 variants included 58 pathogenic variants, 8 likely pathogenic variants, and 85 variants of unknown significance (VUS). A total of 56.25% (18/32) and 65.38% (17/26) of pathogenic variants (likely pathogenic variants are not included) were distributed in exon 14 of BRCA1 and exon 11 of BRCA2, respectively. The most common pathogenic variants among this Hakka population are c.2635G > T (p.Glu879*) (n = 7) in the BRCA1 gene and c.5164_5165del (p.Ser1722Tyrfs*4) (n = 7) in the BRCA2 gene among the Hakka population. A hotspot mutation in the Chinese population, the BRCA1 c.5470_5477del variant was not found in this Hakka population. The prevalence and spectrum of variants in the BRCA genes in the Hakka patients are different from that in other ethnic groups. Conclusions The most common pathogenic variant in this population is c.2635G > T in the BRCA1 gene, and c.5164_5165delAG in the BRCA2 gene in this population. The prevalence and spectrum of variants in the BRCA1 and BRCA2 genes in the Hakka patients from southern China are different from those in other ethnic groups.
Background Glioblastoma (GB) is the most common and most aggressive malignant brain tumor. In understanding its resistance to conventional treatments, iron metabolism and related pathways may represent a novel avenue. As for many cancer cells, GB cell growth is dependent on iron, which is tightly involved in red-ox reactions related to radiotherapy effectiveness. From new observations indicating an impact of RX radiations on the expression of ceruloplasmin (CP), an important regulator of iron metabolism, the aim of the present work was to study the functional effects of constitutive expression of CP within GB lines in response to beam radiation depending on the oxygen status (21% O2 versus 3% O2). Methods and results After analysis of radiation responses (Hoechst staining, LDH release, Caspase 3 activation) in U251-MG and U87-MG human GB cell lines, described as radiosensitive and radioresistant respectively, the expression of 9 iron partners (TFR1, DMT1, FTH1, FTL, MFRN1, MFRN2, FXN, FPN1, CP) were tested by RTqPCR and western blots at 3 and 8 days following 4 Gy irradiation. Among those, only CP was significantly downregulated, both at transcript and protein levels in the two lines, with however, a weaker effect in the U87-MG, observable at 3% O2. To investigate specific role of CP in GB radioresistance, U251-MG and U87-MG cells were modified genetically to obtain CP depleted and overexpressing cells, respectively. Manipulation of CP expression in GB lines demonstrated impact both on cell survival and on activation of DNA repair/damage machinery (γH2AX); specifically high levels of CP led to increased production of reactive oxygen species, as shown by elevated levels of superoxide anion, SOD1 synthesis and cellular Fe2 + . Conclusions Taken together, these in vitro results indicate for the first time that CP plays a positive role in the efficiency of radiotherapy on GB cells.
Representative immunohistochemical images of CD3+, CD8+, and Foxp3+ lymphocytes in the tumor center (TC) and invasive margin (IM)
Kaplan–Meier curves of RFS and OS according to the levels of inflammatory indices. CAR, C-reactive protein/albumin ratio; GPS, Glasgow prognostic score; NLR, neutrophil/lymphocyte ratio; OS, overall survival; PLR, platelet/lymphocyte ratio; RFS, recurrence-free survival
Relationship between the level of inflammatory indices and presence of tumor-infiltrating lymphocytes
Background Inflammatory indices and tumor-infiltrating lymphocytes (TILs) have prognostic value in many cancer types. This study aimed to assess the prognostic value of inflammatory indices and evaluate their correlation with survival and presence of TILs in patients with colorectal liver metastasis (CRLM). Methods Medical records of 117 patients who underwent hepatectomy for CRLM were retrospectively reviewed. We calculated inflammatory indices comprising the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, C-reactive protein/albumin ratio (CAR), and Glasgow prognostic score (GPS). Furthermore, we evaluated the relationship between these ratios and the GPS and survival rates and immunohistochemical results of tumor-infiltrating CD3+, CD8+, and Foxp3+ lymphocytes. Results The patients with low CAR values and low GPS had significantly better overall survival as per the log-rank test (p = 0.025 and p = 0.012, respectively). According to the multivariate analysis using the Cox proportional hazard model, the CAR (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.33–0.99; p = 0.048) and GPS (HR, 0.40; 95% CI, 0.19–0.83; p = 0.013) were independent prognostic factors. Additionally, Foxp3+ lymphocytes were more common in samples from the patients with a low CAR (p = 0.041). Moreover, the number of CD3+ TILs was significantly higher in the patients with a low GPS (p = 0.015). Conclusions The CAR and GPS are simple, inexpensive, and objective markers associated with predicting survival in patients with CRLM. Moreover, they can predict the presence of Foxp3+ and CD3+ lymphocytes in the invasive margin of a tumor. Trial registration Retrospectively registered.
Inclusion/exclusion procedure of study sample
Background Despite benefits of endocrine therapy (ET) for patients with hormone-receptor (HR)-positive breast cancer, many patients do not initiate or discontinue ET against recommendations. Methods We identified variables associated with ET initiation and continuation, analyzing pooled data from two longitudinal studies at a National Cancer Institute comprehensive cancer center in St. Louis, Missouri. The sample included 533 women with newly diagnosed, non-metastatic, HR-positive breast cancer who completed interviews at enrollment and 6, 12, and 24 months after definitive surgical treatment. Logistic regression models estimated the adjusted odds ratio and 95% confidence interval (aOR [95% CI]) for each of self-reported ET initiation by the 12-month interview and continuation for ≥12 months by the 24-month interview in association with self-reported diabetes, elevated depressed mood, menopausal-symptom severity and obesity, adjusting for race, age, insurance status, chemotherapy, and radiation therapy. Results Overall, 81.4% (434/533) of patients initiated ET, and 86.5% (371/429) continued ET ≥12 months. Patients with diabetes had lower odds of initiating ET (0.50 [0.27-0.91]). Patients reporting greater menopausal-symptom severity had lower odds of continuing ET (0.72 [0.53-0.99]). Conclusion Efforts to increase ET initiation among patients with diabetes and better manage severe menopausal symptoms among ET users might promote ET continuation. Clinical trial information : #NCT00929084.
Background Most recent laboratory studies have suggested a promising role of vitamin D and its analogs as novel chemotherapeutic agents for cancer treatment. However, epidemiological evidence, especially regarding the effects of vitamin D on gastric cancer is still inconsistent. Objectives Our research aimed to evaluate the associations between vitamin D intake and the risk of developing gastric cancer through a case-control study in North Vietnam. Methods We accessed databases of the previous completed case-control studies to derive 1182 incident gastric cancer cases and 2995 hospital controls selected from hospitals in Hanoi from 2003 to 2019. Vitamin D intake was computed by multiplying the food frequency intake with nutrient content based on the Viet Nam Food Composition Tables. Data were collected through face-to-face interviews by trained interviewers using the validated semi-quantitative food frequency and demographic lifestyle questionnaires. The odds ratio and 95% confidence interval (OR and 95%CI) were estimated using unconditional logistic regression analysis. Results We observed a continual decline in gastric cancer risk according to the level-up of vitamin D intake in both genders, men, and women [Fifth vs. bottom quintile, OR, 95%CI: 0.68 (0.53, 0.86), OR, 95%CI: 0.72 (0.53, 0.97), OR, 95%CI: 0.58 (0.38, 0.89), respectively. Per increment quintile, the statistically significant decreased risk was seen by 7% in men and 13% in women. The significant inverse association between vitamin D intake remained in the subgroups of ever and never tobacco smoking; negative and positive H. pylori infection. Conclusion The findings suggested that sufficient vitamin D intake was associated with a lower risk of Gastric Cancer in the Vietnamese population.
Kaplan–Meier plots of overall survival (OS) for the comparison of patient groups (A) ARBs vs. ACEIs and (B) ACEIs vs. non-RASIs
The Kaplan–Meier plot of disease-free survival (DFS) for the comparison of patient groups (ARBs vs. ACEIs)
The forest plots of hazard ratio results from a reduced multivariate Cox regression model for (A) overall survival (OS) and (B) disease-free survival (DFS) prognostic factors; * indicates p < 0.05, ** p < 0.01, *** p < 0.001
Background Renin-angiotensin system inhibitors (RASIs) are widely used in the treatment of hypertension. However, their impact on the outcome of the combined treatment of rectal cancer is poorly understood. The aim of this study was to assess the effect of RASIs on the survival of rectal cancer patients with associated hypertension after neoadjuvant treatment and radical resection. Methods Between 2008 and 2016, 242 radical (R0) rectal resections for cancer were performed after neoadjuvant treatment in patients with associated hypertension. At the time of treatment, 158 patients were on RASIs, including 35 angiotensin-receptor antagonists (ARB) users and 123 angiotensin-converting enzyme inhibitors (ACEI) users. Eighty-four patients were on drugs other than RASIs (non-RASI users). The survival analysis was performed using the Kaplan–Meier estimator with the log-rank test and the Cox proportional hazards model. Results The log-rank test showed a significantly worse overall survival (OS) in the group of ACEI users compared to ARB users (p = 0.009) and non-RASI users (p = 0.013). Disease-free survival (DFS) was better in the group of ARB users compared to ACEI users. However, the difference was not statistically significant (p = 0.064). The Multivariate Cox analysis showed a significant beneficial effect of ARBs on OS (HR: 0.326, 95% CI: 0.147–0.724, p = 0.006) and ARBs on DFS (HR: 0.339, 95% CI: 0.135–0.850, p = 0.021) compared to ACEIs. Other factors affecting OS included age (HR: 1.044, 95% CI: 1.016–1.073, p = 0.002), regional lymph node metastasis (ypN +) (HR: 2.157, 95% CI: 1.395–3.334, p = 0.001) and perineural invasion (PNI) (HR: 3.864, 95% CI: 1.799–8.301, p = 0.001). Additional factors affecting DFS included ypN + (HR: 2.310, 95% CI: 1.374–3.883, p = 0.002) and PNI (HR: 4.351, 95% CI: 1.584–11.954, p = 0.004). Conclusions The use of ARBs instead of ACEIs may improve the outcome of the combined therapy for rectal cancer patients with associated hypertension.
Background A deep understanding of potential molecular biomarkers and therapeutic targets related to the progression of colorectal cancer (CRC) from early stages to metastasis remain mostly undone. Moreover, the regulation and crosstalk among different cancer-driving molecules including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs) in the transition from stage I to stage IV remain to be clarified, which is the aim of this study. Methods We carried out two separate differential expression analyses for two different sets of samples (stage-specific samples and tumor/normal samples). Then, by the means of robust dataset analysis we identified distinct lists of differently expressed genes (DEGs) for Robust Rank Aggregation (RRA) and weighted gene co-expression network analysis (WGCNA). Then, comprehensive computational systems biology analyses including mRNA-miRNA-lncRNA regulatory network, survival analysis and machine learning algorithms were also employed to achieve the aim of this study. Finally, we used clinical samples to carry out validation of a potential and novel target in CRC. Results We have identified the most significant stage-specific DEGs by combining distinct results from RRA and WGCNA. After finding stage-specific DEGs, a total number of 37 DEGs were identified to be conserved across all stages of CRC (conserved DEGs). We also found DE-miRNAs and DE-lncRNAs highly associated to these conserved DEGs. Our systems biology approach led to the identification of several potential therapeutic targets, predictive and prognostic biomarkers, of which lncRNA LINC00974 shown as an important and novel biomarker. Conclusions Findings of the present study provide new insight into CRC pathogenesis across all stages, and suggests future assessment of the functional role of lncRNA LINC00974 in the development of CRC.
Background The amino acid transporter SLC6A14, which transports 18 of the 20 proteinogenic amino acids, is too low to be detected in healthy normal tissues but is significantly increased in some solid cancers. However, little is known about the roles of SLC6A14 in colorectal cancer (CRC). Methods The mRNA and protein levels of SLC6A14 were detected using TCGA database, real-time polymerase chain reaction, western blot, and tissue microarrays, respectively. Amino acids concentration was determined by LC-MS/MS. Cell proliferation and apoptosis were determined using MTT assay and flow cytometry. Transwell invasion assay and wound healing assay were employed to analyze cell migration and invasion. The protein levels of Akt-mTOR signaling pathway and MMPs proteins were detected by western blot. Results Both of the mRNA and protein levels of SLC6A14 were upregulated in CRC tissues, and the protein levels of SLC6A14 were closely related to the tumor cells differentiation: the higher the expression of SLC6A14 was, the poorer the differentiation of the tumor cells was. Further knockdown SLC6A14 with siRNA or treatment with α-MT in CRC cell lines reduced cell proliferation and migration in vitro and inhibited xenograft tumor growth in vivo. Mechanistically, SLC6A14 was demonstrated to regulate the expression and phosphorylation of Akt-mTOR, which mediates the promoting tumor growth function of SLC6A14. Blockade of SLC6A14 with α-MT inhibited the activation of mTOR signaling. Conclusion SLC6A14 was upregulated in CRC and could promote tumor progression by activating the Akt-mTOR signaling pathway, which may serve as an effective molecular target for the treatment of CRC.
KK-LC-1 expression in various human cancers and related to prognosis in LUAD. A Human KK-LC-1 expression in various tumors according to the TIMER database. B The expression levels of KK-LC-1 in LUAD and para-cancerous lung tissues. C KK-LC-1 expression in LUAD and matched normal tissues by TCGA database. D The overall survival rate of KK-LC-1 expression in LUAD
KK-LC-1 expression in serum and related to diagnosis in LUAD. A The expression level of KK-LC-1in LUAD serum and healthy person’s serum. ROC curve of serum B KK-LC-1 and C CEA. D KK-LC-1 expression in LUAD patient’s preoperative and postoperative serum. E ROC curve of serum KK-LC-1 to validate pre-operative cases from post-operative in LUAD
Association of KK-LC-1 expression with immune infiltration in LUAD according to the TIMER database. A The correlation between KKLC and immune cells by TIMER. B The correlation between KKLC and immune cells by TISIDB. C 22 types of tumor-infiltrating immune cells were analyzed in high and low KK-LC-1 expression groups
Association of KK-LC-1 expression with immune marker sets in LUAD based on TIMER database. The correlation between KK-LC-1 expression and the gene markers of A Monocyte (CD68 and CSF1R); B TAM (CD68, IL10 and CCL2); C M1 Macrophage (NOS2, IRF5 and PTGS2); D M2 Macrophage (CD163,VSIG4 and MS4A4A)
The prognostic value of high and low expression of KK-LC-1 in LUAD according to immune cell subgroups using Kaplan-Meier potter. The increased and decreased expression of KK-LC-1 in various immune cell subgroups have diverse prognosis in LUAD (A-H)
Background Cancer-testis antigens (CTAs) have emerged as potential clinical biomarkers targeting immunotherapy. KK-LC-1 is a member of CTAs, which has been demonstrated in a variety of tumors tissues and been found to elicit immune responses in cancer patients. However, the expression level and immune infiltration role of KK-LC-1 in lung adenocarcinoma (LUAD) remains to be elucidated. Methods In this study, the mRNA expression and overall survival rate of KK-LC-1 were evaluated by the TIMER and TCGA database in LUAD tissues and KK-LC-1 expression was further validated by clinical serum samples using quantitative RT-PCR. The relationship of KK-LC-1 with clinicopathologic parameters was analyzed. ROC curve result showed that miR-1825 was able to distinguish preoperative breast cancer patients from healthy people and postoperative patients. Then, the ROC curves were used to examine the ability of KK-LC-1 to distinguish preoperative LUAD patients from healthy and postoperative patients. The correlation between KK-LC-1 and infiltrating immune cells and immune marker sets was investigated via TIMER, TISIDB database, and CIBERSORT algorithm. The Kaplan-Meier plotter was used to further evaluate the prognostic value based on the expression levels of KK-LC-1 in related immune cells. Results The results showed that KK-LC-1 was significantly over-expressed in LUAD, and high levels of expression of KK-LC-1 were also closely correlated with poor overall survival. We also found that KK-LC-1 associated with TMN stage, NSE and CEA. The ROC curve result showed that KK-LC-1 was able to distinguish preoperative LUAD cancer patients from healthy people and postoperative patients. Moreover, KK-LC-1 had a larger AUC with higher diagnostic sensitivity and specificity than CEA. Based on the TIMER, TISIDB database, and CIBERSORT algorithm, the expression of KK-LC-1 was negatively correlated with CD4+ T cell, Macrophage, and Dendritic Cell in LUAD. Moreover, Based on the TIMER database, KK-LC-1 expression had a remarkable correlation with the type markers of Monocyte, TAM, M1 Macrophage, and M2 Macrophage. Furthermore, KK-LC-1 expression influenced the prognosis of LUAD patients by directly affecting immune cell infiltration by the Kaplan-Meier plotter analysis. Conclusions In conclusion, KK-LC-1 may serve as a promising diagnostic and prognostic biomarker in LUAD and correlate with immune infiltration and prognosis.
Numbers and age-standardized rates of NMSC-related incidence (a and b), deaths (c and d), and DALYs (e and f) across countries. Abbreviations: DALYs: disability-adjusted life years; NMSC: non-melanoma skin cancer
Trends in the NMSC-related ASIR (a and b), ASMR (c and d), and the age-standardized DALYs (e and f) by sex globally: observed (dashed lines) and predicted rates of the BAPC model (solid lines). The blue region shows the upper and lower limits of the 95% UIs. Abbreviations: DALYs: disability-adjusted life years; NMSC: non-melanoma skin cancer; BAPC: Bayesian age-period-cohort; UIs: uncertainty intervals
Trends in NMSC-related numbers of incidence cases (a and b), deaths cases (c and d), and DALYs cases (e and f) by sex globally: observed (before 2019) and predicted (after 2019) numbers. Shading indicates if the rate remained stable (baseline reference), decreased by 1% per year (optimistic reference, lower limit), and increased by 1% per year (pessimistic reference, upper limit) based on the observed rate in 2019. The curve formed by the triangle is the prediction result of the BAPC model. Abbreviations: DALYs: disability-adjusted life years; NMSC: non-melanoma skin cancer; BAPC: Bayesian age-period-cohort
Trends in NMSC-related number of incidence cases (a and b), deaths cases (c and d), and DALYs cases (e and f) by sex globally: observed (before 2019) and predicted (after 2019) numbers. Shading indicates if the rate remained stable (baseline reference), decreased by 1% per year (optimistic reference, lower limit), and increased by 1% per year (pessimistic reference, upper limit) based on the observed rate in 2019. Three methods are used in the prediction. The red line is calculated by the predicted rate of each 5 years group and the average population size of the 5 year group. The blue line method is to calculate the rate of each group in terms of the predicted rate of each 5 years group and the average population situation of the 5 year group. The yellow line is calculated by the predicted rate of each 5 years group and the annual population situation. Abbreviations: DALYs: disability-adjusted life years; NMSC: non-melanoma skin cancer
Trends in NMSC-related incidence (a and b), deaths (c and d), and DALYs rates (e and f) by sex globally: observed (solid lines) and predicted rates of the Norpred APC model (dashed lines). Abbreviations: DALYs: disability-adjusted life years; NMSC: non-melanoma skin cancer; APC: age-period-cohort
Background The disease burden of non-melanoma skin cancer (NMSC) has become a significant public health threat. We aimed to conduct a comprehensive analysis to mitigate the health hazards of NMSC. Methods This study had three objectives. First, we reported the NMSC-related disease burden globally and for different subgroups (sex, socio-demographic index (SDI), etiology, and countries) in 2019. Second, we examined the temporal trend of the disease burden from 1990 to 2019. Finally, we used the Bayesian age-period-cohort (BAPC) model integrated nested Laplacian approximation to predict the disease burden in the coming 25 years. The Norpred age-period-cohort (APC) model and the Autoregressive Integrated Moving Average (ARIMA) model were used for sensitivity analysis. Results The disease burden was significantly higher in males than in females in 2019. The results showed significant differences in disease burden in different SDI regions. The better the socio-economic development, the heavier the disease burden of NMSC. The number of new cases and the ASIR of basal cell carcinoma (BCC) were higher than that of squamous cell carcinoma (SCC) in 2019 globally. However, the number of DALYs and the age-standardized DALYs rate were the opposite. There were statistically significant differences among different countries. The age-standardized incidence rate (ASIR) of NMSC increased from 54.08/100,000 (95% uncertainty interval (UI): 46.97, 62.08) in 1990 to 79.10/100,000 (95% UI: 72.29, 86.63) in 2019, with an estimated annual percentage change (EAPC) of 1.78. Other indicators (the number of new cases, the number of deaths, the number of disability-adjusted life years (DALYs), the age-standardized mortality rate (ASMR), and the age-standardized DALYs rate) showed the same trend. Our predictions suggested that the number of new cases, deaths, and DALYs attributable to NMSC would increase by at least 1.5 times from 2020 to 2044. Conclusions The disease burden attributable to NMSC will continue to increase or remain stable at high levels. Therefore, relevant policies should be developed to manage NMSC, and measures should be taken to target risk factors and high-risk groups.
Top-cited authors
Arndt Hartmann
  • Friedrich-Alexander-University of Erlangen-Nürnberg
Joe W Gray
  • Oregon Health and Science University
Ming Sun
  • University of Texas MD Anderson Cancer Center
Dong-Young Noh
  • Seoul National University
Univ.-Prof. Dr. Stephanie E. Combs
  • Technische Universität München